[SURGICAL TREATMENT OF PARKINSON'S DISEASE WITH LEVODOPA-INDUCED MOVEMENT DISTURBANCES].

Aim - to evaluate the efficacy of stereotactic pallidotomy and bilateral deep brain stimulation (DBS) of subthalamic nuclei (STN) in patients with Parkinson disease with motor fluctuations and levodopa-induced dyskinesias. 36 patients (age range 31-73 years (mean age 56.2±3.2 years) were enrolled in study. Mean duration of PD was 9.8±1.1years. All patients used levodopa-drugs, mean levodopa dose was 1075±304.1 mg/day. Mean duration of motor fluctuations and levodopa-induced dyskinesias before surgery was 2,18±0,8 years. Patients = were divided into 2 groups - 22 patients underwent stereotactic unilateral pallidotomy and 14 patients underwent bilateral DBS (STN target). Neurological and psychological status assessed before and after treatment by: UPDRS II, Hoehn and Yahr scale, Schwab and England scale, MMSE, Beck's Depression Inventory, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale and PDQ-39. Surgery performed on CRW stereotactic system. Postoperative follow-upranged from 1 to 8.5 years (mean 4.1±1.1 years). Regression of tremor, rigidity, bradykinesia and levodopa-induced dyskinesia observed in most patients after stereotactic interventions. The best results were achieved in patients who underwent DBS. In this group UPDRS II score improved by 74% in ON period and by 63% in OFF period. After pallidotomy UPDRS II score improved by 55% in ON period and by 47% in OFF period. Levodopa-induced dyskinesia stopped in 21 from 22 (95.5%) patients who had it before surgery after unilateral pallidotomy and in 11 from 12 (91.7%) patients after DBS. Surgical complications occurred in 3 (13.6%) case after pallidotomy, which induced transient neurological deficit. Our results demonstrate that both stereotactic interventions - pallidotomy and DBS are effective and safe methods of treatment of PD with levodopa-induced dyskinesias and motor fluctuations. Both surgeries improve overall motor function, increased patient's mobility and improve quality of life.

[Unilateral posteroventral pallidotomy in the treatment of drug-induced dyskinesia in Parkinson's disease]. / Odnostoronniaia posteroventral'naia pallidotomiia v lechenii lekarstvennykh diskinezii pri bolezni Parkinsona.

OBJECTIVE: to determine the efficacy of unilateral posteroventral pallidotomy (PVP) in the treatment of drug-induced dyskinesia (DID) in Parkinson's disease (PD). MATERIAL AND METHODS: We analyzed surgical treatment of 14 patients with PD complicated by DID who underwent unilateral PVP at the Research Center of Neurology in the period between 2012 and 2015. The clinical type of DID was mainly represented by peak-dose choreoathetoid dyskinesia, more pronounced in the distal limbs, and predominantly unilateral. The severity of drug-induced dyskinesia was assessed on the UPDRS scale (part IV-A) before surgery and at 1 week and 6 months after surgery. RESULTS: One week after pallidotomy, all of the 14 patients had a regression of contralateral dyskinesia by 68.3±9.7%; 50% of patients had a regression of ipsilateral dyskinesias by 43%, on average. In 50% of cases, the dose of levodopa was reduced by 15%, on average. On examination at 6 months after surgery, regression of contralateral dyskinesia was 55.7±8.8%, and the severity of ipsilateral DID returned to the preoperative level. The use of pallidotomy significantly improved the indicators of daily activity and quality of life of patients. There were no significant postoperative complications. Three patients had mild speech disorders in the form of dysarthria, which regressed 2-3 weeks after surgery.

Serotonergic and dopaminergic mechanisms in graft-induced dyskinesia in a rat model of Parkinson's disease.

Dyskinesia seen in the off-state, referred as graft-induced dyskinesia (GID), has emerged as a serious complication induced by dopamine (DA) cell transplantation in parkinsonian patients. Although the mechanism underlying the appearance of GID is unknown, in a recent clinical study the partial 5-HT(1A) agonist buspirone was found to markedly reduce GID in three grafted patients, who showed significant serotonin (5-HT) hyperinnervation in the grafted striatum in positron emission tomography scanning (Politis et al., 2010, 2011). Prompted by these findings, this study was performed to investigate the involvement of serotonin neurons in the appearance of GID in the rat 6-hydroxydopamine model. L-DOPA-primed rats received transplants of DA neurons only, DA plus 5-HT neurons or 5-HT neurons only into the lesioned striatum. In DA cell-grafted rats, with or without 5-HT neurons, but not in 5-HT grafts, GID was observed consistently after administration of amphetamine (1.5mg/kg, i.p.) indicating that grafted DA neurons are required to induce GID. Strikingly, a low dose of buspirone produced a complete suppression of GID. In addition, activation of 5-HT(1A) and 5-HT(1B) receptors by 8-OH-DPAT and CP 94253, known to inhibit the activity of 5-HT neurons, significantly reduced GID, whereas induction of neurotransmitter release by fenfluramine administration significantly increased GID, indicating an involvement of the 5-HT system in the modulation of GID. To investigate the involvement of the host 5-HT system in GID, the endogenous 5-HT terminals were removed by intracerebral injection of 5,7-dihydroxytryptamine, but this treatment did not affect GID expression. However, 5-HT terminal destruction suppressed the anti-GID effect of 5-HT(1A) and 5-HT(1B) agonists, demonstrating that the 5-HT(1) agonist combination exerted its anti-GID effect through the activation of pre-synaptic host-derived receptors. By contrast, removal of the host 5-HT innervation or pre-treatment with a 5-HT(1A) antagonist did not abolish the anti-GID effect of buspirone, showing that its effect is independent from activation of either pre- or post-synaptic 5-HT(1A) receptors. Since buspirone is known to also act as a DA D(2) receptor antagonist, the selective D(2) receptor antagonist eticlopride was administered to test whether blockade of D(2) receptors could account for the anti-dyskinetic effect of buspirone. In fact, eticlopride produced complete suppression of GID in grafted animals already at very low dose. Together, these results point to a critical role of both 5-HT(1) and D(2) receptors in the modulation of GID, and suggest that 5-HT neurons exert a modulatory role in the development of this side effect of neuronal transplantation.

Cell transplantation in Parkinson's disease: problems and perspectives.

PURPOSE OF REVIEW: We review recent experiments conducted using embryonic tissue and stem cell transplants in experimental models of Parkinson's disease. We also highlight the challenges which remain to be met in order for cell therapy to become clinically effective and safe. RECENT FINDINGS: The outcome of previous clinical transplantation trials was variable in terms of motor recovery. We discuss whether transplants can mitigate L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias and consider the risk factors which predispose to graft-induced dyskinesias. In addition, we introduce Transeuro, a new European Union-funded multicenter consortium which plans to perform transplantation trials.Stem cells have emerged as an alternative source for the generation of dopaminergic precursors. We briefly outline progress made in the use of human embryonic stem cells and focus predominantly on the emerging field of induced pluripotency. We conclude by introducing the exciting and novel method of direct reprogramming which involves the conversion of fibroblasts to neurons without inducing a pluripotent state. SUMMARY: The area of cell transplantation has been revitalized by the identification of parameters which predispose patients to graft-induced dyskinesias and by the emergence of novel methods of generating dopaminergic neurons. Hopefully, the Transeuro clinical trials will give further impetus and act as a stepping stone to future trials employing stem-cell-derived neurons.

Long-term effect of unilateral pallidotomy on levodopa-induced dyskinesia.

Unilateral pallidotomy has been effectively used to treat parkinsonism and reduce levodopa induced dyskinesia (LID). We sought to determine the long-term effects of pallidotomy on LID in 10 patients who had initial benefit from pallidotomy but went on to require DBS surgery for symptom progression. The Dyskinesia Rating Scale (DRS) was used to rate and quantify LID in a blinded fashion. Though sample size was small, there was a trend towards a reduction in LID lasting up to 12 years suggesting that posteroventral pallidotomy may provide sustained benefit in reducing LID.

Effects of GDF5 overexpression on embryonic rat dopaminergic neurones in vitro and in vivo.

Transplantation of embryonic dopaminergic neurones has shown promise for the treatment of Parkinson's disease (PD), but this approach is limited by the poor survival of the transplanted cells. Exogenous dopaminergic neurotrophic factors such as growth/differentiation factor 5 (GDF5) have been found to enhance the survival of transplanted dopaminergic neurones. However, this approach is limited by the rapid degradation of such factors in vivo; thus, methods for long-term delivery of these factors are under investigation. The present study shows, using optimised lipid-mediated transfection procedures, that overexpression of GDF5 significantly improves the survival of dopaminergic neurones in cultures of embryonic day (E) 13 rat ventral mesencephalon (VM) and protects them against 6-hydroxydopamine (6-OHDA)-induced toxicity. In another experiment, E13 VM cells were transfected with GDF5 after 1 day in vitro (DIV), then transplanted into 6-OHDA-lesioned adult rat striata after 2 DIV. The survival of these E13 VM dopaminergic neurones after transfection and transplantation was as least as high as that of freshly dissected E14 VM dopaminergic neurones, demonstrating that transfection was not detrimental to these cells. Furthermore, GDF5-overexpressing E13 VM transplants significantly reduced amphetamine-induced rotational asymmetry in the lesioned rats. This study shows that lipid-mediated transfection in vitro prior to transplantation is a valid approach for the introduction of neurotrophic proteins such as GDF5, as well as lending further support to the potential use of GDF5 in neuroprotective therapy for PD.

Pallidotomy for severe tardive jaw-opening dystonia.

Bilateral pallidotomy was performed in a schizophrenic patient with severe jaw-opening dystonia developed after chronic neuroleptic treatment. The dystonia led to sustained mandibular joint dislocation, and tracheotomy was performed after suffocation. The jaw-opening dystonia disappeared immediately following pallidotomy; the tracheotomy was closed, and he regained eating and speech ability. Analysis of the neuronal firing of the globus pallidus revealed low neuronal firing rates in the internal pallidum (GPi) and an irregular burst pattern of the GPi cells compared to those in Parkinson's disease. These results suggest that pallidotomy is a treatment option for tardive jaw-opening dystonia and that dystonia of this type is driven by abnormal neural activities in the GPi.

How do you treat motor complications in Parkinson's disease: Medicine, surgery, or both?

The motor complications associated with levodopa therapy, namely, fluctuations in motor response and dyskinesias, occur in the majority of Parkinson's disease patients. These complications can impair a patient's quality of life and even cause pronounced disability. "Off" states that result in freezing of gait and falling are disabling for many patients. Dyskinesias most commonly occur at peak dose and typically alternate with the wearing-off state. Once these problems appear, they usually persist, and the physician needs to make continual adjustments in medications to minimize these problems. Medical treatments should be attempted before treatments such as deep brain stimulation are considered because of the potential adverse effects that are associated with surgery. The timing of surgery, however, is also important because younger patients and less advanced patients tend to have a better outcome. There is thus a need for experienced and knowledgeable physicians and surgeons who are able to handle these motor complications. This review discusses available medications and surgical approaches, and their outcomes.

Neurosurgical Approaches to Levodopa-Induced Dyskinesia.

Levodopa has long been the standard of care for Parkinson disease (PD); however, the eventual onset of motor fluctuations and levodopa-induced dyskinesia (LID) complicates its utility in advanced PD. Current neurosurgical interventions remain some of the best options for LID. Deep brain stimulation (DBS) is currently the procedure of choice for patients with advanced PD, patients refractory to medical management, and patients with motor complications from levodopa therapy. Significant progress has been achieved in recent years, however, as newer techniques are making their way through preclinical and clinical studies. Use of interventional magnetic resonance imaging (iMRI) and a skull-mounted aiming device to guide electrode placement has improved accuracy in recent DBS studies. Adaptive "closed-loop" DBS represents another exciting advancement in the field, in which real-time feedback allows dynamic modulation of the stimulation delivered to the basal ganglia. Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel approach to creating precise lesioning in the brain that has shown promising results in preliminary studies for various movement disorders, including dyskinesias, and may transform the neuroablation field. Transcranial magnetic stimulation, which can induce local and distant effects in cortical and subcortical areas, has shown efficacy in managing certain PD and LID symptoms in early studies. Finally, direct stimulation of the motor cortex and the cerebellum has shown therapeutic effects in PD and LID patients in certain studies. Taken together, many of these new techniques have shown great promise in early studies and may eventually be preferred treatment options for LID patients.

Serotonin neuron transplants exacerbate L-DOPA-induced dyskinesias in a rat model of Parkinson's disease.

Clinical trials in patients with Parkinson's disease have shown that transplants of fetal mesencephalic dopamine neurons can form a new functional innervation of the host striatum, but the clinical benefits have been highly variable: some patients have shown substantial recovery in motor function, whereas others have shown no improvement and even a worsening in the 3,4-dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinetic side effects. Differences in the composition of the grafted cell preparation may contribute to these discrepancies. In particular, the number of serotonin neurons contained in the graft can vary greatly depending on the dissection of the fetal tissue. Importantly, serotonin neurons have the ability to store and release dopamine, formed from exogenously administered L-DOPA. Here, we have evaluated the effect of transplants containing serotonin neurons, or a mixture of dopamine and serotonin neurons, on L-DOPA-induced dyskinesias in 6-hydroxydopamine-lesioned animals. As expected, dopamine neuron-rich grafts induced functional recovery, accompanied by a 60% reduction in L-DOPA-induced dyskinesia that developed gradually over the first 10 weeks. Rats with serotonin-rich grafts with few dopamine neurons, in contrast, showed a progressive worsening of their L-DOPA-induced dyskinesias over time, and no functional improvement. The antidyskinetic effect of dopamine-rich grafts was independent of the number of serotonin neurons present. We conclude that serotonin neurons in the grafts are likely to have a detrimental effect on L-DOPA-induced dyskinesias in cases in which the grafts contain no or few dopamine neurons.

Paradoxes of functional neurosurgery: clues from basal ganglia recordings.

Deep brain stimulation (DBS) can be remarkably effective in treating movement disorders such as Parkinson's disease, dystonia, and essential tremor. Yet these effects remain essentially unexplained, even paradoxical. Equally challenging is the fact that DBS of motor targets in the basal ganglia appears to reverse abnormalities of movement without any obvious deleterious effects on remaining aspects of movement. Here, we explore the extent to which the noisy signal hypothesis might help solve some of these apparent paradoxes. Essentially the hypothesis, first tentatively advanced by Marsden and Obeso (1994), suggests that disease leads to a pattern of basal ganglia activity that disrupts local and distant function and that surgery acts to suppress or override this noisy signal. Critical to the success this theory is that different disease phenotypes are associated with different patterns of noisy signal, and we survey the evidence to support this contention, with specific emphasis on different types of pathological synchronization. However, just as DBS may suppress or override noisy signals in the basal ganglia, it must equally antagonize any remaining physiological functioning in these key motor structures. We argue that the latter effect of DBS becomes manifest when baseline motor performance is relatively preserved, i.e., when pathological activity is limited. Under these circumstances, the deleterious effects of DBS are no longer obscured by its therapeutic actions in suppressing noisy signals. Whether true, oversimplified or simply incorrect, the noisy signal hypothesis has served to focus attention on the detailed character of basal ganglia discharge and its variation with disease and therapy.

Bilateral deep brain stimulation of the globus pallidus to treat tardive dyskinesia.

CONTEXT: Tardive dyskinesia (TD) is a common and potentially disabling disorder induced by use of antipsychotic drugs for which medical treatment often gives disappointing results. OBJECTIVE: To assess the efficacy of bilateral deep brain stimulation of the internal part of the globus pallidus to treat severe TD. DESIGN: Prospective phase 2 multicenter study. SETTING: Six French university hospitals. Patients Patients with severe TD refractory to medical treatment were studied to evaluate the severity of abnormal involuntary movements before and after 6 months of bilateral globus pallidus deep brain stimulation. A 2-step open Fleming procedure was used to avoid unnecessary accrual of patients. A successful outcome was defined as a decrease of more than 40% in the main outcome measure at 6 months. The early stopping rule was invoked if the number of successful outcomes in 10 patients was fewer than 2, or 5 or more. A double-blind evaluation in the presence and absence of stimulation was performed at 6 months after surgery. Main Outcome Measure Change in score on the Extrapyramidal Symptoms Rating Scale. RESULTS: At 6 months after surgery, the Extrapyramidal Symptoms Rating Scale score had decreased compared with baseline by more than 40% (mean improvement, 61%; range, 44%-75%) in the first 10 patients included. In accord with the 2-step open Fleming procedure, we ended the trial at the first step and concluded that pallidal stimulation is an effective treatment for TD. The efficacy of the treatment was confirmed by a double-blind evaluation, with a mean decrease of 50% (range, 30%-66%) (P = .002) in the Extrapyramidal Symptoms Rating Scale score when stimulation was applied compared with the absence of stimulation. There were no marked changes in the patients' psychiatric status. CONCLUSION: Although these results need to be confirmed in a larger group of patients with a longer follow-up, bilateral globus pallidus deep brain stimulation seems to offer a much-needed new treatment option for disabling TD.

Mood improvement after deep brain stimulation of the internal globus pallidus for tardive dyskinesia in a patient suffering from major depression.

Deep brain stimulation (DBS) has the unique characteristic to very precisely target brain structures being part of functional brain circuits in order to reversibly modulate their function. It is an established adjunctive treatment of advanced Parkinson's disease and has virtually replaced ablative techniques in this indication. Several cases have been published relating effectiveness in neuroleptics-induced tardive dyskinesia. It is also investigated as a potential treatment of mood disorders. We report on the case of a 62 years old female suffering from a treatment refractory major depressive episode with comorbid neuroleptic-induced tardive dyskinesia. She was implanted a deep brain stimulation treatment system bilaterally in the globus pallidus internus and stimulated for 18 months. As well the dyskinesia as also the symptoms of depression improved substantially as measured by the Hamilton Rating Scale of Depression (HRSD) score and the Burke-Fahn-Marsden-Dystonia-Rating-Scale (BFMDRS) score. Scores dropped for HRSD from 26 at baseline preoperatively to 13 after 18 months; and for BFMDRS from 27 to 17.5. This case illustrates the potential of deep brain stimulation as a technique to be investigated in the treatment of severe and disabling psychiatric and movement disorders. DBS at different intracerebral targets being actually investigated for major depression might have similar antidepressant properties because they interact with the same cortico-basal ganglia-thalamocortical network found to be dysfunctional in major depression.

Bilateral subthalamotomy for advanced Parkinson disease.

BACKGROUND: Unilateral subthalamotomy has been reported to be effective in the treatment of rigidity, bradykinesia, and tremor of the contralateral limb. However, gait, clinical fluctuation, and postural stability are not significantly improved by unilateral lesioning of the STN in the long term. We sought to determine if bilateral surgery of the STN offers more benefits in the treatment of advanced PD. METHODS: Radiofrequency thermal coagulation was performed bilaterally in the STN in 10 patients. Under microelectrode and stereotactic guidance, surgery was directed at the dorsolateral portion of the STN in stages and followed by MRI in each patient to confirm lesion location. Patients have been followed for a median duration of 26 months as measured from the date of first surgery (range, 6-48 months) with UPDRS before and after surgery. RESULTS: Bilateral subthalamotomy demonstrated persistent benefits in bradykinesia, rigidity of the limbs, and consequently the improvement in activities of daily living, motor function, Schwab and England scales. In addition, significant improvement in axial motor features, gait, postural stability, and clinical fluctuation were present with bilateral STN surgeries. The benefits were sustained at the last evaluation period of 36 months. Tremor and drug-induced dyskinesia improved in early postoperative period, but the benefits declined over time. The reduction of daily l-dopa equivalent was 34%. No speech impairment was observed. Mild choreic movement occurred in 2 of 20 procedures that resolved spontaneously in 4 to 8 weeks. CONCLUSION: For advanced PD present with bilateral symptoms, axial motor impairment, or clinical fluctuation, staged bilateral subthalamotomy appears as a safe and effective treatment in the long term.

[Effects of bilateral deep brain stimulation in the subthalamic nucleus using two methods of target structure verification]. / Dinamika motornykh simptomov bolezni Parkinsona na fone khronicheskoi dvustoronnei élektrostimuliatsii subtalamicheskogo iadra s ispol'zovaniem dvukh metodik verifikatsii struktury misheni.

AIM: To evaluate the efficacy of deep brain stimulation in the subthalamic nucleus (DBS STN) in patients with Parkinson's disease (PD) using different methods of targeting according to the dynamics of motor symptoms of PD. MATERIAL AND METHODS: The study involved 90 patients treated with DBS STN. In 30 cases intraoperative microelectrode recording (MER) was used. MER was not performed in 30 patients of the comparison group. The control group consisted of 30 patients with PD who received conservative treatment. Hoehn and Yahr scale, Tinetti Balance and Mobility Scale (TBMS), Unified Parkinson's Disease Rating Scale (UPDRS), Parkinson's Disease Quality of Life-39 Scoring System (РDQ-39), Schwab & England ADL Scale were used. Levodopa equivalent daily dose (LEDD, 2010) was calculated for each patient. RESULTS AND CONCLUSION: The effect of DBS STN using intraoperative microelectrode recording on the main motor symptoms, motor complications, walking as well as indicators of quality of life and daily activities was shown. In both DBS STN groups, there was a significant reduction in the LEDD and marked improvement of the control of motor symptoms of PD. A significant reduction in the severity of motor fluctuations (50%) and drug-induced dyskinesia (51%) was observed. Quality of life and daily activity in off-medication condition were significantly improved in both DBS STN groups of patients, irrespective of the method of target planning (75-100%), compared with the control group.

Effects of fibroblast transplantation into the internal pallidum on levodopa-induced dyskinesias in parkinsonian non-human primates.

Recent studies have shown that fibroblast transplantation can modify the activity of basal ganglia networks in models of Parkinson's disease. To determine its effects on parkinsonian motor symptoms, we performed autologous dermal fibroblast transplantation into the internal pallidum (GPi) in two parkinsonian rhesus monkeys with stable levodopa-induced dyskinesias (LIDs). Levodopa responses were assessed every week after transplantation for three months. A reduction of between 58% and 64% in total LIDs on the contralateral side was observed in both animals. No clear LID changes were observed on the ipsilateral side. These effects lasted the entire 3-month period in one monkey, but declined after 6-8 weeks in the other. The antiparkinsonian effects of levodopa did not diminish. The results of this pilot study indicate that fibroblast transplantation into the GPi may have beneficial effects on LIDs and warrant further investigation for potential therapeutic use.

Changes in glutamate receptors in dyskinetic parkinsonian monkeys after unilateral subthalamotomy.

OBJECT: Unilateral subthalamotomy is a surgical procedure that may be used to alleviate disabling levodopa-induced dyskinesias (LIDs) in patients with Parkinson disease (PD). However, the mechanisms involved in LID remain largely unknown. The subthalamic nucleus (STN) is the sole glutamatergic nucleus within the basal ganglia, and its lesion may produce changes in glutamate receptors in various areas of the basal ganglia. The authors aimed to investigate the biochemical changes in glutamate receptors in striatal and pallidal regions of the basal ganglia after lesion of the STN in parkinsonian macaque monkeys. METHODS: The authors treated 12 female ovariectomized monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD-like symptoms, treated 8 of these animals with 3,4-dihydroxy-l-phenylalanine (L-DOPA; levodopa) to induce LID, and performed unilateral subthalamotomy in 4 of these 8 monkeys. Four additional monkeys were treated with saline only and were used as controls. The MPTP monkeys had previously been shown to respond behaviorally to lower doses of levodopa after the STN lesion. Autoradiography of slices from postmortem brain tissues was used to visualize changes in the specific binding of striatal and pallidal ionotropic glutamate receptors (that is, of the α-amino-3-hydroxy 5-methyl-4-isoxazole propionate [AMPA] and N-methyl-d-aspartate [NMDA] NR1/NR2B subunit receptors) and of metabotropic glutamate (mGlu) receptors (that is, mGlu2/3 and mGlu5 receptors). The specific binding and distribution of glutamate receptors in the basal ganglia of the levodopa-treated, STN-lesioned MPTP monkeys were compared with those in the saline-treated control monkeys and in the saline-treated and levodopa-treated MPTP monkeys. RESULTS: The autoradiographic results indicated that none of the pharmacological and surgical treatments produced changes in the specific binding of AMPA receptors in the basal ganglia. Levodopa treatment increased the specific binding of NMDA receptors in the basal ganglia. Subthalamotomy reversed these increases in the striatum, but in the globus pallidus (GP), the subthalamotomy reversed these increases only contralaterally. Levodopa treatment reversed MPTP-induced increases in mGlu2/3 receptors only in the GP. mGlu2/3 receptor-specific binding in the striatum and GP decreased bilaterally in the levodopa-treated, STN-lesioned MPTP monkeys compared with the other 3 groups. Compared with mGlu5 receptor-specific binding in the control monkeys, that of the levodopa-treated MPTP monkeys increased in the dorsal putamen and remained unchanged in the caudate nucleus and in the GP. CONCLUSIONS: These results implicate glutamate receptors in the previously observed benefits of unilateral subthalamotomy to improve motor control.

Thalamotomy for the alleviation of levodopa-induced dyskinesia: experimental studies in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated parkinsonian monkey.

This work set out to test the hypothesis that thalamotomy in the area of the thalamus which receives the input from the medial segment of the globus pallidus would decrease or prevent levodopa-induced dyskinesia. Peak dose dyskinesia is a major problem in the treatment of parkinsonian patients with levodopa therapy but this remains the best pharmacological agent for treating the condition. The hypothesis was derived from previous work which has suggested that reduced pallidal inhibition of the thalamus results in dyskinesia [Crossman (1990) Movement Dis. 5, 100-108]. A neuroanatomical tracing study was carried out prior to the thalamotomy work, using the anterograde tracer wheatgerm-agglutinin conjugated to horseradish peroxidase. This delineated the anterior part of the ventrolateral thalamus in the primate in terms of its afferent inputs. Wheatgerm agglutinin-horseradish peroxidase was injected into the medial segment of the globus pallidus bilaterally in three Macaca fascicularis and traced to terminals in the ventral thalamus and other brain areas. The appropriate thalamic area involved was plotted on atlas sections in preparation for stereotactic thalamotomy. Previous studies of neuronal input to the ventral thalamus are confusing due to the different nomenclatures used by different workers. Early workers used cytoarchitectonic boundaries which do not correspond with function. There are also differences in nomenclature between man, monkey and other animals. The current study maps the pallidal terminal territory within the thalamus in terms of stereotactic co-ordinates related to a published macaque atlas [Shantha et al. (1968) A Stereotaxic Atlas of the Java Monkey Brain. S. Karger, Basel] and can thus be used by other workers in the field. A well-established primate model of Parkinsonism was used for the thalamotomy study. Eight monkeys (Macaca fascicularis) were rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Regular dosing with levodopa or apomorphine reliably resulted in peak-dose dyskinesia which was scored in terms of its choreic and dystonic components. A radiofrequency electrode was used to create the ablative lesions. Chorea was always reduced and frequently abolished by a thalamotomy located in the pallidal terminal territory. This result was obtained after 10 thalamotomies in a total of six animals. Four animals received bilateral lesions, with an interval between operations and two animals underwent unilateral surgery.(ABSTRACT TRUNCATED AT 400 WORDS)

Improvements in MPTP-induced object retrieval deficits and behavioral deficits after fetal nigral grafting in monkeys.

Improvements in MPTP-induced deficits were only found in subjects that received fetal substantia nigra transplants into the caudate nucleus. The MPTP-induced deficits were assessed using an object retrieval task that examined cognitive and subtle motor performance and by behavioral observation to determine the overall status of the subjects. Subjects that were also moderately or severely impaired by MPTP administration but that received inappropriate donor cells or implant sites (cerebellum to CN or SN to cortex) did not show any evidence of behavioral recovery. These subjects could not respond on the task in the months after grafting and were sacrificed, showing no improvements in parkinsonian signs or healthy behavior signs, up to 5-6 months after surgery. Grafting of SN cells into the striatum of non-MPTP lesioned subjects failed to modify normal behavior or induce abnormal behavior determined by our 2 behavioral assessment methods. In those monkeys that received the appropriate transplants, TH immunohistochemistry revealed that cells of the fetal substantia nigra grafted into the caudate nucleus survived and extended neurites into the host striatum. Indeed, grafted dopamine neurons were often associated with appreciable innervation of the caudate nucleus and appeared to be well incorporated into the host brain. In contrast, examination of the striatum of subjects in the inappropriate-graft group (e.g., cerebellar cells grafted into the caudate) showed no evidence of TH staining within the graft or host caudate nucleus. This indicated that there was no evidence of dopamine neurons present in the grafted tissue and that the mere presence of a fetal graft did not appear to induce sprouting in these MPTP-treated subjects. Although behavioral recovery occurred in only those monkeys that received appropriate transplants (fetal SN to host CN) and not in those that received inappropriate grafts (fetal cerebellum to CN or fetal SN to cortex), the CSF HVA levels did not distinguish those monkeys with improved parkinsonism from those that remained severely parkinsonian. The finding that in some SN-CN grafted subjects reported here, there was evidence of increased dopamine and lowered HVA/dopamine ratio in the vicinity of the SN grafts (cf. Elsworth et al., 1990b) is consistent with the hypothesis that graft-derived or graft-induced dopamine production is responsible for behavioral recovery. In addition, the finding that CSF HVA levels in non-MPTP lesioned subjects were unchanged by fetal SN grafts further indicates that CSF HVA levels may not be sufficiently sensitive to changes in central dopamine production to reflect release of dopamine from relatively small grafts that may, in lesioned subjects, modify behavior.(ABSTRACT TRUNCATED AT 400 WORDS)

Levodopa-induced dyskinesias treated by pallidotomy.

Pallidotomy has been reported to improve parkinsonian symptoms, but its effects on levodopa-induced dyskinesia (LID) have not been thoroughly examined. We describe here the results of stereotactic, unilateral, posteroventral pallidotomy on LID in 42 patients (22 women), who were followed for up to 9 months. Their mean age was 60. 6+/-9.3 (range: 40-74), age at onset was 46.1+/-9.1 (range: 24-46), and duration of symptoms was 14.5+/-5.3 (range: 4-25) years. Three months following pallidotomy, the percent time with dyskinesia decreased from 37.0 to 17.3 (P<0.0001) and the percent time the patients were 'on' with dyskinesias decreased even more, from 71.0 to 22.9 (P<0.0001). Furthermore, the number of patients with troublesome (moderate to violent) dyskinesia had decreased from 36 (86%) prior to surgery to only 5 (12%) after surgery. The mean unified Parkinson disease rating scale (UPDRS) scores for LID-related disability and pain decreased from 1.95 to 0.74 (P<0. 0001) and from 1.02 to 0.17 (P<0.0001), respectively. Since the pre- and post-pallidotomy daily levodopa dosage remained essentially the same, the improvement in LID could not be attributed to a reduction in levodopa. Surgery-related complications occurred in eight (19%) patients, but none of them had persistent disability as a result of these complications. We conclude that pallidotomy is an effective and safe procedure in the treatment of medically intractable LID.