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This study aims to study the effffects of Tiaoshen Changzhi acupuncture on behavior and striatum ΔFosB in rats with Levodopa-induced Dyskinesias (LIDs). In this experimental study, Levodopa-induced Dyskinesia (LID) rat models were established by 6-OHDA double-target injection and randomly assigned to six groups, with ten rats in each group. The rats were subjected to difffferent interventions for 28 days, and their behavior was observed. Additionally, the content of ΔFosB, a marker of neuronal activation, in the rat striatum was detected by immunohistochemistry and qRT-PCR. In contrallateral rotation behavior experiment and AIM experiment, the score of the model group was significantly increased, compared with the model group, the score of the Western medicine group, the ordinary acupuncture group and the Tiaoshen Changzhi group was significantly decreased (P < 0.01), the score of the Western medicine group and the Tiaoshen Changzhi group was significantly lower than the ordinary acupuncture group (P < 0.01), there was no statistical significance between the Western medicine group and the Tiaoshen Changzhi group (P>0.05). In the left forelimb function test, the score of the model group was significantly decreased, and compared with the model group, the left forelimb function score of the Western medicine group, the ordinary acupuncture group and the Tiaoshen Changzhi group were significantly increased (P < 0.01). The left forelimb function score of the Western medicine group and the Tiaoshen Changzhi group was higher than the ordinary acupuncture group (P < 0.05, P < 0.01). There was no statistical significance between Western medicine group and Tiaoshen Changzhi group (P > 0.05). After treatment, the content of ΔFosB in the striatum of the Western medicine group, the ordinary acupuncture group and the Tiaoshen Changzhi acupuncture group all decreased, the Western medicine group was better than the ordinary acupuncture group (P < 0.01), and the Tiaoshen Changzhi acupuncture group was better than the ordinary acupuncture group (P < 0.05). Tiaoshen Changzhi acupuncture can improve the behavioral performance of LID rats, reduce abnormal involuntary movement and contralateral rotation behavior and enhance the motor function of the left forelimb of rats. One of its therapeutic mechanisms for LID may be to reduce the expression level of ΔFosB in the striatum of LID rats, thereby reducing the symptoms of LID rats.

Background and Objectives: Vertical rhythmic dyskinetic movements that are primarily drug-induced and affect solely the jaw, mouth, and lips without involving the tongue have been historically described as "rabbit" syndrome (RS). Evidence on the unique features and implications of this disorder remains limited. This literature review aims to evaluate the clinical-epidemiological profile, pathological mechanisms, and management of this movement disorder. Materials and Methods: Two reviewers identified and assessed relevant reports in six databases without language restriction published between 1972 and 2024. Results: A total of 85 articles containing 146 cases of RS were found. The mean frequency of RS among adults in psychiatric hospitals was 1.2% (range 0-4.4%). The mean age of affected patients was 49.2 (SD: 17.5), and 63.6% were females. Schizophrenia was the most frequent comorbidity found in 47.6%, followed by bipolar disorder (17.8%), major depressive disorder (10.3%), and obsessive-compulsive disorder (3.7%). Five cases were idiopathic. The most common medications associated with RS were haloperidol (17%), risperidone (14%), aripiprazole (7%), trifluoperazine (5%), and sulpiride (5%). The mean duration of pharmacotherapy before RS was 21.4 weeks (SD: 20.6). RS occurred in association with drug-induced parkinsonism (DIP) in 27.4% and with tardive dyskinesia (TD) in 8.2% of cases. Antipsychotic modification and/or anticholinergic drugs resulted in full or partial recovery in nearly all reported cases in which they were prescribed. Conclusions: RS occurs as a distinct drug-induced syndrome associated primarily but not exclusively with antipsychotics. Distinguishing RS from TD is important because the treatment options for the two disorders are quite different. By contrast, RS may be part of a spectrum of symptoms of DIP with similar course, treatment outcomes, and pathophysiology.

The most commonly used treatment for Parkinson's disease (PD) is levodopa, prescribed in conjunction with carbidopa. Virtually all patients with PD undergo dopamine replacement therapy using levodopa during the course of the disease's progression. However, despite the fact that levodopa is the "gold standard" in PD treatments and has the ability to significantly alleviate PD symptoms, it comes with side effects in advanced PD. Levodopa replacement therapy remains the current clinical treatment of choice for Parkinson's patients, but approximately 80% of the treated PD patients develop levodopa-induced dyskinesia (LID) in the advanced stages of the disease. A better understanding of the pathological mechanisms of LID and possible means of improvement would significantly improve the outcome of PD patients, reduce the complexity of medication use, and lower adverse effects, thus, improving the quality of life of patients and prolonging their life cycle. This review assesses the recent advancements in understanding the underlying mechanisms of LID and the therapeutic management options available after the emergence of LID in patients. We summarized the pathogenesis and the new treatments for LID-related PD and concluded that targeting pathways other than the dopaminergic pathway to treat LID has become a new possibility, and, currently, amantadine, drugs targeting 5-hydroxytryptamine receptors, and surgery for PD can target the Parkinson's symptoms caused by LID.

Background and Purpose: The purpose was to assess the effect of bilateral subthalamic nucleus deep brain stimulation (STN DBS) on diphasic dyskinesia in patients with Parkinson disease (PD) and to assess the factors associated with the remission of diphasic dyskinesia., Methods: Medical records for PD patients who underwent bilateral STN DBS at the Movement Disorder Center of Seoul National University Hospital from March 2005 to November 2016 were reviewed. Patients were evaluated preoperatively and at 3, 6 and 12 months after surgery, and annually thereafter. The presence of peak-dose dyskinesia and diphasic dyskinesia is based on the interview and examination of patients at baseline and at each follow-up., Results: Amongst 202 patients who underwent STN DBS, 66 patients who had diphasic dyskinesia preoperatively were included in the analysis. Diphasic dyskinesia disappeared in 49 (74%) after surgery. In 27 (55.1%) patients whose diphasic dyskinesia disappeared after DBS, peak-dose and diphasic dyskinesia disappeared persistently from as early as 3 months postoperatively. Age at onset was younger and disease duration at surgery was longer in patients whose diphasic dyskinesia persisted compared with patients whose diphasic dyskinesia disappeared. Multivariate Cox regression analysis demonstrated that patients with greater postoperative decrease of dopaminergic medications were more likely to have remission of diphasic dyskinesia., Conclusion: This study showed that bilateral STN DBS is effective in controlling diphasic dyskinesia and should be considered in PD patients with diphasic dyskinesia., (© 2021 European Academy of Neurology.)

Patients with Parkinson's Disease (PD) experience bothersome motor fluctuations and Levodopa-induced Dyskinesias (LIDs). Cerebellar continuous theta burst stimulation (cTBS) was used as an inhibitory protocol of repetitive transcranial magnetic stimulation (rTMS) to reduce LIDs in PD patients. The influence of Val66Met polymorphism of Brain Derived Neurotrophic Factor (BDNF) gene on the therapeutic response to cTBS was investigated and the serum levels of BDNF were measured before and after treatment. Eleven patients were exposed to a session of cTBS and sham stimulation (one week apart) after the administration of 125 % of their usual morning dose of Levodopa and LIDs were video-recorded and evaluated at different time points (0, 15, 30, 45, 60, 90 min after Levodopa). Cerebellar cTBS significantly reduced LIDs with respect to sham stimulation and decreased serum BDNF levels. These effects were evident in the Val66Val group (7 subjects) but not in the Val66Met group (4 subjects). These data confirm the efficacy of cerebellar cTBS in reducing LIDs in PD patients and show that the clinical effect is accompanied by a decrease in serum BDNF levels. Moreover, they suggest that BDNF Val66Met polymorphism may influence the clinical and biological response to cTBS., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To compare the efficacy of subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) on reducing levodopa-induced dyskinesia (LID) in Parkinson's disease, and to explore the potential underlying mechanisms., Methods: We retrospectively assessed clinical outcomes in 43 patients with preoperative LID who underwent DBS targeting the STN (20/43) or GPi (23/43). The primary clinical outcome was the change from baseline in the Unified Dyskinesia Rating Scale (UDysRS) and secondary outcomes included changes in the total daily levodopa equivalent dose, the drug-off Unified Parkinson Disease Rating Scale Part Ⅲ at the last follow-up (median, 18 months), adverse effects, and programming settings. Correlation analysis was used to find potential associated factors that could be used to predict the efficacy of DBS for dyskinesia management., Results: Compared to baseline, both the STN group and the GPi group showed significant improvement in LID with 60.73 ± 40.29% (mean ± standard deviation) and 93.78 ± 14.15% improvement, respectively, according to the UDysRS score. Furthermore, GPi-DBS provided greater clinical benefit in the improvement of dyskinesia (P < 0.05) compared to the STN. Compared to the GPi group, the levodopa equivalent dose reduction was greater in the STN group at the last follow-up (43.81% vs. 13.29%, P < 0.05). For the correlation analysis, the improvement in the UDysRS outcomes were significantly associated with a reduction in levodopa equivalent dose in the STN group (r = 0.543, P = 0.013), but not in the GPi group (r = -0.056, P = 0.801)., Interpretation: Both STN and GPi-DBS have a beneficial effect on LID but GPi-DBS provided greater anti-dyskinetic effects. Dyskinesia suppression for STN-DBS may depend on the reduction of levodopa equivalent dose. Unlike the STN, GPi-DBS might exert a direct and independent anti-dyskinesia effect., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Background: Thalidomide and closely related analogues are used clinically for their immunomodulatory and antiangiogenic properties mediated by the inhibition of the proinflammatory cytokine tumor necrosis factor α. Neuroinflammation and angiogenesis contribute to classical neuronal mechanisms underpinning the pathophysiology of l-dopa-induced dyskinesia, a motor complication associated with l-dopa therapy in Parkinson's disease. The efficacy of thalidomide and the more potent derivative 3,6'-dithiothalidomide on dyskinesia was tested in the 6-hydroxydopamine Parkinson's disease model., Methods: Three weeks after 6-hydroxydopamine infusion, rats received 10 days of treatment with l-dopa plus benserazide (6 mg/kg each) and thalidomide (70 mg/kg) or 3,6'-dithiothalidomide (56 mg/kg), and dyskinesia and contralateral turning were recorded daily. Rats were euthanized 1 hour after the last l-dopa injection, and levels of tumor necrosis factor-α, interleukin-10, OX-42, vimentin, and vascular endothelial growth factor immunoreactivity were measured in their striatum and substantia nigra reticulata to evaluate neuroinflammation and angiogenesis. Striatal levels of GLUR1 were measured as a l-dopa-induced postsynaptic change that is under tumor necrosis factor-α control., Results: Thalidomide and 3,6'-dithiothalidomide significantly attenuated the severity of l-dopa-induced dyskinesia while not affecting contralateral turning. Moreover, both compounds inhibited the l-dopa-induced microgliosis and excessive tumor necrosis factor-α in the striatum and substantia nigra reticulata, while restoring physiological levels of the anti-inflammatory cytokine interleukin-10. l-Dopa-induced angiogenesis was inhibited in both basal ganglia nuclei, and l-dopa-induced GLUR1 overexpression in the dorsolateral striatum was restored to normal levels., Conclusions: These data suggest that decreasing tumor necrosis factor-α levels may be useful to reduce the appearance of dyskinesia, and thalidomide, and more potent derivatives may provide an effective therapeutic approach to dyskinesia. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Prolonged administration of Levodopa (L-dopa) therapy can generate L-dopa-induced dyskinesia (LID). Accumulating evidence indicates that hyper-activation of the dopamine D1 receptor (D1R) and the cAMP signaling cascade in the medium spiny neurons (MSNs) of the striatum are involved in LID. Previous studies have shown that striatal β-arrestin2 overexpression significantly reduces LID severity and have indicated that β-arrestin2 may play a causal role in the dyskinesia sensitization process. L-dopa-induced changes in the expression of signaling molecules and other proteins in the striatum were examined immunohistochemically and by western blot. A rAAV (recombinant adeno-associated virus) vector was used to overexpress and ablate β-arrestin2. We found that striatal overexpression of AAV-mediated β-arrestin2 produced less severe AIMs (abnormal involuntary movements) in response to L-dopa, whereas selective deletion of β-arrestin2 in the striatal neurons dramatically enhanced the severity of dyskinesia induced by L-dopa. Furthermore, no significant improvements in motor behavior (FFT: forelimb functional test) were seen with the inhibition or overexpression of β-arrestin2. Finally, overexpression of β-arrestin2 diminished L-dopa-induced D1R and phosphor-DARPP32/ERK levels. Viral deletion of β-arrestin2 markedly enhanced the key biochemical markers in the direct pathway. We found that increased availability of β-arrestin2 ameliorated dyskinesia severity with no influence on the anti-Parkinsonian action of L-dopa, suggesting a promising approach for controlling LID in Parkinson's disease. In addition, overexpression of β-Arrestin2 prevented the development of LID by inhibiting G protein-dependent D1R and phosphor-DARPP32/ERK signaling in dyskinetic rats., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Bilateral subthalamic nucleus deep brain stimulation (STN DBS) improves motor fluctuations and dyskinesias in patients with Parkinson's disease (PD). Dyskinesia improvement with STN DBS is believed to result entirely from levodopa reduction. However, some studies suggest that STN DBS may also directly suppress dyskinesias. To determine whether bilateral STN DBS improves dyskinesias beyond what would be expected from levodopa reduction alone, we analyzed pre-operative and post-operative dyskinesia scores (sum of MDS-UPDRS items 4.1 and 4.2) from 61 PD patients with bilateral STN DBS. A multiple regression model (adjusted for disease severity, disease duration, active contacts above the STN, use of amantadine, high pre-operative levodopa-equivalent dose (LED), sex, and interaction between active contacts above the STN and amantadine use) was created to describe the relationship between dyskinesia scores and LED prior to DBS. Using this model, a post-operative dyskinesia score was estimated from post-operative LED and compared to the actual post-operative dyskinesia score. The regression model was statistically significant overall (p = 0.003, R 2  = 0.34, adjusted R 2  = 0.24). The actual post-operative dyskinesia score (1.0 ± 1.4) was significantly lower than the score predicted by the model (3.0 ± 1.1, p < 0.0001). Dyskinesias after STN DBS improved more than predicted by levodopa reduction alone. Our data support the idea that STN stimulation may directly improve dyskinesias.

A large and ever-growing number of medications can induce various movement disorders. Drug-induced movement disorders are disabling but are often under-recognised and inappropriately managed. In particular, second generation antipsychotics, like first generation agents, are associated with potentially debilitating side-effects, most notably tardive syndromes and parkinsonism, as well as potentially fatal acute syndromes. Appropriate, evidence-based management is essential as these drugs are being prescribed to a growing population vulnerable to these side-effects, including children and elderly people. Prevention of the development of drug-induced movement disorders is an important consideration when prescribing medications that can induce movement disorders. Recent developments in diagnosis, such as the use of dopamine transporter imaging for drug-induced parkinsonism, and treatment, with the approval of valbenazine and deutetrabenazine, the first drugs indicated for tardive syndromes, have improved outcomes for many patients with drug-induced movement disorders. Future research should focus on development of safer antipsychotics and specific therapies for the different tardive syndromes and the treatment of drug-induced parkinsonism., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Levodopa-induced dyskinesias are an often debilitating side effect of levodopa therapy in Parkinson's disease. Although up to 90% of individuals with PD develop this side effect, uniformly effective and well-tolerated antidyskinetic treatment remains a significant unmet need. The pathognomonic loss of striatal dopamine in PD results in dysregulation and disinhibition of striatal CaV1.3 calcium channels, leading to synaptopathology that appears to be involved in levodopa-induced dyskinesias. Although there are clinically available drugs that can inhibit CaV1.3 channels, they are not adequately potent and have only partial and transient impact on levodopa-induced dyskinesias., Methods: To provide unequivocal target validation, free of pharmacological limitations, we developed a CaV1.3 shRNA to provide high-potency, target-selective, mRNA-level silencing of striatal CaV1.3 channels and examined its ability to impact levodopa-induced dyskinesias in severely parkinsonian rats., Results: We demonstrate that vector-mediated silencing of striatal CaV1.3 expression in severely parkinsonian rats prior to the introduction of levodopa can uniformly and completely prevent induction of levodopa-induced dyskinesias, and this antidyskinetic benefit persists long term and with high-dose levodopa. In addition, this approach is capable of ameliorating preexisting severe levodopa-induced dyskinesias. Importantly, motoric responses to low-dose levodopa remained intact in the presence of striatal CaV1.3 silencing, indicating preservation of levodopa benefit without dyskinesia liability., Discussion: The current data provide some of the most profound antidyskinetic benefit reported to date and suggest that genetic silencing of striatal CaV1.3 channels has the potential to transform treatment of individuals with PD by allowing maintenance of motor benefit of levodopa in the absence of the debilitating levodopa-induced dyskinesia side effect. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

In this review, we discuss respiratory dyskinesia, which is a rare adverse reaction to antipsychotic medications. The condition may mimic psychogenic hyperventilation syndrome or other respiratory or cardiac disorder. Respiratory dyskinesia is mostly seen in patients with tardive dyskinesia but may precede manifestations of tardive dyskinesia. If a patient receiving antipsychotic medication presents with symptoms of tachypnoea or acute respiratory distress, the possibility of respiratory dyskinesia should be considered, since it is a potentially reversible condition.

Although L-3,4-dihydroxyphenylalanine (L-DOPA) is currently the most effective medication for treating Parkinson's disease (PD) motor symptoms, its prolonged administration causes several adverse effects, including dyskinesia. To identify the mechanisms underlying the effects of acupuncture on L-DOPA-induced dyskinesia (LID), antidyskinetic effects of acupuncture were investigated in two mouse models of PD. Acupuncture stimulation at GB34 alleviated abnormal involuntary movements (AIMs) in Pitx3-deficient aphakia mice (ak/ak) following L-DOPA administration and these effects were reproduced in 6-hydroxydopamine (6-OHDA)-lesioned mice with LID. A transcriptome analysis of the hypothalamus revealed pro-melanin-concentrating hormone (Pmch) gene was highly expressed in acupuncture-treated mouse from ak/ak model of LID as well as 6-OHDA model of LID. Acupuncture combined with the administration of MCH receptor antagonist did not have any beneficial effects on dyskinesia in L-DOPA-injected ak/ak mice, but the intranasal administration of MCH attenuated LID to the same degree as acupuncture in both ak/ak and 6-OHDA mice with LID. A gene expression profile with a hierarchical clustering analysis of the dyskinesia-induced ak/ak mouse brain revealed an association between the mechanisms underlying acupuncture and MCH. Additionally, altered striatal responses to L-DOPA injection were observed after prolonged acupuncture and MCH treatments, which suggests that these treatment modalities influenced the compensatory mechanisms of LID. In summary, present study demonstrated that acupuncture decreased LID via hypothalamic MCH using L-DOPA-administered ak/ak and 6-OHDA mouse models and that MCH administration resulted in novel antidyskinetic effects in these models. Thus, acupuncture and MCH might be valuable therapeutic candidates for PD patients suffering from LID.

Tardive dyskinesias (TDs) are still common long-term sequelae of antipsychotic treatment. They are generally irreversible and associated with cognitive deficits, a decrease in quality of life and increased mortality. Furthermore, they potentially contribute to further stigmatization of the affected patients. However due to limited treatment options, antipsychotic drugs are still one of the cornerstones in treatment of most severe mental illnesses. Therefore, knowledge about risk factors and prevention of TDs is crucial. If TDs occur, the immediate optimization of the antipsychotic drug regimen is required. Targeted medical treatments such as VMAT - 2 inhibitors can be considered. The novel VMAT-2 inhibitors are not yet approved in Germany. Other drugs that are currently used to treat TDs include clonazepam and gingko biloba. This review summarizes the current evidence of treatment options of TDs and seeks to formulate clinical recommendations for the prevention and management of TDs., Competing Interests: Kongress- und Reisekostenunterstützung durch die Firma Amomed Pharma GmbHVortragshonorar sowie Kongress- und Reisekostenunterstützung durch die Firma Lundbeck GmbH, (© Georg Thieme Verlag KG Stuttgart · New York.)

Levodopa-induced dyskinesia is a common complication in Parkinson disease. Pathogenic mechanisms include phasic stimulation of dopamine receptors, nonphysiological levodopa-to-dopamine conversion in serotonergic neurons, hyperactivity of corticostriatal glutamatergic transmission, and overstimulation of nicotinic acetylcholine receptors on dopamine-releasing axons. Delay in initiating levodopa is no longer recommended, as dyskinesia development is a function of disease duration rather than cumulative levodopa exposure. We review current and in-development treatments for peak-dose dyskinesia but suggest that improvements in levodopa delivery alone may reduce its future prevalence. Ann Neurol 2018;84:797-811., (© 2018 American Neurological Association.)

Drug-induced parkinsonism (DIP) and tardive dyskinesia (TD) are iatrogenic consequences of antidopaminergic drugs. Both are particularly prevalent among the elderly and those with dementia. However, despite their prevalence, these disorders are often overlooked. Both entities share risk factors, physiopathological mechanisms and, to some degree, therapeutic approaches. Withdrawing the causal agent, reducing the dose or switching to a less potent antidopaminergic drug should be the first therapeutic options. Here we review both entities and emerging therapies including the recently approved drugs deutetrabenazine and valbenazine. We discuss relevant aspects for clinical practice such as new diagnostic techniques and the latest advances in the understanding of DIP and TD.

There has been a debate in the literature about the distinction between primary and secondary negative symptoms of schizophrenia. Our aim was to study the associations between negative symptoms and potential sources of secondary negative symptoms over time. A sample of 275 participants with at least mid-moderate negative symptoms was randomized into body psychotherapy or Pilates class in a previous study. No significant differences were found between groups over time and changes in the symptom domains were modest. The present investigation considers the longitudinal correlation between variables of interest at baseline, 3 and 9 months follow-up. Measures were the Clinical Assessment Interview for Negative Symptoms (CAINS), the Positive and Negative Symptom Scale (PANSS), the Calgary Depression Scale (CDSS) and the Simpson-Angus Extrapyramidal side-effects Scale (SAS). Mixed models were computed to test the longitudinal association between these variables. In a sensitivity analysis, the dosages of antipsychotic, illness duration and allocated intervention were taken into account. Overall, the course of extrapyramidal side-effects, depressive and positive symptoms was significantly related to the course of negative symptoms. Only extrapyramidal effects were longitudinally correlated to expressive negative symptoms. The sensitivity analyses showed unaltered results for positive symptoms and depression but a lack of association between extrapyramidal effects and the CAINS outcomes. In conclusion, the unambiguous interpretation between primary and secondary negative symptoms may lead to refined treatment approaches for schizophrenia and to increased effects of the interventions.

Diagnosis and treatment of motor phenomena in schizophrenia spectrum disorders Abstract. Motor abnormalities are intrinsic features of schizophrenia spectrum disorders. They may be spontaneous or antipsychotic drug-induced. The four most important symptom groups are abnormal involuntary movements or dyskinesia, Parkinsonism, catatonia and neurological soft signs. In addition, there are further motor abnormalities, which are less frequent and less operationalized. The suspected etiology of motor abnormalities is strongly associated with altered neurodevelopment. Delayed maturation in conjunction with environmental insults may give further rise to motor symptoms. For the four most relevant motor abnormalities clinical examination procedures and rating scales are available, aiding clinicians in both screening and evaluation of symptom severity. Besides these currently instrumental measures are being tested for wide spread and easy application. Treatment of motor abnormalities is necessary according to subjective well-being. Treatment options are few and remain symptomatic. The most important strategy is critical evaluation of antispychotic pharmacotherapy. Benefitial effects on motor phenomena have been noted with clozapine. Currently, specific substances against tardive dyskinesia and non-invasive brain stimulation techniques are being evaluated. However, the effeciacy of these approaches will only be available in the near future.

Background: Antipsychotic (neuroleptic) medication is used extensively to treat people with chronic mental illnesses. Its use, however, is associated with adverse effects, including movement disorders such as tardive dyskinesia (TD) - a problem often seen as repetitive involuntary movements around the mouth and face. This review, one in a series examining the treatment of TD, covers miscellaneous treatments not covered elsewhere., Objectives: To determine whether drugs, hormone-, dietary-, or herb-supplements not covered in other Cochrane reviews on TD treatments, surgical interventions, electroconvulsive therapy, and mind-body therapies were effective and safe for people with antipsychotic-induced TD., Search Methods: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials including trial registers (16 July 2015 and 26 April 2017), inspected references of all identified studies for further trials and contacted authors of trials for additional information., Selection Criteria: We included reports if they were randomised controlled trials (RCTs) dealing with people with antipsychotic-induced TD and schizophrenia or other chronic mental illnesses who remained on their antipsychotic medication and had been randomly allocated to the interventions listed above versus placebo, no intervention, or any other intervention., Data Collection and Analysis: We independently extracted data from these trials and we estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CIs). We assumed that people who left early had no improvement. We assessed risk of bias and created 'Summary of findings' tables using GRADE., Main Results: We included 31 RCTs of 24 interventions with 1278 participants; 22 of these trials were newly included in this 2017 update. Five trials are awaiting classification and seven trials are ongoing. All participants were adults with chronic psychiatric disorders, mostly schizophrenia, and antipsychotic-induced TD. Studies were primarily of short (three to six6 weeks) duration with small samples size (10 to 157 participants), and most (61%) were published more than 20 years ago. The overall risk of bias in these studies was unclear, mainly due to poor reporting of allocation concealment, generation of the sequence, and blinding.Nineteen of the 31 included studies reported on the primary outcome 'No clinically important improvement in TD symptoms'. Two studies found moderate-quality evidence of a benefit of the intervention compared with placebo: valbenazine (RR 0.63, 95% CI 0.46 to 0.86, 1 RCT, n = 92) and extract of Ginkgo biloba (RR 0.88, 95% CI 0.81 to 0.96, 1 RCT, n = 157), respectively. However, due to small sample sizes we cannot be certain of these effects.We consider the results for the remaining interventions to be inconclusive: Low- to very low-quality evidence of a benefit was found for buspirone (RR 0.53, 95% CI 0.33 to 0.84, 1 RCT, n = 42), dihydrogenated ergot alkaloids (RR 0.45, 95% CI 0.21 to 0.97, 1 RCT, n = 28), hypnosis or relaxation, (RR 0.45, 95% CI 0.21 to 0.94, 1 study, n = 15), pemoline (RR 0.48, 95% CI 0.29 to 0.77, 1 RCT, n = 46), promethazine (RR 0.24, 95% CI 0.11 to 0.55, 1 RCT, n = 34), insulin (RR 0.52, 95% CI 0.29 to 0.96, 1 RCT, n = 20), branched chain amino acids (RR 0.79, 95% CI 0.63 to 1.00, 1 RCT, n = 52), and isocarboxazid (RR 0.24, 95% CI 0.08 to 0.71, 1 RCT, n = 20). There was low- to very low-certainty evidence of no difference between intervention and placebo or no treatment for the following interventions: melatonin (RR 0.89, 95% CI 0.71 to 1.12, 2 RCTs, n = 32), lithium (RR 1.59, 95% CI 0.79 to 3.23, 1 RCT, n = 11), ritanserin (RR 1.00, 95% CI 0.70 to 1.43, 1 RCT, n = 10), selegiline (RR 1.37, 95% CI 0.96 to 1.94, 1 RCT, n = 33), oestrogen (RR 1.18, 95% CI 0.76 to 1.83, 1 RCT, n = 12), and gamma-linolenic acid (RR 1.00, 95% CI 0.69 to 1.45, 1 RCT, n = 16).None of the included studies reported on the other primary outcome, 'no clinically significant extrapyramidal adverse effects'., Authors' Conclusions: This review has found that the use of valbenazine or extract of Ginkgo biloba may be effective in relieving the symptoms of tardive dyskinesia. However, since only one RCT has investigated each one of these compounds, we are awaiting results from ongoing trials to confirm these results. Results for the remaining interventions covered in this review must be considered inconclusive and these compounds probably should only be used within the context of a well-designed evaluative study.

Background: Antipsychotic medication can cause tardive dyskinesia (TD) - late-onset, involuntary, repetitive movements, often involving the face and tongue. TD occurs in > 20% of adults taking antipsychotic medication (first-generation antipsychotics for > 3 months), with this proportion increasing by 5% per year among those who continue to use these drugs. The incidence of TD among those taking newer antipsychotics is not different from the rate in people who have used older-generation drugs in moderate doses. Studies of TD have previously been found to be limited, with no treatment approach shown to be effective., Objectives: To summarise the clinical effectiveness and safety of treatments for TD by updating past Cochrane reviews with new evidence and improved methods; to undertake public consultation to gauge the importance of the topic for people living with TD/the risk of TD; and to make available all data from relevant trials., Data Sources: All relevant randomised controlled trials (RCTs) and observational studies., Review Methods: Cochrane review methods, network meta-analysis (NMA)., Design: Systematic reviews, patient and public involvement consultation and NMA., Setting: Any setting, inpatient or outpatient., Participants: For systematic reviews, adults with TD who have been taking a stable antipsychotic drug dose for > 3 months., Interventions: Any, with emphasis on those relevant to UK NHS practice., Main Outcome Measures: Any measure of TD, global assessments and adverse effects/events., Results: We included 112 studies (nine Cochrane reviews). Overall, risk of bias showed little sign of improvement over two decades. Taking the outcome of 'TD symptoms improved to a clinically important extent', we identified two trials investigating reduction of antipsychotic dose [ n  = 17, risk ratio (RR) 0.42, 95% confidence interval (CI) 0.17 to 1.04; very low quality]. Switching was investigated twice in trials that could not be combined (switching to risperidone vs. antipsychotic withdrawal: one RCT, n  = 42, RR 0.45, 95% CI 0.23 to 0.89; low quality; switching to quetiapine vs. haloperidol: one RCT, n  = 45, RR 0.80, 95% CI 0.52 to 1.22; low quality). In addition to RCTs, six observational studies compared antipsychotic discontinuation with decreased or increased dosage, and there was no clear evidence that any of these strategies had a beneficial effect on TD symptoms (very low-quality evidence). We evaluated the addition to standard antipsychotic care of several treatments, but not anticholinergic treatments, for which we identified no trials. We found no clear effect of the addition of either benzodiazepines (two RCTs, n  = 32, RR 1.12, 95% CI 0.6 to 2.09; very low quality) or vitamin E (six RCTs, n  = 264, RR 0.95, 95% CI 0.89 to 1.01; low quality). Buspirone as an adjunctive treatment did have some effect in one small study ( n  = 42, RR 0.53, 95% CI 0.33 to 0.84; low quality), as did hypnosis and relaxation (one RCT, n  = 15, RR 0.45, 95% CI 0.21 to 0.94; very low quality). We identified no studies focusing on TD in people with dementia. The NMA model found indirect estimates to be imprecise and failed to produce useful summaries on relative effects of interventions or interpretable results for decision-making. Consultation with people with/at risk of TD highlighted that management of TD remains a concern, and found that people are deeply disappointed at the length of time it has taken researchers to address the issue., Limitations: Most studies remain small and poorly reported., Conclusions: Clinicians, policy-makers and people with/at risk of TD are little better informed than they were decades ago. Underpowered trials of limited quality repeatedly fail to provide answers., Future Work: TD reviews have data from current trials extracted, tabulated and traceable to source. The NMA highlights one context in which support for this technique is ill advised. All relevant trials, even if not primarily addressing the issue of TD, should report appropriate binary outcomes on groups of people with this problem. Randomised trials of treatments for people with established TD are indicated. These should be large (> 800 participants), necessitating accrual through accurate local/national registers, including an intervention with acceptable treatments and recording outcomes used in clinical practice., Study Registration: This study is registered as PROSPERO CRD4201502045., Funding: The National Institute for Health Research Health Technology Assessment programme.

Levodopa-induced dyskinesia (LID) represents a severe adverse effect of long-term treatment of Parkinson's disease with levodopa. Neuroimaging studies have contributed to our understanding of LID and may help to identify patients at risk of developing LID. Amantadine can be used for the treatment of LID, and novel drugs are under development. Deep brain stimulation of the subthalamic nucleus and globus pallidus internus alleviates LID, the former indirectly by reducing levodopa intake, the latter through direct effects. Repetitive transcranial magnetic stimulation has been shown to transiently improve LID.

Introduction: Over a 3-year period, we monitored the efficacy and safety of deep-brain stimulation of the globus pallidus pars interna in patients with advanced Parkinson's disease whose cognitive, psychiatric impairment and/or dopa-resistant axial motor signs made them ineligible for surgery targeting the subthalamic nucleus., Methods: A total of 25 patients were assessed before surgery, 1 year and 3 years after surgery, on the UPDRS and a neuropsychological battery., Results: We noted a significant improvement of 65.9% in the Clinical global self-perceived Improvement by Visual Analog Scale and an improvement of 20.6% in the total UPDRS-III motor score at 3 years in the off-dopa condition compared to before surgery. There was an improvement in the treatment's motor complications, as measured by the UPDRS-IV, with a particularly marked reduction of 50% in the Dyskinesia subscore. Cognitive performances remained stable at 1 year but had fallen by the third year. We interpreted this deterioration as due to disease progression., Conclusion: Bilateral pallidal stimulation in patients with contraindications to subthalamic surgery therefore seems to be effective over the long term in treating motor symptoms, especially dyskinesias, with good neuropsychological safety., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aim: The aim of this study was to assess the results of unilateral subthalamic nucleus (STN) stimulation for the treatment of Parkinson"s disease (PD) with marked asymmetry of parkinsonian motor symptoms and early motor complications., Material and Methods: The clinical series consisted of 32 consecutive PD patients, in whom unilateral STN stimulation was performed. All patients were assessed according to the Unified Parkinson"s Disease Rating Scale (UPDRS), and Hoehn and Yahr staging. The patients were assessed preoperatively, and at 12, and 24 months after unilateral STN stimulation. 22 patients were followed for 2 years., Results: Medication off/stimulation on total UPDRS motor scores were improved by 29% when compared to the baseline medication off motor scores. The contralateral motor scores improved by 49%, whereas the axial motor scores by 18% in medication off/stimulation on condition. The duration and severity of levodopa induced dyskinesia were reduced respectively by 73% and by 77%. The daily levodopa dose was decreased by only 10%., Conclusion: Unilateral STN stimulation is a safe and effective procedure for selected patients with marked asymmetry Parkinson"s disease motor symptoms and early motor complications.

The potential for adverse events is often cited as a barrier to the use of subcutaneous apomorphine therapy (intermittent injections and continuous infusion) in the management of Parkinson's disease. However, with proactive management most adverse effects are manageable if reported and tackled early enough. As such, proper clinician and patient awareness of the potential adverse effects is important to minimize their impact on the overall clinical utility of this efficacious antiparkinsonian agent. In this paper, we review the key local and systemic adverse effects reported during apomorphine titration, initiation and long-term treatment, and discuss practical management strategies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an accepted treatment for advanced Parkinson disease (PD). However, there is general reluctance in considering this therapy for PD patients over age 70 years with limited supporting evidence. Present study investigates age impacts in STN-DBS outcomes, focusing particularly on the elderly patients., Patients and Methods: Seventy-two consecutive patients were divided into younger and elderly (n=16, cutoff age=70years) groups. Both groups were comparable in preoperative clinical severity, except the elderly exhibited a levodopa (LD) response (P<0.05) inferior to that of the younger. Improvements in drug-off/DBS-on Unified PD Rating Scale (UPDRS) scores and reduction in daily LD-equivalent dose (LED) after 6 months were evaluated relative to the presurgical drug-off baseline. Preoperative factors predictive of favorable surgical outcomes were analyzed using a multivariate linear regression model., Results: After DBS therapy, elderly patients exhibited clinical improvements particularly in the tremor (56%) and LD-induced dyskinesia (78%). Improvement of axial dysfunction (24%) and reduction of daily LED (24%) showed no intergroup difference. Adverse events, particularly dysarthria, occurred frequently in elderly group. The overall improvements in UPDRS scores were suboptimal in elderly group, correlating with their preoperative inferior LD responses. Elderly patients who presented predominantly with akinesia before surgery achieved superior surgical outcomes (adjusted R(2)=0.657, P<0.001)., Conclusion: STN-DBS therapy is beneficial to some elderly PD patients aged 70 years or older. Tremor, axial dysfunctions and drug-induced dyskinesia are the main indications for the elderly; however, their clinical benefits are inferior to those of younger patients., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Fluctuations of dopamine levels and upregulations of NR2B tyrosine phosphorylation in the striatum have been connected with levodopa (L-dopa)-induced dyskinesia (LID) in Parkinson's disease (PD). Repetitive transcranial magnetic stimulation (rTMS) is one of the noninvasive and potential method treating dyskinesia. Yet, the effect of rTMS on the above key pathological events remains unclear. In this study, we gave L-dopa treatment intraperitoneally for 22 days to 6-hydroxydopamine-lesioned PD rats to prepare LID rats model, and subsequently applied rTMS daily for 3 weeks to LID rats model. The effect of rTMS on abnormal involuntary movements (AIMs) was assessed. After ending the experiments, we further determined tyrosine hydroxylase (TH)-positive dopaminergic neurons number by immunohistochemistry, dopamine levels by HPLC, glial cell line-derived neurotrophic factor (GDNF) levels by ELISA, NR2B tyrosine phosphorylation and interactions of NR2B with Fyn by immunoblotting and immunoprecipitation. The results demonstrated that rTMS obviously attenuated AIMs scores, reduced the loss of nigral dopaminergic neurons and the fluctuations of striatal dopamine levels. Meanwhile, rTMS significantly increased the expression of GDNF, which couldrestore the damage of dopaminergic neurons. Additionally, rTMS also reduced the levels of the NR2B tyrosine phosphorylation andits interactions with Fyn in the lesioned striatum of LID rats model. Thus, these data indicate that rTMS can provide benefit for the therapy of LID by improving the key biochemical deficits related to dyskinesia.

The development of drugs to treat psychosis is a fascinating nexus for understanding mechanisms underlying disorders of mind and movement. Although the risk of drug-induced extrapyramidal syndromes has been mitigated by the acceptance of less potent dopamine antagonists, expansive marketing and off-label use has increased the number of susceptible people who may be at risk for these neurologic effects. Clinicians need to be familiar with advances in diagnosis and management, which are reviewed herein. A better understanding of drug-induced effects on the motor circuit may improve patient safety, enhance antipsychotic effectiveness, and provide insights into mechanisms underlying antipsychotic activity in parallel brain circuits., (Published by Elsevier Inc.)

Parkinson's disease is primarily caused by dysfunction of dopaminergic neurons, however, nondopaminergic (ND) systems are also involved. ND targets are potentially useful to reduce doses of levodopa or to treat nonlevodopa-responsive symptoms. Recent studies have investigated the role of ND drugs for motor and nonmotor symptoms. Adenosine A2A receptor antagonists, mixed inhibitors of sodium/calcium channels and monoamine oxidase-B have recently been found to improve motor fluctuations. N-methyl-d-aspartate receptor antagonists and serotonin 5HT1B receptor agonists demonstrated benefit in levodopa-induced dyskinesia. Conversely, studies using antiepileptic drugs and adrenoreceptor antagonist had conflicting results. Moreover, metabotropic glutamate receptor antagonists also failed to improve symptoms. The current review summarizes the most recent findings on ND drugs over the last 2 years., Competing Interests: Financial & competing interests disclosure ME Freitas received funding from the Paul and Susan Hansen fellowship award. S Fox has received consultancy from Adamas, Astra Zeneca; Kyowa, Teva, Novartis, Orion, Zambon; Speaker honoraria from the International Parkinson and Movement Disorder Society and American Academy of Neurology; Research funding from Michael J Fox Foundation for PD research, NIH, Parkinson Society Canada and Toronto Western Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Dyskinesias encompass a variety of different hyperkinetic phenomenologies, particularly chorea, dystonia, stereotypies, and akathisia. Levodopa-induced dyskinesia (LID) is one of the main types of drug-induced dyskinesia, occurring in patients with Parkinson's disease (PD) who have been treated with levodopa for long time, but this side effect may be encountered even within a few weeks or months after initiation of levodopa therapy. Based on the temporal pattern in relationship to levodopa dosing, LIDs are divided into "peak-dose dyskinesia," "diphasic dyskinesia," and "wearing off" or "off-period" dyskinesia, of which peak-dose dyskinesia is the most common, followed by off-period, and then diphasic dyskinesia. Treatment strategy includes identifying the kind of dyskinesia and tailoring treatment accordingly. Peak-dose dyskinesia is treated mainly by reducing individual doses of levodopa and adding amantadine and dopamine agonists, whereas off-period dystonia often responds to baclofen and botulinum toxin injections. Diphasic dyskinesias, occurring particularly in patients with young-onset PD, are the most difficult to treat. While fractionation of levodopa dosage is the most frequently utilized strategy, many patients require deep brain stimulation to control their troublesome motor fluctuations and LIDs. A variety of emerging (experimental) drugs currently in development promise to provide better control of LIDs and other levodopa-related complications in the near future.

Dyskinesias encompass a variety of different hyperkinetic phenomenologies, particularly chorea, dystonia, stereotypies, and akathisia. The main types of drug-induced dyskinesias include levodopa-induced dyskinesia (LID) in patients with Parkinson's disease and tardive syndrome (TS), typically present in patients with psychiatric or gastrointenstinal disorders treated with dopamine receptor blocking drugs, also referred to as neuroleptics. Besides preventive measures (i.e., avoiding the use of the offending drugs), general treatment strategies include slow taper of the offending agent and use of dopamine-depleting agents like tetrabenazine. Botulinum toxin may be helpful for wearing off focal dystonia and some forms of tardive dystonia. Deep brain stimulation is usually reserved for patients with disabling motor fluctuations, LID, and for severe TS that cannot be managed medically.

The dyskinesia of Parkinson's Disease is most likely due to excess levels of dopamine in the striatum. The mechanism may be due to aberrant synthesis but also, a deficiency or absence of the Dopamine Transporter. In this study we have examined the proposition that reinstating Dopamine Transporter expression in the striatum would reduce dyskinesia. We transplanted c17.2 cells that stably expressed the Dopamine Transporter into dyskinetic rats. There was a reduction in dyskinesia in rats that received grafts expressing the Dopamine Transporter. Strategies designed to increase Dopamine Transporter in the striatum may be useful in treating the dyskinesia associated with human Parkinson's Disease.

Transcranial direct current stimulation (tDCS) is a non-invasive technique for inducing prolonged functional changes in the human cerebral cortex. This simple and safe neurostimulation technique for modulating motor functions in Parkinson's disease could extend treatment option for patients with movement disorders. We assessed whether tDCS applied daily over the cerebellum (cerebellar tDCS) and motor cortex (M1-tDCS) improves motor and cognitive symptoms and levodopa-induced dyskinesias in patients with Parkinson's disease (PD). Nine patients (aged 60-85 years; four women; Hoehn & Yahr scale score 2-3) diagnosed as having idiopathic PD were recruited. To evaluate how tDCS (cerebellar tDCS or M1-tDCS) affects motor and cognitive function in PD, we delivered bilateral anodal (2 mA, 20 min, five consecutive days) and sham tDCS, in random order, in three separate experimental sessions held at least 1 month apart. In each session, as outcome variables, patients underwent the Unified Parkinson's Disease Rating Scale (UPDRS III and IV) and cognitive testing before treatment (baseline), when treatment ended on day 5 (T1), 1 week later (T2), and then 4 weeks later (T3), at the same time each day. After patients received anodal cerebellar tDCS and M1-tDCS for five days, the UPDRS IV (dyskinesias section) improved (p < 0.001). Conversely, sham tDCS, cerebellar tDCS, and M1-tDCS left the other variables studied unchanged (p > 0.05). Despite the small sample size, our preliminary results show that anodal tDCS applied for five consecutive days over the motor cortical areas and cerebellum improves parkinsonian patients' levodopa-induced dyskinesias.

Background: In late stage Parkinson patients there is an unmet need for new treatments to adequately control motor complications, especially dyskinesias. In several preliminary studies, it has been suggested that applying unilateral low-frequency repetitive transcranial magnetic stimulation (LF rTMS), delivered at the primary motor cortex (MC) or the supplementary motor area (SMA), may reduce levodopa-induced dyskinesias (LID), either in a single or a multiple session stimulation protocol. In our current clinical research, we examined whether single or multiple (accelerated) sham-controlled bilateral LF rTMS session(s) applied to the primary motor cortices are able to reduce levodopa-induced dyskinesias in patients with advanced Parkinson's disease., Methods: During a levodopa challenge test, we first investigated the effect of a single sham-controlled session of LF rTMS (1 Hz) to both left and right primary motor cortical areas on dyskinesias and motor function in nine late-stage Parkinson patients. In a second study, patients were assigned to a five day sham-controlled bilateral motor cortex cross-over accelerated LF rTMS protocol and effects on dyskinesias, motor and executive function and emotional status were assessed., Results: We found no significant clinical change in levodopa-induced dyskinesias and motor function with either stimulation protocol., Conclusions: One or multiple bilateral LF rTMS session(s) applied to the primary motor cortex were unable to reduce levodopa-induced dyskinesias in late-stage Parkinson patients.

Aripiprazole, a dopamine stabilizing atypical antipsychotic is used in treatment of tardive dyskinesia caused by other neuroleptics. Tardive dyskinesia is rarely caused by Aripiprazole and has only been documented in high risk patients i.e., female gender, advanced age, affective illness, coexisting neurological disorders. Here the author describes two atypical cases of tardive dyskinesia associated with Aripiprazole. First case of tardive dyskinesia was observed in a neuroleptic naïve young adult male with paranoid illness after six months of treatment with Aripiprazole upon addition of Fluoxetine and the second case was a middle aged female with affective illness where dyskinetic movements appeared after stopping Aripiprazole. The role of Fluoxetine in causing tardive dyskinesia with Aripiprazole and covert dyskinesia due to Aripiprazole with appropriate management is discussed.

Background: The inhibition of neuronal activity by electrical deep brain stimulation is one of the mechanisms explaining the amelioration of levodopa-induced dyskinesia. However, electrical deep brain stimulation cannot specifically activate or inactivate selected types of neurons., Objectives: We applied optogenetics as an alternative treatment to deep brain stimulation for levodopa-induced dyskinesia, and also to confirm that the mechanism of levodopa-induced dyskinesia amelioration by subthalamic nucleus deep brain stimulation is mediated through neuronal inhibition., Methods: 6-hydroxydopamine-induced hemiparkinsonian rats received injections of hSynapsin1-NpHR-YFP adeno-associated virus (AAV) or hSynapsin1-YFP AAV. Two weeks after viral injections, all rats were treated with daily injections of levodopa. Then, the optic fiber was implanted into the ipsilateral subthalamic nucleus. We performed various behavioral tests to evaluate the changes in levodopa-induced dyskinesias after optogenetic expression and illumination in the subthalamic nucleus., Results: The behavioral tests revealed that optical inhibition of the subthalamic nucleus significantly ameliorated levodopa-induced dyskinesia by reducing the duration of the dyskinesias as well as the severity of axial dyskinesia., Conclusions: These findings will provide a useful foundation for the future development of optogenetic modulation systems that could be considered as an approach to dyskinesia therapy., (© 2016 S. Karger AG, Basel.)

Selective activation of 5-HT1 receptors has been shown to produce near to full suppression of L-DOPA-induced dyskinesia (LID) in animal models of Parkinson's disease; however, a reduction of the therapeutic effect of L-DOPA has been reported in several studies. Conversely, we recently found that increasing the serotonergic tone with chronic administration of the serotonin precursor 5-hydroxy-tryptophan (5-HTP) can reduce LID in 6-OHDA-lesioned rats, without affecting L-DOPA efficacy. To directly compare the effects of selective versus non-selective serotonin receptor activation, here we first tested different acute doses of the 5-HT1A/1B receptor agonist eltoprazine and 5-HTP on LID in order to identify doses of the individual compounds showing similar anti-dyskinetic efficacy in L-DOPA-primed dyskinetic rats. About 50% reduction of LID was observed with 0.1 mg/kg and 24 mg/kg of eltoprazine and 5-HTP, respectively; we then compared the effect of the two drugs, individually and in combination, on L-DOPA-induced stepping test in L-DOPA-naïve parkinsonian animals and LID over three weeks of L-DOPA treatment. Results showed that eltoprazine induced significant worsening of L-DOPA-mediated performance in the stepping test, while 5-HTP did not. Interestingly, combination of 5-HTP with eltoprazine prevented the reduction in the forelimb use induced by eltoprazine. Moreover, 5-HTP and eltoprazine given individually showed similar efficacy also upon chronic treatment, and had additive effect in dampening the appearance of LID when given in combination. Finally, chronic administration of eltoprazine and/or 5-HTP did not affect striatal serotonin innervation, compared to l-DOPA alone, as measured by serotonin transporter expression., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the effect of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) on levodopa-induced peak-dose dyskinesia in patients with Parkinson's disease (PD)., Materials and Methods: A retrospective review was conducted on patients who underwent STN DBS for PD from May 2000 to July 2012. Only patients with levodopa-induced dyskinesia prior to surgery and more than 1 year of available follow-up data after DBS were included. The outcome measures included the dyskinesia subscore of the Unified Parkinson's Disease Rating Scale (UPDRS) part IV (items 32 to 34 of UPDRS part IV) and the levodopa equivalent daily dose (LEDD). The patients were divided into two groups based on preoperative to postoperative LEDD change at 12 months after the surgery: Group 1, LEDD decrease >15%; Group 2, all other patients. Group 2 was further divided by the location of DBS leads., Results: Of the 100 patients enrolled, 67 were in Group 1, while those remaining were in Group 2. Twelve months after STN DBS, Groups 1 and 2 showed improvements of 61.90% and 57.14%, respectively, in the dyskinesia subscore. Group 1 was more likely to experience dyskinesia suppression; however, the association between the groups and dyskinesia suppression was not statistically significant (p=0.619). In Group 2, dyskinesia was significantly decreased by stimulation of the area above the STN in 18 patients compared to stimulation of the STN in 15 patients (p=0.048)., Conclusion: Levodopa-induced dyskinesia is attenuated by STN DBS without reducing the levodopa dosage.

Parkinson's disease (PD) is a neurological disorder characterized by tremors, rigidity and bradykinesia. PD is caused by selective degeneration of the dopaminergic neurons, which originate in the substantia nigra pars compacta (SNc) and project into the striatum. Levodopa is the most effective drug, used in the treatment of PD. However, the long-term use of levodopa produce complications which are highly disabling fluctuations and dyskinesias and representing one of the major challenge to the existing drug therapy of PD. Recent studies has indicated that the pulsatile stimulation of striatal postsynaptic receptors led to sensitization of dopaminergic receptors which leads to levodopa induced dyskinesias. In spite of the extensive research in this field, the pathogenesis of levodopa induced dyskinesia is still unclear. In recent years animal models of PD has provided important information to understand the effect of specific receptors and post-receptor molecular mechanisms underlying the development of dyskinetic movements. The present review is aimed to discuss the neurobiological mechanisms of levodopa induced dyskinesia and the therapeutic strategies to overcome this problem., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Introduction: Chronic treatment with levodopa is associated with the development of motor fluctuations and dyskinesias particularly in young Parkinson patients. In some cases, dyskinesias become so severe that they interfere with normal movement and negatively impact quality of life., Areas Covered: In this review, we discuss benefits and limits of available therapeutic approaches aimed at delaying or managing dyskinesias as well as new strategies that are currently under investigation., Expert Opinion: Among available treatments, monotherapy with dopamine agonists in the early phases of the disease reduces the risk for dyskinesias compared with levodopa. Nevertheless, dopamine agonists are unable to prevent dyskinesias once levodopa is added, which is always required once disease severity progresses. Convincing evidence of dyskinesia improvement has been shown only for deep brain stimulation and to some extent also for duodenal levodopa infusion and subcutaneous apomorphine. These approaches are expensive, have restrictive inclusion criteria and can cause potentially serious side effects. Alternative therapies include drugs targeting nondopaminergic neurotransmitter systems. Amantadine improves dyskinesias but its long-term effect is often unsatisfactory. Glutamatergic and gabaergic compounds have been tested in clinical trials, with promising results. By contrast, adrenergic drugs, fipamezole and idazoxan, did not show antidyskinetic effect.

Regulators of G-protein signalling (RGS) proteins are implicated in striatal G-protein coupled receptor (GPCR) sensitisation in the pathophysiology of l-DOPA-induced abnormal involuntary movements (AIMs), also known as dyskinesia (LID), in Parkinson's disease (PD). In this study, we investigated RGS protein subtype 4 in the expression of AIMs in the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of LID. The effects of RGS4 antisense brain infusion on the behavioural and molecular correlates of l-DOPA priming in 6-OHDA-lesioned rats were assessed. In situ hybridisation revealed that repeated l-DOPA/benserazide treatment caused an elevation of RGS4 mRNA levels in the striatum, predominantly in the lateral regions. The increased expression of RGS4 mRNA in the rostral striatum was found to positively correlate with the behavioural (AIM scores) and molecular (pre-proenkephalin B, PPE-B expression) markers of LID. We found that suppressing the elevation of RGS4 mRNA in the striatum by continuous infusion of RGS4 antisense oligonucleotides, via implanted osmotic mini-pumps, during l-DOPA priming, reduced the induction of AIMs. Moreover, ex vivo analyses of the rostral dorsolateral striatum showed that RGS4 antisense infusion attenuated l-DOPA-induced elevations of PPE-B mRNA and dopamine-stimulated [(35)S]GTPγS binding, a marker used for measuring dopamine receptor super-sensitivity. Taken together, these data suggest that (i) RGS4 proteins play an important pathophysiological role in the development and expression of LID and (ii) suppressing the elevation of RGS4 mRNA levels in l-DOPA priming attenuates the associated pathological changes in LID, dampening its physiological expression. Thus, modulating RGS4 proteins could prove beneficial in the treatment of dyskinesia in PD., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The plasticity of primary motor cortex (M1) in patients with Parkinson's disease (PD) and levodopa-induced dyskinesias (LIDs) is severely impaired. We recently reported in young healthy subjects that inhibitory cerebellar stimulation enhanced the sensorimotor plasticity of M1 that was induced by paired associative stimulation (PAS). This study demonstrates that the deficient sensorimotor M1 plasticity in 16 patients with LIDs could be reinstated by a single session of real inhibitory cerebellar stimulation but not sham stimulation. This was evident only when a sensory component was involved in the induction of plasticity, indicating that cerebellar sensory processing function is involved in the resurgence of M1 plasticity. The benefit of inhibitory cerebellar stimulation on LIDs is known. To explore whether this benefit is linked to the restoration of sensorimotor plasticity of M1, we conducted an additional study looking at changes in LIDs and PAS-induced plasticity after 10 sessions of either bilateral, real inhibitory cerebellar stimulation or sham stimulation. Only real and not sham stimulation had an antidyskinetic effect and it was paralleled by a resurgence in the sensorimotor plasticity of M1. These results suggest that alterations in cerebellar sensory processing function, occurring secondary to abnormal basal ganglia signals reaching it, may be an important element contributing to the maladaptive sensorimotor plasticity of M1 and the emergence of abnormal involuntary movements., (© The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Dyskinesias are one of the most frequent and disabling complications of the long-term treatment of Parkinson's disease (PD). Although the cause is not completely understood, it appears that an imbalance between excitatory and inhibitory inputs from the basal ganglia to the motor cortex leads to overactivation of motor and premotor areas. Overactivation of the supplementary motor area (SMA) has been observed in neuroimaging studies in dyskinetic PD patients. We investigated the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) of the SMA on levodopa-induced dyskinesias (LID) and motor performance in PD. We tested whether longer duration (10days) and higher number of total pulses (1800 pulses) would enhance the beneficial effect. Seventeen dyskinetic PD patients were randomly assigned to real rTMS or sham (placebo) rTMS, and 1Hz rTMS or sham rTMS was applied over the SMA for 10 consecutive days. Patients were assessed at baseline and 1day after the last rTMS with a levodopa challenge test, and video recordings were taken. Dyskinesias and motor performance were rated off-line by two blinded raters using video recordings. After 10days of treatment with rTMS, we observed that 1Hz rTMS delivered over the SMA had decreased LID lasting for 24hours without a change in motor performance, whereas sham rTMS induced no significant change in dyskinesia scores. These results support a possible therapeutic effect of low-frequency rTMS in LID. However, in order to suggest rTMS as an effective treatment, long-term observations and further investigations with a larger patient population are essential., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Levodopa-induced dyskinesias (LIDs) represent one major motor disability of Parkinson's disease (PD) therapy. Thus, research effort is still devoted to finding agents that may improve parkinsonism and concomitantly reduce or avoid dyskinesia. Rodent and nonhuman primate models provide useful tools to study the molecular and neuronal bases of LIDs. Among the various strategies investigated recently, the use of drugs targeting metabotropic glutamate receptors has received large attention. In particular, use of antagonists of the subtype 5 of metabotropic glutamate receptors revealed promising preclinical and clinical results., (© 2014 International Parkinson and Movement Disorder Society.)

3,4-Dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinesia (LID) is a debilitating side effect of long-term dopamine replacement therapy in Parkinson's Disease. At present, there are few therapeutic options for treatment of LID and mechanisms contributing to the development and maintenance of these drug-induced motor complications are not well understood. We have previously shown that pharmacological reduction of cholinergic tone attenuates the expression of LID in parkinsonian mice with established dyskinesia after chronic L-DOPA treatment. The present study was undertaken to provide anatomically specific evidence for the role of striatal cholinergic interneurons by ablating them before initiation of L-DOPA treatment and determining whether it decreases LID. We used a novel approach to ablate striatal cholinergic interneurons (ChIs) via Cre-dependent viral expression of the diphtheria toxin A subunit (DT-A) in hemiparkinsonian transgenic mice expressing Cre recombinase under control of the choline acetyltransferase promoter. We show that Cre recombinase-mediated DT-A ablation selectively eliminated ChIs when injected into striatum. The depletion of ChIs markedly attenuated LID without compromising the therapeutic efficacy of L-DOPA. These results provide evidence that ChIs play a key and selective role in LID and that strategies to reduce striatal cholinergic tone may represent a promising approach to decreasing L-DOPA-induced motor complications in Parkinson's disease.