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Objective: IRF2BPL mutation has been associated with a rare neurodevelopmental disorder with abnormal movements, including dystonia. However, the role of IRF2BPL in dystonia remains elusive. We aimed to investigate IRF2BPL mutations in a Taiwanese dystonia cohort. Methods: A total of 300 unrelated patients with molecularly unassigned isolated (n = 256) or combined dystonia (n = 44) were enrolled between January 2015 and July 2023. The IRF2BPL variants were analyzed based on whole exome sequencing. The in silico prediction of the identified potential pathogenic variant was performed to predict its pathogenicity. We also compared the clinical and genetic features to previous literature reports. Results: We identified one adolescent patient carrying a de novo heterozygous pathogenic variant of IRF2BPL, c.379C>T (p.Gln127Ter), who presented with generalized dystonia, developmental regression, and epilepsy (0.33% of our dystonia cohort). This variant resides within the polyglutamine (poly Q) domain before the first PEST sequence block of the IRF2BPL protein, remarkably truncating the protein structure. Combined with other patients with IRF2BPL mutations in the literature (n = 60), patients with variants in the poly Q domain have a higher rate of nonsense mutations (p < 0.001) and epilepsy (p = 0.008) than patients with variants in other domains. Furthermore, as our index patient, carriers with substitutions before the first PEST sequence block have significantly older age of onset (p < 0.01) and higher non‐epilepsy symptoms, including generalized dystonia (p = 0.003), and ataxia (p = 0.003). Interpretation: IRF2BPL mutation is a rare cause of dystonia in our population. Mutations in different domains of IRF2BPL exhibit different phenotypes. [ABSTRACT FROM AUTHOR]

Background and purpose: Dystonia is a heterogeneous movement disorder, and it remains unclear whether neurodegeneration is involved. Neurofilament light chain (NfL) is a biosignature of neurodegeneration. We aimed to investigate whether plasma NfL levels were elevated and associated with disease severity in patients with dystonia. Method: We enrolled 231 unrelated dystonia patients (isolated dystonia n = 203; combined dystonia n = 28) and 54 healthy controls from movement disorder clinics. Clinical severity was evaluated using the Fahn Marsden Dystonia Rating Scale, the Unified Dystonia Rating Scale, and the Global Dystonia Rating Scale. Blood NfL levels were measured by single‐molecule array. Results: Plasma NfL levels were significantly higher in those with generalized dystonia compared to those with focal dystonia (20.1 ± 8.8 vs. 11.7 ± 7.2 pg/mL; p = 0.01) or controls (p < 0.01), while the level was comparable between the focal dystonia group and controls (p = 0.08). Furthermore, the dystonia combined with parkinsonism group had higher NfL levels than the isolated dystonia group (17.4 ± 6.2 vs. 13.5 ± 7.5 pg/mL; p = 0.04). Notably, whole‐exome sequencing was performed in 79 patients and two patients were identified as having likely pathogenic variants: one had a heterozygous c.122G>A (p.R41H) variant in THAP1 (DYT6) and the other carried a c.1825G>A (p.D609N) substitution in ATP1A3 (DYT12). No significant correlation was found between plasma NfL levels and dystonia rating scores. Conclusion: Plasma NfL levels are elevated in patients with generalized dystonia and dystonia combined with parkinsonism, suggesting that neurodegeneration is involved in the disease process of this subgroup of patients. [ABSTRACT FROM AUTHOR]

Neuronal oscillations at beta frequencies (20-50 Hz) in the cortico-basal ganglia circuits have long been the leading theory for bradykinesia, the slow movements that are cardinal symptoms in Parkinson's disease (PD). The beta oscillation theory helped to drive a frequency-based design in the development of deep brain stimulation therapy for PD. However, in contrast to this theory, here we have found that bradykinesia can be completely dissociated from beta oscillations in rodent models. Instead, we observed that bradykinesia is causatively regulated by the burst-firing pattern of the subthalamic nucleus (STN) in a feed-forward, or efferent-only, mechanism. Furthermore, STN burst-firing and beta oscillations are two independent mechanisms that are regulated by different NMDA receptors in STN. Our results shift the understanding of bradykinesia pathophysiology from an interactive oscillatory theory toward a feed-forward mechanism that is coded by firing patterns. This distinct mechanism may improve understanding of the fundamental concepts of motor control and enable more selective targeting of bradykinesia-specific mechanisms to improve PD therapy., Introduction A cardinal feature of Parkinson's disease (PD) is slow movements, known as bradykinesia. The neuronal activities related to bradykinesia are two electrophysiological landmarks in PD: oscillations, the pathological augmentation [...]

Parkinson's disease (PD) is the most prevalent hypokinetic movement disorder, and symptomatic PD pathogenesis has been ascribed to imbalances between the direct and indirect pathways in the basal ganglia circuitry. Here, we applied glutamate receptor blockers to the subthalamic nucleus (STN) of parkinsonian rats and evaluated locomotor behaviors via single-unit and local-field recordings. Using this model, we found that inhibition of NMDAergic cortico -subthalamic transmission ameliorates parkinsonian motor deficits without eliciting any vivid turning behavior and abolishes electrophysiological abnormalities, including excessive subthalamic bursts, cortico-subthalamic synchronization, and in situ beta synchronization in both the motor cortex and STN. Premotor cortex stimulation revealed that cortico-subthalamic transmission is deranged in PD and directly responsible for the excessive stimulation-dependent bursts and time-locked spikes in the STN, explaining the genesis of PD-associated pathological bursts and synchronization, respectively. Moreover, application of a dopaminergic agent via a microinfusion cannula localized the therapeutic effect to the STN, without correcting striatal dopamine deficiency. Finally, optogenetic overactivation and synchronization of cortico-subthalamic transmission alone sufficiently and instantaneously induced parkinsonian-associated locomotor dysfunction in normal mice. In addition to the classic theory emphasizing the direct-indirect pathways, our data suggest that deranged cortico-subthalamic transmission via the NMDA receptor also plays a central role in the pathophysiology of parkinsonian motor deficits., Introduction According to the classic view, the basal ganglia circuitry is composed of 2 major pathways (1, 2). The excitatory direct pathway and the inhibitory indirect pathway are counterbalanced to [...]

To investigate whether varying practice context during gait training could reduce context dependency and facilitate transfer of improved gait performance to a new context. A single-blind, parallel-group randomized controlled trial. Medical university rehabilitation settings. Forty-nine participants with Parkinson disease were recruited and randomized into the constant (CONS) or varied (VARI) context group. All participants received 12 sessions of treadmill and over-ground gait training. The CONS group was trained in a constant environmental context throughout the study, whereas the VARI group received training in 2 different contexts in an alternating order. The primary outcome was gait performance, including velocity, cadence, and stride length. The participants were assessed in the original training context as well as in a novel context at posttest to determine the influence of changed environmental context on gait performance. Though both groups improved significantly after training, the CONS group showed greater improvement in stride length than the VARI group when assessed in the original practice context. However, the CONS group showed a decreased velocity and stride length in the novel context, whereas the VARI group maintained their performance. Varying practice context could facilitate transfer of improved gait performance to a novel context. [ABSTRACT FROM AUTHOR]

Background and purpose: Multiple system atrophy (MSA) has no definitive genetic or environmental (G‐E) risk factors, and the integrated effect of these factors on MSA etiology remains unknown. This study was undertaken to investigate the integrated effect of G‐E factors associated with MSA and its subtypes, MSA‐P and MSA‐C. Methods: A consecutive case–control study was conducted at two medical centers, and the interactions between genotypes of five previously reported susceptible single nucleotide polymorphisms (SNPs; SNCA_rs3857059, SNCA_rs11931074, COQ2_rs148156462, EDN1_rs16872704, MAPT_rs9303521) and graded exposure (never, ever, current) of four environmental factors (smoking, alcohol, drinking well water, pesticide exposure) were analyzed by a stepwise logistic regression model. Results: A total of 207 MSA patients and 136 healthy controls were enrolled. In addition to SNP COQ2_rs148156462 (TT), MSA risk was correlated with G‐E interactions, including COQ2_rs148156462 (Tc) × pesticide nonexposure, COQ2_rs148156462 (TT) × current smokers, SNCA_rs11931074 (tt) × alcohol nonusers, and SNCA_rs11931074 (GG) × well water nondrinkers (all p < 0.01), with an area under the receiver operating characteristic curve (AUC) of 0.804 (95% confidence interval [CI] = 0.671–0.847). Modulated risk of MSA‐C, with MSA‐P as a control, correlated with COQ2_rs148156462 (TT) × alcohol nondrinkers, SNCA_rs11931074 (GG) × well water ever drinkers, SNCA_rs11931074 (Gt) × well water never drinkers, and SNCA_rs3857059 (gg) × pesticide nonexposure (all p < 0.05), with an AUC of 0.749 (95% CI = 0.683–0.815). Conclusions: Certain COQ2 and SNCA SNPs interact with common environmental factors to modulate MSA etiology and subtype disposition. The mechanisms underlying the observed correlation between G‐E interactions and MSA etiopathogenesis warrant further investigation. [ABSTRACT FROM AUTHOR]

Background and purpose: Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant inherited disorder that manifests as a mixture of cerebellar ataxia, parkinsonism, and polyneuropathy; in type IV SCA3, pure parkinsonism is the only symptom. Currently, no disease‐modifying treatment is available, but variable responses to antiparkinsonism agents have been reported. However, the benefits of deep brain stimulation (DBS) for treating parkinsonism in this subtype of SCA3 remain unclear. Methods: A 39‐year‐old male patient with a rare disorder of type IV SCA3 presented with pure parkinsonism including unilateral resting tremor, rigidity, and bradykinesia at the age of 30 years. Young‐onset Parkinson disease was diagnosed at the age of 32 years. His family history revealed a mild ataxia in his father since the age of 55 years. Genetic testing confirmed an expanded CAG repeated number, with 66 in this case and 63 in his father for SCA3 mutation. Excellent response to levodopa and dopamine agonists in the first 3 years was noted, but wearing‐off phenomena, levodopa‐induced dyskinesia, and severe impulse control disorders later developed. To alleviate drug‐induced complications, he received bilateral subthalamic nucleus deep brain stimulation (STN‐DBS) in the absence of cerebellar signs, depression, and cognitive impairment. Results: As of 2019, no impulsive control disorders, motor fluctuations, or DBS‐related complications were observed during a 4‐year follow‐up, with 66% Unified Parkinson's Disease Rating Scale Part III reduction at medication OFF state noted, whereas levodopa equivalent daily dosage decreased by almost half. Conclusions: STN‐DBS may be considered as adjunct treatment for severe dopa‐related motor/nonmotor complications in patients with parkinsonian phenotype of SCA 3. [ABSTRACT FROM AUTHOR]

An increase in neuronal burst activities in the subthalamic nucleus (STN) is a well-documented electrophysiological feature of Parkinson disease (PD). However, the causal relationship between subthalamic bursts and PD symptoms and the ionic mechanisms underlying the bursts remain to be established. Here, we have shown that T- type C [a.sup.2+] channels are necessary for subthalamic burst firing and that pharmacological blockade of T-type C[a.sup.2+] channels reduces motor deficits in a rat model of PD. N[i.sup.2+], mibefradil, NNC 55-0396, and efonidipine, which inhibited T-type C[a.sup.2+] currents in acutely dissociated STN neurons, but not C[d.sup.2+] and nifedipine, which preferentially inhibited L-type or the other non-T-type C[a.sup.2+] currents, effectively diminished burst activ-ity in STN slices. Topical administration of inhibitors of T-type C[a.sup.2+] channels decreased in vivo STN burst activity and dramatically reduced the locomotor deficits in a rat model of PD. C[d.sup.2+] and nifedipine showed no such electrophysiological and behavioral effects. While low-frequency deep brain stimulation (DBS) has been considered ineffective in PD, we found that lengthening the duration of the low-frequency depolarizing pulse effectively improved behavioral measures of locomotion in the rat model of PD, presumably by decreasing the availability of T-type C[a.sup.2+] channels. We therefore conclude that modulation of subthalamic T-type C[a.sup.2+] cur-rents and consequent burst discharges may provide new strategies for the treatment of PD., Introduction Parkinson disease (PD) is closely related to aberrant corticobasal ganglia loop functions in a state of dopamine deficiency (1, 2). The subthalamic nucleus (STN) has been proposed to play [...]

Background and purpose: Levodopa‐induced dyskinesia (LID) is a common motor complication in patients with Parkinson's disease (PD). Although amantadine is indicated for LID treatment, it is uncertain whether early treatment with amantadine reduces the risk of LID in patients with PD. We aimed to evaluate the association between amantadine treatment and LID onset in patients with early‐stage PD. Methods: This was a hospital‐based retrospective cohort study that used electronic medical records from January 1, 2009 to October 31, 2016. The effect of amantadine on LID onset was compared with those of anticholinergics and monoamine oxidase type B inhibitors in patients with PD. Propensity‐score weighting and landmark analysis were used to reduce potential confounding. The time to LID onset was analyzed using Cox models. Sensitivity analyses were performed to determine the robustness of the results. Results: The analyses included 807, 661, and 518 patients at 6‐, 12‐, and 18‐month landmark points, respectively. Amantadine use was associated with delayed LID onset in the 6‐ and 12‐month landmark analyses, with adjusted hazard ratios of 0.65 (95% confidence interval [CI] = 0.49–0.86) and 0.64 (95% CI = 0.47–0.88), respectively. Sensitivity analysis findings were comparable to those of the main analysis. Conclusions: Early treatment with amantadine may delay LID onset more than treatment with other symptomatic agents. Further studies are needed to elucidate the mechanism of amantadine in LID onset delay and to validate our findings. [ABSTRACT FROM AUTHOR]

BACKGROUND: Recent advances in technology have warranted the use of wearable sensors to monitor gait and posture. However, the psychometric properties of using wearable devices to measure gait-related outcomes have not been fully established in patients with Parkinson's disease (PD). OBJECTIVE: This study aimed to investigate the test-retest reliability of body-worn sensors for gait evaluation in people with PD. Additionally, the influence of disease severity on the reliability was determined. METHODS: Twenty individuals with PD were recruited. During the first evaluation, the participants wore inertial sensors on their shoes and walked along a walkway thrice at their comfortable walking speed. The participants were then required to return to the lab after 3–5 days to complete the second evaluation with the same study procedure. Test-retest reliability of gait-related outcomes were calculated. To determine whether the results would be affected by disease severity, reliability was re-calculated by subdividing the participants into early and mid-advanced stages of the disease. RESULTS: The results showed moderate to good reliability (ICC = 0.64–0.87) of the wearable sensors for gait assessment in the general population with PD. Subgroup analysis showed that the reliability was higher among patients at early stages (ICC = 0.71–0.97) compared to those at mid-advanced stages (ICC = 0.65–0.81) of PD. CONCLUSIONS: Wearable sensors could reliably measure gait parameters in people with PD, and the reliability was higher among individuals at early stages of the disease compared to those at mid-advanced stages. Absolute reliability values were calculated to act as references for future studies. [ABSTRACT FROM AUTHOR]

Purpose: Dystonia type 6 (DYT6) is an autosomal dominant monogenic movement disorder that often involves craniocervical and laryngeal regions, but can in rare circumstance present as trunk dystonia or severe scoliosis. Deep brain stimulation of the globus pallidus internus (GPi-DBS) has yielded favorable results in the treatment of DYT6 patients. This report describes the case of a 14-year-old male adolescent with DYT6 dystonia and severe scoliosis who was successfully treated by GPi DBS. Patients and Methods: The diagnosis of DYT6 dystonia was made after excluding other etiologies and was confirmed by next-generation sequencing. The patient underwent bilateral GPi-DBS implantation surgery under general anesthesia. Results: The patient's Burke–Fahn–Marsden Dystonia Rating Scale score was 24 before surgery and decreased to 13.5 at 3 months, 3 at 6 months, and 2 at 12 months after bilateral GPi-DBS, corresponding to a 91% improvement from baseline to 12 months post-surgery. The patient's scoliosis improved significantly within 6 months after DBS. No complications occurred during surgery. Conclusion: An adolescent DYT6 patient with dystonia-related severe scoliosis was treated by bilateral GPi-DBS. The patient had an excellent outcome at 12 months after surgery, which prevented him from developing severe spinal deformity and disability. Early diagnosis of dystonia in adolescent patients can lead to timely and effective treatment. The etiology of severe scoliosis in adolescents should be carefully evaluated and differential diagnosis including dystonia should be considered. GPi-DBS in patients with DYT6 dystonia can prevent deformity. [ABSTRACT FROM AUTHOR]

Background: Recent evidence indicates that lipophilic statins have a neuroprotective benefit in animal models of Parkinson's disease (PD). The objective of this study was to evaluate whether lovastatin has the potential to slow motor symptom progression in patients with early‐stage PD. Methods: This double‐blind, randomized, placebo‐controlled trial enrolled 77 patients with early‐stage PD between May 23, 2017, and July 12, 2018, with follow‐up ending September 1, 2019. Lovastatin 80 mg/day or placebo with 1:1 randomization was administered for 48 weeks. Mean change in the parts I–III scores of the Movement Disorder Society–Unified Parkinson's Disease Rating Scale (MDS‐UPDRS), changes in the striatal dopamine uptake ratio measured by 18F‐dopa PET scan, and changes in PD medications between baseline and the week 48 visit were measured. Results: Of the 77 randomized patients, 70 (90.9%) completed the study. There was a slightly beneficial trend of the MDS‐UPDRS motor score in the lovastatin group (−3.18 ± 5.50) compared with the placebo group (−0.50 ± 6.11); P = 0.14 adjusted for age, sex, disease duration, and baseline LEDD. Mean percentage change in the striatal 18F‐dopa uptake ratio deteriorated less in the lovastatin group than in the placebo group on the dominant side of caudate (1.2% ± 7.3% vs −7.1% ± 8.2%, P < 0.01) and putamen (2.3% ± 7.1% vs −6.4% ± 8.1%, P < 0.01). We found no between‐group differences in the change in part I or part II MDS‐UPDRS scores. Lovastatin was generally well tolerated. Conclusions: Lovastatin treatment in patients with early‐stage PD was associated with a trend of less motor symptom worsening and was well tolerated. A future larger long‐term follow‐up study is needed to confirm our findings. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Recent genetic progress has allowed for the molecular diagnosis of Parkinson's disease. However, genetic causes of PD vary widely in different ethnicities. Mutational frequencies and clinical phenotypes of genes associated with PD in Asian populations are largely unknown. The objective of this study was to identify the mutational frequencies and clinical spectrums of multiple PD-causative genes in a Taiwanese PD cohort.Methods: A total of 571 participants including 324 patients with early-onset parkinsonism (onset age, <50 years) and 247 parkinsonism pedigrees were recruited at a tertiary referral center in Taiwan from 2002 to 2017. Genetic causes were identified by an integrated approach including gene dosage analysis, a targeted next-generation sequencing panel containing 40 known PD-causative genes, repeat-primed polymerase chain reaction, and whole-exome sequencing analysis.Results: Thirty of the 324 patients with early-onset parkinsonism (9.3%) were found to carry mutations in Parkin, PINK1, or PLA2G6 or had increased trinucleotide repeats in SCA8. Twenty-nine of 109 probands with autosomal-recessive inheritance of parkinsonism (26.6%) were found to carry mutations in Parkin, PINK1, GBA, or HTRA2. The genetic causes for the 138 probands with an autosomal-dominant inheritance pattern of parkinsonism were more heterogeneous. Seventeen probands (12.3%) carried pathogenic mutations in LRRK2, VPS35, MAPT, GBA, DNAJC13, C9orf72, SCA3, or SCA17. A novel missense mutation in the UQCRC1 gene was found in a family with autosomal-dominant inheritance parkinsonism via whole-exome sequencing analysis.Conclusions: Our findings provide a better understanding of the genetic architecture of PD in eastern Asia and broaden the clinical spectrum of PD-causing mutations. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Social functioning is crucial for the determinants of Parkinson's disease (PD) with dementia; however, there is no social functioning scale applicable to PD. Objective: This study aimed to develop a social functioning scale specific to PD (PDSFS) and provide a cut-off score to improve diagnosis accuracy. Methods: The items were developed through literature, interview patients, and PD expertise. After the pilot study, one hundred fifty-seven patients and 74 healthy participants were enrolled and completed the Mini-Mental State Examination, Clock Drawing Test, Activities of Daily Living, Neuropsychiatric Inventory, Adaptive Behavior Assessment System–Second Edition (ABAS–II) and part III of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS–UPDRS). Results: The final PDSFS has 23 items. The exploratory factor analysis revealed three factors, including "Family Life, Hobbies and Self-Care", "Interpersonal Relationship and Recreational Leisure", and "Social Bond". The internal consistency coefficient was 0.883, and the test-retest reliability was 0.774, respectively. The total score of the PDSFS was significantly related to the total score of ABAS–II (r = 0.609, p < 0.001), and was not correlated with the third part of MDS–UPDRS (p = 0.736). A significant intergroup difference was found (p < 0.001), and the healthy controls had the highest PDSFS score, followed by non-demented PD and PD dementia. The optimal cut-off score for PD patients with dementia was 39 (sensitivity: 0.735; specificity: 0.857). Conclusions: PDSFS is a practical and psychometrically sound tool to access the social functioning of the PD population. [ABSTRACT FROM AUTHOR]

Background and Purpose: Freezing of gait (FOG) is a debilitating gait disorder in people with Parkinson's disease (PD). While various neuroimaging techniques have been used to investigate the pathophysiology of FOG, changes in corticomotor excitability associated with FOG have yet to be determined. Research to date has not concluded if changes in corticomotor excitability are associated with gait disturbances in this patient population. This study aimed to use transcranial magnetic stimulation (TMS) to investigate corticomotor excitability changes associated with FOG. Furthermore, the relationship between corticomotor excitability and gait performances would be determined. Methods: Eighteen participants with PD and FOG (PD + FOG), 15 without FOG (PD − FOG), and 15 non-disabled adults (Control) were recruited for this study. Single and paired-pulse TMS paradigms were used to assess corticospinal and intracortical excitability, respectively. Gait performance was measured by the 10-Meter-Walk test. Correlation analysis was performed to evaluate relationships between TMS outcomes and gait parameters. Results: Compared with the Control group, the PD + FOG group showed a significantly lower resting motor threshold and reduced short intracortical inhibition (SICI). Correlation analysis revealed a relationship between resting motor evoked potential and step length, and between SICI and walking velocity in the Control group. While the silent period correlated with step length in the PD − FOG group, no significant relationship was observed in the PD + FOG group. Discussion and Conclusion: Compared to the Control group, the PD + FOG group exhibited reduced corticomotor inhibition. Distinct correlations observed among the three groups suggest that the function of the corticomotor system plays an important role in mediating walking ability in non-disabled adults and people with PD − FOG, while people with PD + FOG may rely on neural networks other than the corticomotor system to control gait. [ABSTRACT FROM AUTHOR]

Highlights • Some neurological disorders share common pathophysiological features. • Glutamatergic hyperactivity-related excitotoxicity is involved in neurodegeneration. • Ceftriaxone increases glutamate transporter-1 expression and glutamate reuptake and suppresses excitotoxicity. • Ceftriaxone may have potential for treating neuronal disorders. Abstract Several neurodegenerative disorders, namely Parkinson's disease dementia, dementia with Lewy bodies, and Alzheimer's disease, share common pathophysiological features, such as (1) cognitive deficits, (2) glutamatergic hyperactivity-related excitotoxicity, and (3) deposition of α-synuclein (α-syn) and β-amyloid (Aβ). Ceftriaxone (CEF) is a well-tested and safe drug that has been used as an antibiotic for several decades. Recent studies have demonstrated the following effects of CEF: (1) increasing glutamate transporter-1 expression and glutamate reuptake and suppressing excitotoxicity, (2) binding well with α-syn and inhibition of α-syn polymerization, (3) modulating expression of genes related to Aβ metabolism, and (4) enhancing neurogenesis and recovery of neuronal density. In addition, our data revealed that CEF ameliorates seizure and abnormal neuronal firing in the brain. These results suggest the potential of CEF in treating neuronal disorders. This paper addresses the effects and pharmacology of CEF. [ABSTRACT FROM AUTHOR]

Pedunculopontine nucleus region deep brain stimulation (DBS) is a promising but experimental therapy for axial motor deficits in Parkinson's disease (PD), particularly gait freezing and falls. Here, we summarise the clinical application and outcomes reported during the past 10 years. The published dataset is limited, comprising fewer than 100 cases. Furthermore, there is great variability in clinical methodology between and within surgical centers. The most common indication has been severe medication refractory gait freezing (often associated with postural instability). Some patients received lone pedunculopontine nucleus DBS (unilateral or bilateral) and some received costimulation of the subthalamic nucleus or internal pallidum. Both rostral and caudal pedunculopontine nucleus subregions have been targeted. However, the spread of stimulation and variance in targeting means that neighboring brain stem regions may be implicated in any response. Low stimulation frequencies are typically employed (20-80 Hertz). The fluctuating nature of gait freezing can confound programming and outcome assessments. Although firm conclusions cannot be drawn on therapeutic efficacy, the literature suggests that medication refractory gait freezing and falls can improve. The impact on postural instability is unclear. Most groups report a lack of benefit on gait or limb akinesia or dopaminergic medication requirements. The key question is whether pedunculopontine nucleus DBS can improve quality of life in PD. So far, the evidence supporting such an effect is minimal. Development of pedunculopontine nucleus DBS to become a reliable, established therapy would likely require a collaborative effort between experienced centres to clarify biomarkers predictive of response and the optimal clinical methodology. © 2017 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) conventionally target at basal ganglia or thalamic structures, modulating nodal points in the cortico-basal ganglia circuit, in order to effectively treat various movement disorders, including Parkinson's disease, tremor and dystonia (especially mobile type dystonia). However, there are still some other movement disorders, such as dystonia (especially fixed type dystonia), ataxia and freezing of gait, which are not responding well to the current DBS therapy. Cerebellum, similar to basal ganglia, also plays a critical role in the pathophysiology of movement disorders. Deep cerebellar structures, such as dentate nucleus or superior cerebellar peduncle, are noticed for their potential role as treatment targets in movement disorders in recent years. With increasing evidences of animal DBS experiments, recent clinical human subject studies reported that some movement disorders patients not responding to DBS with conventional targets, may benefit significantly from cerebellar DBS. These pioneer study results are invaluable for understanding the clinical use of cerebellar DBS for treatment of movement disorders. We review the recent data of cerebellar DBS performed by different groups and summarize the indications, surgical targets, programming details and outcomes in these clinical reports. We then synthesize the current pathophysiological study of cerebellum on different movement disorders and discuss the potential mechanism of action of cerebellar DBS. In addition to basal ganglia, it is important to study new DBS targets in the cerebellum for more comprehensive treatment of movement disorders. • Cerebellum plays a critical role in movement disorders, such as dystonia, tremor and ataxia. • Deep brain stimulation (DBS) targeting at cerebellum can be an effective tool to treat these movement disorders. • Key targets for cerebellar DBS include dentate nucleus (DN) and superior cerebellar peduncle (SCP). • Further exploration into the pathophysiology and the mechanisms of action are necessary for future development. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is one of the most prevalent movement disorder caused by degeneration of the dopaminergic neurons in substantia nigra pars compacta. Deep brain stimulation (DBS) at the subthalamic nucleus (STN) has been a new and effective treatment of PD. It is interesting how a neurological disorder caused by the deficiency of a specific chemical substance (i.e., dopamine) from one site could be so successfully treated by a pure physical maneuver (i.e., DBS) at another site. STN neurons could discharge in the single-spike or the burst modes. A significant increase in STN burst discharges has been unequivocally observed in dopamine-deprived conditions such as PD, and was recently shown to have a direct causal relation with parkinsonian symptoms. The occurrence of burst discharges in STN requires enough available T-type Ca currents, which could bring the relatively negative membrane potential to the threshold of firing Na spikes. DBS, by injection of negative currents into the extracellular space, most likely would depolarize the STN neuron and then inactivate the T-type Ca channel. Burst discharges are thus decreased and parkinsonian locomotor deficits ameliorated. Conversely, injection of positive currents into STN itself could induce parkinsonian locomotor deficits in animals without dopaminergic lesions. Local application of T-type Ca channel blockers into STN would also dramatically decrease the burst discharges and improve parkinsonian locomotor symptoms. Notably, zonisamide, which could inhibit T-type Ca currents in STN, has been shown to benefit PD patients in a clinical trial. From the pathophysiological perspectives, PD can be viewed as a prototypical disorder of 'brain arrhythmias'. Modulation of relevant ion channels by physical or chemical maneuvers may be important therapeutic considerations for PD and other diseases related to deranged neural rhythms. [ABSTRACT FROM AUTHOR]

Mutations in the angiogenic factor, angiogenin (ANG), have been identified in patients with both familial and sporadic amyotrophic lateral sclerosis (ALS) and are thought to have a neuroprotective function. Parkinsonism has been noted in kindreds with ANG mutations and variants in the ANG gene have been found to associate with PD in two Caucasian populations. We therefore hypothesized that mutations in ANG may also contribute to idiopathic Parkinson's disease (PD). We sequenced ANG gene in a total of 1498 participants comprising 750 PD patients and 748 age/gender matched controls from Taiwan. We identified one novel synonymous substitution, c.C100T (p.L10L), in a single heterozygous state in one PD patient, which was not observed in controls. The clinical phenotypes and [99mTc]-TORDAT-SPECT images of the p.L10L carrier were similar to that seen in idiopathic PD. In addition, we also identified one common variant, c.T330G (p.G110G, rs11701), which was previously reported to associate with PD risk in Caucasians. However, the frequency of TG/GG genotype was comparable between PD cases and controls (odds ratio: 0.85, 95% confidence interval: 0.29–2.55, P = 0.78). Our results did not support that ANG rs11701 variant is a genetic risk factor for PD in our population. We conclude that mutations in ANG are not a common cause for idiopathic PD. [ABSTRACT FROM AUTHOR]

Neurodegeneration with brain iron accumulation (NBIA) is a genetically and phenotypically heterogeneous group of inherited neurodegenerative disorder characterized by basal ganglia iron deposition. Mutations in Pantothenate Kinase 2 (PANK2) are major genetic causes for patients with NBIA. The location of PANK2 in the mitochondria suggests mutant PANK2 causing mitochondrial dysfunction in the pathogenesis of NBIA. Here, we used the Sendai virus delivery system to generate induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells of a female patient having compound heterozygous mutations in PANK2. This cellular model could provide a platform for pathophysiological studies of NBIA in the future. [ABSTRACT FROM AUTHOR]

The inosine monophosphate dehydrogenase gene (IMPDH2) was recently reported as a novel gene associated with autosomal dominantly inherited dystonia. We investigated 245 Taiwanese patients with molecularly unassigned isolated or combined dystonia without features of neurodevelopmental disorders and found none had pathogenic variants. Our findings suggest that IMPDH2 may not play a major role in dystonia. • No pathogenic variants of IMPDH2 were identified in Taiwanese dystonia patients. • The IMPDH2 gene may not play a major role in dystonia in our population. • Future IMPDH2 screening in dystonia with neurodevelopmental disorders is needed. [ABSTRACT FROM AUTHOR]

Neuronal oscillations at beta frequencies (20-50 Hz) in the cortico-basal ganglia circuits have long been the leading theory for bradykinesia, the slow movements that are cardinal symptoms in Parkinson's disease (PD). The beta oscillation theory helped to drive a frequency-based design in the development of deep brain stimulation therapy for PD. However, in contrast to this theory, here we have found that bradykinesia can be completely dissociated from beta oscillations in rodent models. Instead, we observed that bradykinesia is causatively regulated by the burst-firing pattern of the subthalamic nucleus (STN) in a feed-forward, or efferent-only, mechanism. Furthermore, STN burst-firing and beta oscillations are two independent mechanisms that are regulated by different NMDA receptors in STN. Our results shift the understanding of bradykinesia pathophysiology from an interactive oscillatory theory toward a feed-forward mechanism that is coded by firing patterns. This distinct mechanism may improve understanding of the fundamental concepts of motor control and enable more selective targeting of bradykinesia-specific mechanisms to improve PD therapy. [ABSTRACT FROM AUTHOR]