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.

[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.

[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.

[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.

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.

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.

Amphetamine-induced dyskinesia in the transplanted hemi-Parkinsonian mouse.

The transplantation of dopamine-rich tissue into the putamen of patients with Parkinson's disease shows much potential for use as a therapeutic strategy. However, a number of grafted individuals subsequently developed a set of abnormal involuntary movements (AIMs), unrelated to the dyskinesia caused by L-DOPA treatment, which have been termed graft-induced dyskinesia. Given the small number of patients, pre-clinical modeling of graft-induced dyskinesia in animal models will be critical to determine the underlying mechanisms and amelioration potential of this technique. Here we show that abnormal involuntary movements of the limbs, trunk and face can be observed in transplanted hemi-parkinsonian mice following amphetamine administration, similar to those previously described to model graft-induced dyskinesias in rats. C57Bl6 and CD1 mice were first rendered hemi-parkinsonian with 6-hydroxydopamine, treated with L-DOPA for 21 days until dyskinetic, and then transplanted with a single cell suspension of embryonic ventral mesencephalon (VM E12.5) tissue from corresponding strains into the denervated striatum. At 16 weeks post-transplantation, a single injection of amphetamine-elicited dyskinesia in a subgroup of mice of both strains, behavioural pattern not observed pre-transplantation. The number of surviving dopaminergic cells in the graft did not differ between those that developed AIMs and those that did not. The movements were phenotypically comparable to those seen in the rat model and parallels can be drawn to the human form of the movements, although the mouse model maybe less reproducible than the rat equivalent. This mouse model will facilitate assessment of graft-induced dyskinesia with mouse-derived stem cell lines and exploration of mechanisms using transgenic mice in future studies.

Surgical approach to l-dopa-induced dyskinesias.

Many patients treated chronically with l-dopa for Parkinson disease (PD) become functionally disabled by l-dopa-induced dyskinesias (LID). Evolved from early empirical procedures, modern stereotactic surgical lesioning techniques and deep brain stimulation (DBS) can effectively treat LID while simultaneously improving the cardinal motor symptoms of PD. Here we review the common surgical targets used to treat LID, and compare their relative efficacy. We explain the anti-dyskinetic action of surgery at each of these targets based on evolving models of basal ganglia function. Finally, we discuss the appropriate selection of patients with LID for surgery and address relevant technical and management issues in these patients.

Current options and future possibilities for the treatment of dyskinesia and motor fluctuations in Parkinson's disease.

Dyskinesia and motor fluctuations affect up to 90% of patients with Parkinson's disease (PD) within ten years of L-DOPA pharmacotherapy, and represent a major challenge to a successful clinical management of this disorder. There are currently two main treatment options for these complications, namely, deep brain electrical stimulation or continuous infusion of dopaminergic agents. The latter is achieved using either subcutaneous apomorphine infusion or enteric L-DOPA delivery. Some patients also benefit from the antidyskinetic effect of amantadine as an adjunct to L-DOPA treatment. Ongoing research in animal models of PD aims at discovering additional, novel treatment options that can either prevent or reverse dyskinesia and motor fluctuations. Alternative methods of continuous L-DOPA delivery (including gene therapy), and pharmacological agents that target nondopaminergic receptor systems are currently under intense experimental scrutiny. Because clinical response profiles show large individual variation in PD, an increased number of treatment options for dyskinesia and motor fluctuations will eventually allow for antiparkinsonian and antidyskinetic therapies to be tailor-made to the needs of different patients and/or PD subtypes.

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.

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.

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.

L-dopa-induced dyskinesia and stereotactic surgery for Parkinson's disease.

OBJECTIVE: To assess the impact of different surgical targets and techniques, such as ablation and deep brain stimulation, to treat patients with L-dopa-induced dyskinesia (LID), a major therapeutic complication of Parkinson's disease. METHODS: This review analyzes the effects of early surgical procedures to treat hyperkinesia and the current methods and targets used to combat LID in Parkinson's disease, which are mainly thalamotomy, pallidotomy, and deep brain stimulation of the globus pallidus internus and the subthalamic nucleus. RESULTS: Available information indicates that surgery of the globus pallidus internus and thalamus (the pallidal receiving area) and of the subthalamic nucleus has a pronounced antidyskinetic effect. This effect is associated with a concomitant improvement in the parkinsonian ("off"-medication) state. Although it is more profound with pallidal and subthalamic surgery, such an effect can also be observed to some extent with thalamic surgery. The latter is attributable to the fact that surgery of the ventralis intermedius is primarily effective for treating tremor. An integral pallidothalamic pathway is needed for dyskinesia to be expressed. Thus, LID is less frequent after subthalamotomy or deep brain stimulation of the subthalamic nucleus through a functional effect mediated by the physiological normalization of the motor system and by an indirect effect associated with a reduction in the daily dose of L-dopa. CONCLUSION: Surgery is the only treatment available for Parkinson's disease that can predictably improve both the parkinsonian motor syndrome and LID. The exact mechanisms involved in these effects are not well understood. Pallidal and thalamic surgery affecting pallidal relays reduce LID frequency by disrupting the pallidothalamic circuit, probably eliminating the neuronal activity associated with dyskinesia. Alternatively, the antidyskinetic effect of subthalamic nucleus surgery may in part be attributable to a reduction in the L-dopa dose as well as to the stabilization of the basal ganglia circuits after the surgical procedure.

Systemic administration of an mGluR5 antagonist, but not unilateral subthalamic lesion, counteracts l-DOPA-induced dyskinesias in a rodent model of Parkinson's disease.

Altered glutamatergic neurotransmission is central to the expression of Parkinson's disease (PD) symptoms and may underlie l-DOPA-induced dyskinesias. Drugs acting on glutamate metabotropic receptors (mGluR) of group I can modulate subthalamic nucleus (STN) overactivity, which plays a pivotal role in these phenomena, and may counteract dyskinesias. To address these issues, we investigated the effects of a 3-week treatment with mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), or of a subthalamic lesion, on abnormal involuntary movements (AIMs) and associated striatal expression of transcription factor FosB/Delta FosB caused by chronic l-DOPA administration, in rats with a nigrostriatal lesion. MPEP virtually abolished AIMs and reduced, dramatically, striatal expression of FosB/Delta FosB. Reduced FosB/Delta FosB expression, coupled with nonsignificant reduction of AIMs, was also observed in STN-lesioned rats. Our data confirm the role of glutamatergic neurotransmission in the pathogenesis of dyskinesias and the potential of mGluR5 antagonists in the treatment of l-DOPA-induced dyskinesias.

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.

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 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.

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.