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Directional deep brain stimulation (dDBS) is preferred by patients with advanced Parkinson’s disease (PD) and by programming neurologists. However, real-life data of dDBS use is still scarce. We reviewed the clinical data of 53 PD patients with dDBS to 18 months of follow-up. Directional stimulation was favored in 70.5% of dDBS leads, and single segment activation (SSA) was used in 60% of dDBS leads. Current with SSA was significantly lower than with other stimulation types. During the 6-month follow-up, a 44% improvement in the Unified Parkinson’s Disease Rating Scale (UPDRS-III) points and a 43% decline in the levodopa equivalent daily dosage (LEDD) was observed. After 18 months of follow-up, a 35% LEDD decrease was still noted. The Hoehn and Yahr (H&Y) stages and scores on item no 30 “postural stability” in UPDRS-III remained lower throughout the follow-up compared to baseline. Additionally, dDBS relieved non-motor symptoms during the 6 months of follow-up. Patients with bilateral SSA had similar clinical outcomes to those with other stimulation types. Directional stimulation appears to effectively reduce both motor and non-motor symptoms in advanced PD with minimal adverse effects in real-life clinical care.

BACKGROUND There are limited data regarding the effectiveness of levodopa-carbidopa intestinal gel (LCIG) for dyskinesia. OBJECTIVE Compare the effectiveness of LCIG versus oral optimized medical treatment (OMT) for dyskinesia in patients with advanced Parkinson's disease (PD) using the Unified Dyskinesia Rating Scale (UDysRS). METHODS This phase 3b, open-label, multicenter, 12-week, interventional study (NCT02799381) randomized 63 LCIG naive patients with advanced PD (UDysRS ≥30) to LCIG (N = 30) or OMT (N = 33) treatment. Dyskinesia impact was assessed at baseline through week 12 using the UDysRS. PD-related motor and non-motor symptoms, and quality of life (QoL) were also assessed. RESULTS Dyskinesias measured by UDysRS were significantly reduced in the LCIG group (n = 24; -17.37 ± 2.79) compared with the OMT group (n = 26; -2.33 ± 2.56) after 12 weeks (-15.05 ± 3.20; 95% CI, -21.47 to -8.63; P

Alpha-pyrrolidinovalerophenone (alpha-PVP) is a designer drug, the mechanism of action of which resembles that of cocaine and amphetamine. New data about the side effects of alpha-PVP are emerging. We present a case report of an acute ischemic stroke following the recreational use of alpha-PVP. The ischemic lesions were located in the middle cerebral artery and deep watershed areas of the left cerebral hemisphere. Occupational therapy and physiotherapy were initiated, and the patient was discharged with only a mild right hemiparesis.

Background Deep brain stimulation of the globus pallidus interna (GPi‐DBS) is a highly efficacious treatment for cervical dystonia. Typically, the treatment response is delayed, appearing and increasing even months after implantation. However, it is not known how fast the symptoms reappear and whether there is a long‐term therapeutic effect after the stimulation is discontinued. Objectives To study symptom reappearance after switching GPi‐DBS off in cervical dystonia. Methods Twelve patients with bilateral GPi‐DBS were included in the study. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) was evaluated during the study with DBS stimulation on, after switching the stimulation off and 2 days after the stimulation was switched off. Presurgical symptom severity and best postsurgical response were extracted from the hospital records. Results At the time of the investigation, GPi‐DBS was associated with 67 (SD 39)% symptom improvement of presurgical symptoms severity (P = 0.001). Symptom improvement decreased to 27 (53)% (P = 0.046) (n = 12) acutely after switching the stimulation off and was further reduced to 4 (56)% 2 days after discontinuation (P = 0.01) (n = 11), reaching the presurgical level (P = 0.42). In descriptive analyses, older age was associated with faster worsening of symptoms (P

Objective To evaluate motor fluctuations in patients with advanced Parkinson’s disease (PD) using a small-sized wearable device for surface electromyography (EMG) with accelerometry (ACC) for 24 hours. Methods Seven PD patients with medication were measured once, and nine patients with directional deep brain stimulation (dDBS) twice: before and after the dDBS reprogramming. EMG and ACC parameters were compared with clinical rating scores and patients’ home diaries. Results The combination of EMG and ACC parameters (first principal component PC1) correlated significantly with patient’s condition as quantified by the motor score of Unified Parkinson’s Disease Rating Scale and it changed significantly with dDBS reprogramming in line with decreased PD symptoms. Monitoring data detected in comparison with the home diaries: 91 % concordance with tremor, 76 % with rigidity, and 74 % with dyskinesia. In the DBS group, the wake-up time with abnormal neuromuscular function was reduced with reprogramming in all except one patient based on measurements. Conclusions A wearable device measuring simultaneously both muscle activity and motion can provide continuous and dynamic information about patient’s condition and motor fluctuations at home. Significance The present method may help to modify pharmacologic management and DBS treatment in advanced PD.

Funding Information: The authors acknowledge the Finnish National Agency for Education and Päivikki and Sakari Sohlberg Foundation for funding for Olesia Korsun, and the Academy of Finland (grant number 321460) and Paulo Foundation for funding for Hanna Renvall. The authors acknowledge Kati Valkonen for providing the clinical patient data, and all the patients for their participation. Open access funding enabled and organized by Projekt DEAL. Publisher Copyright: © 2022 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd. Despite optimal oral drug treatment, about 90% of patients with Parkinson's disease develop motor fluctuation and dyskinesia within 5–10 years from the diagnosis. Moreover, the patients show non-motor symptoms in different sensory domains. Bilateral deep brain stimulation (DBS) applied to the subthalamic nucleus is considered the most effective treatment in advanced Parkinson's disease, and it has been suggested to affect sensorimotor modulation and relate to motor improvement in patients. However, observations on the relationship between sensorimotor activity and clinical improvement have remained sparse. Here, we studied the somatosensory evoked magnetic fields in 13 right-handed patients with advanced Parkinson's disease before and 7 months after stimulator implantation. Somatosensory processing was addressed with magnetoencephalography during alternated median nerve stimulation at both wrists. The strengths and the latencies of the ~60-ms responses at the contralateral primary somatosensory cortices were highly variable but detectable and reliably localized in all patients. The response strengths did not differ between preoperative and postoperative DBSON measurements. The change in the response strength between preoperative and postoperative condition in the dominant left hemisphere of our right-handed patients correlated with the alleviation of their motor symptoms (p =.04). However, the result did not survive correction for multiple comparisons. Magnetoencephalography appears an effective tool to explore non-motor effects in patients with Parkinson's disease, and it may help in understanding the neurophysiological basis of DBS. However, the high interindividual variability in the somatosensory responses and poor tolerability of DBSOFF condition warrants larger patient groups and measurements also in non-medicated patients.

Gut microbiota alterations in Parkinson’s disease (PD) have been found in several studies and are suggested to contribute to the pathogenesis of PD. However, previous results could not be adequately adjusted for a potential confounding effect of PD medication and disease duration, as almost all PD participants were already using dopaminergic medication and were included several years after diagnosis. Here, the gut microbiome composition of treatment-naïve de novo PD subjects was assessed compared to healthy controls (HC) in two large independent case-control cohorts (n=136 and 56 PD, n=85 and 87 HC), using 16S-sequencing of fecal samples. Relevant variables such as technical batches, diet and constipation were assessed for their potential effects.Overall gut microbiome composition differed between PD and HC in both cohorts, suggesting gut microbiome alterations are already present in de novo PD subjects at the time of diagnosis, without the possible confounding effect of dopaminergic medication. Although no differentially abundant taxon could be replicated in both cohorts, multiple short chain fatty acids (SCFA) producing taxa were decreased in PD in both cohorts. In particular, several taxa belonging to the family Lachnospiraceae were decreased in abundance. Fewer taxonomic differences were found compared to previous studies, indicating smaller effect sizes in de novo PD.Trial registrationDUPARC: NCT04180865NMDAT: NCT02650843

Background The neurophysiological correlates of gastrointestinal symptoms (GISs) in Parkinson's disease (PD) are not well understood. It has been proposed that in patients with a gastrointestinal origin of PD dopaminergic neurodegeneration would be more symmetric. Objectives The aim is to assess the associations between GISs and asymmetry of nigrostriatal dopaminergic neurodegeneration in PD. Methods Ninety PD patients were assessed using motor and GIS scales and I-123-FP-CIT SPECT. We calculated the asymmetry index and the predominant side of motor symptoms and dopamine transporter (DAT) imaging defect and assessed their association with GISs. Results There were no significant differences in GISs between symmetric and asymmetric dopaminergic defect. Left predominant defect was related to more GIS and higher constipation scores. Conclusions GISs were associated with left predominant reduction in putaminal DAT binding but not asymmetry per se. It remains open whether left-sided DAT deficit is related to more pronounced GI involvement or symptom perception in PD. (c) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Exaggerated subthalamic beta oscillatory activity and increased beta range cortico-subthalamic synchrony have crystallized as the electrophysiological hallmarks of Parkinson's disease. Beta oscillatory activity is not tonic but occurs in 'bursts' of transient amplitude increases. In Parkinson's disease, the characteristics of these bursts are altered especially in the basal ganglia. However, beta oscillatory dynamics at the cortical level and how they compare with healthy brain activity is less well studied. We used magnetoencephalography (MEG) to study sensorimotor cortical beta bursting and its modulation by subthalamic deep brain stimulation in Parkinson's disease patients and age-matched healthy controls. We show that the changes in beta bursting amplitude and duration typical of Parkinson's disease can also be observed in the sensorimotor cortex, and that they are modulated by chronic subthalamic deep brain stimulation, which, in turn, is reflected in improved motor function at the behavioural level. In addition to the changes in individual beta bursts, their timing relative to each other was altered in patients compared to controls: bursts were more clustered in untreated Parkinson's disease, occurring in 'bursts of bursts', and re-burst probability was higher for longer compared to shorter bursts. During active deep brain stimulation, the beta bursting in patients resembled healthy controls' data. In summary, both individual bursts' characteristics and burst patterning are affected in Parkinson's disease, and subthalamic deep brain stimulation normalizes some of these changes to resemble healthy controls' beta bursting activity, suggesting a non-invasive biomarker for patient and treatment follow-up.

Altres ajuts: Projekt DEAL; German Research Foundation (Grant KFO 219). To identify predictors of 36-month follow-up quality of life (QoL) outcome after bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD). In this ongoing, prospective, multicenter international study (Cologne, Manchester, London) including 73 patients undergoing STN-DBS, we assessed the following scales preoperatively and at 6-month and 36-month follow-up: PD Questionnaire-8 (PDQ-8), NMSScale (NMSS), Scales for Outcomes in PD (SCOPA)-motor examination, -activities of daily living, and -complications, and levodopa equivalent daily dose (LEDD). We analyzed factors associated with QoL improvement at 36-month follow-up based on (1) correlations between baseline test scores and QoL improvement, (2) step-wise linear regressions with baseline test scores as independent and QoL improvement as dependent variables, (3) logistic regressions and receiver operating characteristic curves using a dichotomized variable "QoL responders"/"non-responders". At both follow-ups, NMSS total score, SCOPA-motor examination, and -complications improved and LEDD was reduced significantly. PDQ-8 improved at 6-month follow-up with subsequent decrements in gains at 36-month follow-up when 61.6% of patients were categorized as "QoL non-responders". Correlations, linear, and logistic regression analyses found greater PDQ-8 improvements in patients with younger age, worse PDQ-8, and worse specific NMS at baseline, such as 'difficulties experiencing pleasure' and 'problems sustaining concentration'. Baseline SCOPA scores were not associated with PDQ-8 changes. Our results provide evidence that 36-month QoL changes depend on baseline neuropsychological and neuropsychiatric non-motor symptoms burden. These findings highlight the need for an assessment of a wide range of non-motor and motor symptoms when advising and selecting individuals for DBS therapy.

Deep brain stimulation (DBS) has proven its clinical efficacy in Parkinson's disease (PD), but its exact mechanisms and cortical effects continue to be unclear. Subthalamic (STN) DBS acutely modifies auditory evoked responses, but its long-term effect on auditory cortical processing remains ambiguous. We studied with magnetoencephalography the effect of long-term STN DBS on auditory processing in patients with advanced PD. DBS resulted in significantly increased contra-ipsilateral auditory response latency difference at ~100 ms after stimulus onset compared with preoperative state. The effect is likely due to normalization of neuronal asynchrony in the auditory pathways. The present results indicate that STN DBS in advanced PD patients has long-lasting effects on cortical areas outside those confined to motor processing. Whole-head magnetoencephalography provides a feasible tool to study motor and non-motor neural networks in PD, and to track possible changes related to cortical reorganization or plasticity induced by DBS.

BACKGROUND: Levodopa‐carbidopa intestinal gel (LCIG) effectively reduces off time and dyskinesia and increases on time in advanced Parkinson's disease (PD). However, patients with LCIG‐infusion experience frequent complications and some discontinue treatment early on. OBJECTIVES: The objectives of this study were to find predictive factors for early dropout from the LCIG infusion, analyze the treatment burden on the tertiary health care system, and explore changes in medication during the LCIG treatment. METHODS: LCIG‐infusion was administrated to 103 patients between July 2006 and May 2020 at the Helsinki University Hospital, accumulating 350 years of follow‐up data. We evaluated, retrospectively, changes in medication during treatment, discontinuation of the infusion, and adverse events from the patient records. RESULTS: Living alone was a predictive factor for early dropout (OR = 3.88; 95% CI = 1.03–14.66; P = 0.045). The treatment burden on the tertiary health care system increased after the initiation of LCIG infusion mostly because of common complications related to the infusion system (median change of in‐ and out‐patient visits +1, P = 0.03). Mean levodopa equivalent daily dose (LEDD) rose from baseline to 6 months (1246.7 vs. 1684.9, P = 0.001) and stabilized thereafter. Patients commonly switched from “polypharmacy” to “LCIG‐only” or “LCIG + oral levodopa” medication‐groups during long‐term treatment. CONCLUSIONS: Recurrent complications related to the infusion system increase the treatment burden on tertiary healthcare system after the initiation of LCIG‐infusion. Most patients continue long‐term with the infusion. Few patients discontinue infusion during the first year after initiation and living alone appears to be a risk factor for this outcome.

Background: Several publications have described differences in cross-sectional comparisons of gut microbiota between patients with Parkinson's disease and control subjects, with considerable variability of the reported differentially abundant taxa. The temporal stability of such microbiota alterations and their relationship to disease progression have not been previously studied with a high-throughput sequencing based approach. Methods: We collected clinical data and stool samples from 64 Parkinson's patients and 64 control subjects twice, on average 2.25 years apart. Disease progression was evaluated based on changes in Unified Parkinson's Disease Rating Scale and Levodopa Equivalent Dose, and microbiota were characterized with 16S rRNA gene amplicon sequencing. Findings: We compared patients to controls, and patients with stable disease to those with faster progression. There were significant differences between microbial communities of patients and controls when corrected for confounders, but not between timepoints. Specific bacterial taxa that differed between patients and controls at both timepoints included several previously reported ones, such as Roseburia, Prevotella and Bifidobacterium. In progression comparisons, differentially abundant taxa were inconsistent across methods and timepoints, but there was some support for a different distribution of enterotypes and a decreased abundance of Prevotella in faster-progressing patients. Interpretation: The previously detected gut microbiota differences between Parkinson's patients and controls persisted after 2 years. While we found some evidence for a connection between microbiota and disease progression, a longer follow-up period is required to confirm these findings. (C) 2019 The Authors. Published by Elsevier B.V.

Deep brain stimulation (DBS) is an effective treatment for Parkinson’s disease (PD) patients with motor fluctuations and dyskinesias. The key DBS efficacy studies were performed in PD patients with unknown genotypes; however, given the estimated monogenic mutation prevalence of approximately 5–10%, most commonly LRRK2, PRKN, PINK1 and SNCA, and risk-increasing genetic factors such as GBA, proper characterization is becoming increasingly relevant. We performed a systematic review of 46 studies that reported DBS effects in 221 genetic PD patients. The results suggest that monogenic PD patients have variable DBS benefit depending on the mutated gene. Outcome appears excellent in patients with the most common LRRK2 mutation, p.G2019S, and good in patients with PRKN mutations but poor in patients with the more rare LRRK2 p.R1441G mutation. The overall benefit of DBS in SNCA, GBA and LRRK2 p.T2031S mutations may be compromised due to rapid progression of cognitive and neuropsychiatric symptoms. In the presence of other mutations, the motor changes in DBS-treated monogenic PD patients appear comparable to those of the general PD population. Electronic supplementary material The online version of this article (10.1007/s00415-019-09181-8) contains supplementary material, which is available to authorized users.

Introduction: The Unified Dyskinesia Rating Scale (UDysRS) was developed to provide a comprehensive rating tool of dyskinesia in Parkinson’s disease (PD). Because dyskinesia therapy trials involve multicenter studies, having a scale that is validated in multiple non-English languages is pivotal to international efforts to treat dyskinesia. The aim of the present study was to organize and perform an independent validation of the UDysRS Finnish version. Methods: The UDysRS was translated into Finnish and then back-translated into English using 2 independent teams. Cognitive pretesting was conducted on the Finnish version and required modifications to the structure or wording of the translation. The final Finnish version was administered to 250 PD patients whose native language is Finnish. The data were analyzed to assess the confirmatory factor structure to the Spanish UDysRS (the reference standard). Secondary analyses included an exploratory factor analysis (EFA), independent of the reference standard. Results: The comparative fit index (CFI), in comparison with the reference standard factor structure, was 0.963 for Finnish. In the EFA, where variability from sample to sample is expected, isolated item differences of factor structure were found between the Finnish and Reference Standard versions of the UDysRS. These subtle differences may relate to differences in sample composition or variations in disease status. Conclusion: The overall factor structure of the Finnish version was consistent with that of the reference standard, and it can be designated as the official version of the UDysRS for Finnish speaking populations.

Background: The gastrointestinal tract is considered as a potential origin of Parkinson’s disease (PD) pathology. Besides constipation, appendectomy and inflammatory bowel disease have also been associated with a higher PD-risk, but findings have been inconsistent. To date, there is only one previous study suggesting that irritable bowel syndrome (IBS) is associated with an increased risk of PD. Objective: To evaluate whether IBS is associated with a higher risk of PD. Methods: In this retrospective registry-based cohort study, we identified 28,150 patients that were diagnosed with IBS (IBS+) during the years 1998–2014, using data from the Finnish Care Register for Health Care. In addition, 98,789 IBS-free reference subjects (IBS-) of same age and gender and living in the same municipality were included. The study subjects were followed until the end of the year 2014 to analyze the incidence of PD. The association between IBS and PD was assessed by a Cox proportional hazards model. Results: Diagnosis of IBS was associated with a higher hazard of PD with an adjusted hazard ratio (aHR) of 1.70 (95% CI 1.27–2.26). However, the ratio of hazard rates for PD between IBS+ and IBS- subjects was not constant over time. The Cox model with time-varying coefficient for IBS status showed that the hazard of PD was significantly higher in IBS patients only during the first two years of follow-up (aHR 2.96, 95% CI 1.78–4.92). Conclusion: Our findings indicate that the association between IBS and PD is likely explained by reverse causation and detection bias. It remains open whether IBS is an actual risk factor or a prodromal symptom of PD.

Advanced Parkinson's disease (PD) is characterized by an excessive oscillatory beta band activity in the sub thalamic nucleus (STN). Deep brain stimulation (DBS) of STN alleviates motor symptoms in PD and suppresses the STN beta band activity. The effect of DBS on cortical sensorimotor activity is more ambiguous; both increases and decreases of beta band activity have been reported. Non-invasive studies with simultaneous DBS are problematic due to DBS-induced artifacts. We recorded magnetoencephalography (MEG) from 16 advanced PD patients with and without STN DBS during rest and wrist extension. The strong magnetic artifacts related to stimulation were removed by temporal signal space separation. MEG oscillatory activity at 5-25 Hz was suppressed during DBS in a widespread frontoparietal region, including the sensorimotor cortex identified by the cortico-muscular coherence. The strength of suppression did not correlate with clinical improvement. Our results indicate that alpha and beta band oscillations are suppressed at the frontoparietal cortex by STN DBS in PD.

Background: STB DBS (deep brain stimulation of the subthalamic nucleus) is commonly used to treat advanced Parkinson disease (PD) while posterior hypothalamic DBS for cluster headache (CH) remains experimental. Methods: We present a case where a middle-aged man was diagnosed with both CH and PD and received medical treatment for both. The patient was treated with bilateral STN DBS after developing side effects related to L-dopa. Findings: STN DBS not only alleviated PD symptoms but also the CH, and hence the CH treatment could be withdrawn. During follow-up PD progressed but the effect on CH symptoms was sustained. Conclusions: The anatomical proximity of the medial STN and hypothalamus, their similar connectivity via the hyperdirect pathway, and the autonomic effects of STN DBS could explain symptom relief for both PD and CH.

Introduction: Parkinson's disease (PD) is associated with neuropathological changes in olfactory and gastrointestinal tissues, and PD patients frequently suffer from hyposmia, hyposalivation, and dysphagia. Since hyposmia and gastrointestinal dysfunction are frequently premotor symptoms, it has been speculated that an external, for example microbial, agent could trigger the pathologic process in the corresponding organs, subsequently spreading to the central nervous system. We recently showed evidence for compositional differences between the fecal microbiota of PD patients and control subjects. In this study, our objective was to explore a possible connection between nasal and oral microbiota and PD. Methods: We compared the oral and nasal bacterial communities of PD patients (oral: n = 72, nasal: n = 69) and control subjects (oral: n = 76, nasal: n = 67) using a 16S rRNA gene amplicon sequencing approach. Results: Oral and nasal microbiota differed markedly from each other, with no notable similarity within subjects. Oral microbiota of PD patients and control subjects had differences in beta diversity and abundances of individual bacterial taxa. An increase in the abundance of opportunistic oral pathogens was detected in males, both with and without PD. Our data did not reveal convincing differences between the nasal microbiota of control subjects and PD patients. Conclusion: The oral microbiome deserves additional research regarding its connection to PD and its biomarker potential. The higher abundance of oral pathogens in men underlines the importance of monitoring and promoting male dental health. (C) 2017 Elsevier Ltd. All rights reserved.

The mapping of the sensorimotor cortex gives information about the cortical motor and sensory functions. Typical mapping methods are navigated transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG). The differences between these mapping methods are, however, not fully known. TMS center of gravities (CoGs), MEG somatosensory evoked fields (SEFs), corticomuscular coherence (CMC), and corticokinematic coherence (CKC) were mapped in ten healthy adults. TMS mapping was performed for first dorsal interosseous (FDI) and extensor carpi radialis (ECR) muscles. SEFs were induced by tactile stimulation of the index finger. CMC and CKC were determined as the coherence between MEG signals and the electromyography or accelerometer signals, respectively, during voluntary muscle activity. CMC was mapped during the activation of FDI and ECR muscles separately, whereas CKC was measured during the waving of the index finger at a rate of 3–4 Hz. The maximum CMC was found at beta frequency range, whereas maximumCKC was found at the movement frequency. The mean Euclidean distances between different localizations were within 20 mm. The smallest distance was found between TMS FDI and TMS ECR CoGs and longest between CMC FDI and CMC ECR sites. TMS-inferred localizations (CoGs) were less variable across participants than MEG-inferred localizations (CMC, CKC). On average, SEF locations were 8 mm lateral to the TMS CoGs (p < 0.01). No differences between hemispheres were found. Based on the results, TMS appears to be more viable than MEG in locating motor cortical areas.