Daily Habits in Parkinson's Disease: Validation of the Daily Habit Scale.

Objective: The objective of the study was to validate a new scale for assessing habitual behavior-the Daily Habit Scale in patients with Parkinson's disease. Background: Parkinson's disease patients are impaired in habit learning and skill acquisition. Despite repeated practice, they have difficulty developing habitual responses. Methods: One hundred seventy-nine patients (Median (Mdn) = 69 [64-76], 65 females) participated in the study. Corrected item-to-total correlations were calculated to assess the item-convergent and item discriminant validity. Confirmatory factor analysis and assessment of internal consistency were also carried out. Concurrent validity in respect to measures of anxiety and depression, apathy, impulsivity, personality, multidimensional health locus of control, and health-related quality of life was also calculated. To determine the test-retest reliability of the scale, 30 patients (Mdn = 69 [66-73], 9 females) completed a second copy of the scale 6 months after the first. Results: Twenty-nine items (76%) and 9 items (24%) of the 38-item scale, respectively, showed a very good and good convergent validity. All the items discriminated between their own factor and the other factors. The comparative fit index of 0.932 indicated an acceptable model fit of the data, whereas the root mean square error of approximation of 0.06 moderate model fit. The scale had a good internal consistency (Cronbach α = 0.792), and a moderate test-retest reliability (0.57). Females had higher scores on two factors compared to men (Factor 3: household activities and Factor 8: sleep-related activities). Conclusions: The Daily Habit Scale is a reliable and valid tool to measure daily habits in Parkinson's disease.

EEG functional connectivity after perinatal stroke.

Impaired cognitive functioning after perinatal stroke has been associated with long-term functional brain network changes. We explored brain functional connectivity using a 64-channel resting-state electroencephalogram in 12 participants, aged 5-14 years with a history of unilateral perinatal arterial ischemic or haemorrhagic stroke. A control group of 16 neurologically healthy subjects was also included-each test subject was compared with multiple control subjects, matched by sex and age. Functional connectomes from the alpha frequency band were calculated for each subject and the differences in network graph metrics between the 2 groups were analyzed. Our results suggest that the functional brain networks of children with perinatal stroke show evidence of disruption even years after the insult and that the scale of changes appears to be influenced by the lesion volume. The networks remain more segregated and show a higher synchronization at both whole-brain and intrahemispheric level. Total interhemispheric strength was higher in children with perinatal stroke compared with healthy controls.

Age related changes and sex related differences of functional brain networks in childhood: A high-density EEG study.

OBJECTIVE: The aim of this study was to explore functional network age-related changes and sex-related differences during the early lifespan with a high-density resting state electroencephalography (rs-EEG). METHODS: We analyzed two data sets of high-density rs-EEG in healthy children and adolescents. We recorded a 64-channel EEG and calculated functional connectomes in 27 participants aged 5-18 years. To validate our results, we used publicly available data and calculated functional connectomes in another 86 participants aged 6-18 years from a 128-channel rs-EEG. We were primarily interested in alpha frequency band, but we also analyzed theta and beta frequency bands. RESULTS: We observed age-related increase of characteristic path, clustering coefficient and interhemispheric strength in the alpha frequency band of both data sets and in the beta frequency band of the larger validation data set. Age-related increase of global efficiency was seen in the theta band of the validation data set and in the alpha band of the test data set. Increase in small worldness was observed only in the alpha frequency band of the test data set. We also observed an increase of individual peak alpha frequency with age in both data sets. Sex-related differences were only observed in the beta frequency band of the larger validation data set, with females having higher values than same aged males. CONCLUSIONS: Functional brain networks show indices of higher segregation, but also increasing global integration with maturation. Age-related changes are most prominent in the alpha frequency band. SIGNIFICANCE: To the best of our knowledge, our study was the first to analyze maturation related changes and sex-related differences of functional brain networks with a high-density EEG and to compare functional connectomes generated from two diverse high-density EEG data sets. Understanding the age-related changes and sex-related differences of functional brain networks in healthy children and adolescents is crucial for identifying network abnormalities in different neurologic and psychiatric conditions, with the aim to identify possible markers for prognosis and treatment.

Effects of deep brain stimulation frequency on eye movements and cognitive control.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for Parkinson's disease (PD). Varying the frequency DBS has differential effects on axial and distal limb functions, suggesting differing modulation of relevant pathways. The STN is also a critical node in oculomotor and associative networks, but the effect of stimulation frequency on these networks remains unknown. This study aimed to investigate the effects of 80 hz vs. 130 Hz frequency STN-DBS on eye movements and executive control. Twenty-one STN-DBS PD patients receiving 130 Hz vs. 80 Hz stimulation were compared to a healthy control group (n = 16). All participants were tested twice in a double-blind manner. We examined prosaccades (latency and gain) and antisaccades (latency of correct and incorrect antisaccades, error rate and gain of the correct antisaccades). Executive function was tested with the Stroop task. The motor condition was assessed using Unified Parkinson's Disease Rating Scale part III. The antisaccadic error rate was higher in patients (p = 0.0113), more so in patients on 80 Hz compared to 130 Hz (p = 0.001) stimulation. The differences between patients and controls and between frequencies for all other eye-movements or cognitive measures were not statistically significant. We show that 80 Hz STN-DBS in PD reduces the ability to maintain stable fixation but does not alter inhibition, resulting in a higher antisaccade error rate presumably due to less efficient fixation, without altering the motor state. This provides a wider range of stimulation parameters that can reduce specific DBS-related effects without affecting motor outcomes.

Does spinal cord stimulation improve gait in Parkinson's disease: A comprehensive review.

INTRODUCTION: Axial disability, including gait disturbances, is common in Parkinson's disease (PD), especially in advanced stages. Epidural spinal cord stimulation (SCS) has been investigated as a treatment option for gait disorders in PD. Here, we review the literature on SCS in PD and evaluate its efficacy, optimal stimulation parameters, optimal electrode locations, possible effects of concurrent deep brain stimulation, and possible working mechanisms on gait. METHODS: Databases were searched for human studies involving PD patients who received an epidural SCS intervention and who had at least one gait-related outcome measure. The included reports were reviewed with respect to design and outcomes. Additionally, the possible mechanisms of action underlying SCS were reviewed. RESULTS: Out of 433 records identified, 25 unique studies with in total 103 participants were included. Most studies included only a few participants. The gait disorders of most PD patients with concurrent pain complaints, mostly low back pain, improved with SCS in almost all cases, regardless of stimulation parameters or electrode location. Higher-frequency stimulation (>200 Hz) seemed to be more effective in pain-free PD patients, but the results were inconsistent. Heterogeneity in outcome measures and follow-up times hindered comparability. CONCLUSIONS: SCS may improve gait in PD patients with neuropathic pain, but its efficacy in pain-free patients remains uncertain due to a lack of thorough double-blind studies. Apart from a well-powered, controlled, double-blind study design, future studies could further explore the initial hints that higher-frequency stimulation (>200 Hz) might be the best approach to improve gait outcomes in pain-free patients.

Gender discrepancies and differences in motor and non-motor symptoms, cognition, and psychological outcomes in the treatment of Parkinson's disease with subthalamic deep brain stimulation.

Available data suggest that there may be gender differences in the effect of STN-DBS in the treatment of Parkinson's disease (PD). The aim of this study was to review data on gender discrepancies and gender differences in clinical outcomes in PD patients treated with deep brain stimulation of the subthalamic nucleus (STN-DBS). Included were original studies that specifically examined gender discrepancies or gender differences in PD patients with STN-DBS. Men receive more DBS than women, for various indications. The decision-making process for DBS in women compared to men is more influenced by personal preferences and external factors. Motor symptoms improve in both genders, but bradykinesia improves more in men. The postoperative reduction of the levodopa equivalent daily dose seems to be more pronounced in men. Men show more cognitive deterioration and less improvement than women after STN-DBS. Women show more depressive symptoms before surgery, but they improve similarly to men. Men show more improvement in impulsivity and less decrease in impulsive behaviour symptoms than women. Anxiety and personality traits remain unchanged in both genders. Voice quality improves more in men and deteriorates less often than in women. Men gain fat-free mass and fat mass, but women only gain fat mass. Regarding sexual function the evidence is inconsistent. More urinary symptoms improve in women than in men. Pain and restless leg syndrome seems to improve more in men. Regarding quality of life, the evidence seems to be inconsistent, and activities of daily living seems to improve in both genders. Better prospective controlled studies, focusing directly on gender differences in PD patients treated with STN-DBS, are needed to better explain gender differences in STN-DBS for PD.

A multicenter study of genetic testing for Parkinson's disease in the clinical setting.

Parkinson's disease (PD) guidelines lack clear criteria for genetic evaluation. We assessed the yield and rationale of genetic testing for PD in a routine clinical setting on a multicenter cohort of 149 early-onset and familial patients by exome sequencing and semi-quantitative multiplex ligation-dependent probe amplification of evidence-based PD-associated gene panel. We show that genetic testing for PD should be considered for both early-onset and familial patients alike, and a clinical yield of about 10% in the Caucasian population can be expected.

The Role of Microelectrode Recording in Deep Brain Stimulation Surgery for Parkinson's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: STN-DBS is a cornerstone in the treatment of advanced Parkinson's disease (PD). The traditional approach is to use an awake operative technique with microelectrode recording (MER). However, more centers start using an asleep MRI-guided technique without MER. OBJECTIVE: We systematically reviewed the literature to compare STN-DBS surgery with and without MER for differences in clinical outcome. METHODS: We systematically searched PubMed, Embase, MEDLINE, and Web of Science databases for randomized clinical trials and consecutive cohort studies published between 01-01-2000 and 26-08-2021, that included at least 10 PD patients who had received bilateral STN-DBS. RESULTS: 2,129 articles were identified. After abstract screening and full-text review, 26 studies were included in the final analysis, comprising a total of 34 study groups (29 MER and 5 non-MER). The standardized mean difference (SMD) in change in motor symptoms between baseline (OFF medication) and 6-24 months follow-up (OFF medication and ON stimulation) was 1.64 for the MER group and 1.87 for non-MER group (p = 0.59). SMD in change in levodopa equivalent daily dose (LEDD) was 1.14 for the MER group and 0.65 for non-MER group (p < 0.01). Insufficient data were available for comparative analysis of PDQ-39 and complications. CONCLUSION: The change in motor symptoms from baseline to follow-up did not differ between studies that used MER and those that did not. The postoperative reduction in LEDD from baseline to follow-up was greater in the MER-group. In the absence of high-quality studies comparing both methods, there is a clear need for a well-designed comparative trial.

Development and Validation of a Daily Habit Scale.

Habits are defined as automatic behaviours triggered by cues and performed without awareness. They are difficult to control and mentally efficient, which contrasts with goal-directed behaviour, which is characterised by active thought, high computational effort, and the ability to modify this behaviour in response to a changing environment and contextual demands. Habits are not only defined by the frequency with which a behaviour is performed but represent a complex construct that also includes the strength and automaticity of the habitual behaviour. We report here the development and validation of a Daily Habit Scale (DHS) to assess the frequency, automaticity, and strength of daily habits in healthy individuals. Item reduction based on factor analysis resulted in a scale with 38 items grouped into eight factors explaining 52.91% of the variance. The DHS showed very good internal consistency (Cronbach alpha = 0.738) and test-retest reliability (Intraclass correlation coefficient = 0.892, p<0.001) as well as convergent and divergent reliability compared to other scales measuring habits. We found a significant effect of age, gender, anxiety, and depression on the DHS. Considering certain limitations of the DHS, such as not considering the context of performance of habits, and the absence of certain items, such as transportation use, the results of this study suggest that DHS is a reliable and valid measure of daily habits that can be used by both clinicians and researchers as a measure of daily habits.

Gender Distribution in Deep Brain Stimulation for Parkinson's Disease: The Effect of Awake versus Asleep Surgery.

There is evidence that men are more likely to undergo deep brain stimulation (DBS) for Parkinson's disease (PD), suggesting that women are relatively undertreated. 121 consecutive PD patients undergoing awake DBS with microelectrode recording and intraoperative clinical testing (30 patients, 5 women) or asleep MRI-guided and CT-verified (91 patients, 38 women) bilateral subthalamic nucleus DBS were included in this study. The results showed an increase in the proportion of female patients from 16.7% to 41.8% after changing our operative technique (OR = 5.61; 95% CI: 1.52-20.78; p = 0.010) from awake to asleep, suggesting that women are more likely to undergo DBS when operated asleep.

The Role of Microelectrode Recording and Stereotactic Computed Tomography in Verifying Lead Placement During Awake MRI-Guided Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease.

BACKGROUND: Bilateral deep brain stimulation of the subthalamic nucleus (STN-DBS) has become a cornerstone in the advanced treatment of Parkinson's disease (PD). Despite its well-established clinical benefit, there is a significant variation in the way surgery is performed. Most centers operate with the patient awake to allow for microelectrode recording (MER) and intraoperative clinical testing. However, technical advances in MR imaging and MRI-guided surgery raise the question whether MER and intraoperative clinical testing still have added value in DBS-surgery. OBJECTIVE: To evaluate the added value of MER and intraoperative clinical testing to determine final lead position in awake MRI-guided and stereotactic CT-verified STN-DBS surgery for PD. METHODS: 29 consecutive patients were analyzed retrospectively. Patients underwent awake bilateral STN-DBS with MER and intraoperative clinical testing. The role of MER and clinical testing in determining final lead position was evaluated. Furthermore, interobserver variability in determining the MRI-defined STN along the planned trajectory was investigated. Clinical improvement was evaluated at 12 months follow-up and adverse events were recorded. RESULTS: 98% of final leads were placed in the central MER-track with an accuracy of 0.88±0.45 mm. Interobserver variability of the MRI-defined STN was 0.84±0.09. Compared to baseline, mean improvement in MDS-UPDRS-III, PDQ-39 and LEDD were 26.7±16.0 points (54%) (p < 0.001), 9.0±20.0 points (19%) (p = 0.025), and 794±434 mg/day (59%) (p < 0.001) respectively. There were 19 adverse events in 11 patients, one of which (lead malposition requiring immediate postoperative revision) was a serious adverse event. CONCLUSION: MER and intraoperative clinical testing had no additional value in determining final lead position. These results changed our daily clinical practice to an asleep MRI-guided and stereotactic CT-verified approach.

Personality Changes After Subthalamic Nucleus Stimulation in Parkinson's Disease.

BACKGROUND: While deep brain stimulation of the subthalamic nucleus (STN-DBS) significantly improves motor deficits in patients with Parkinson's disease (PD), it is still unclear whether it affects personality functioning. OBJECTIVE: The objective of the present study was to examine personality changes in patients with PD after STN-DBS from the perspectives of both the patients and caregivers. Moreover, by assessing the premorbid personalities of the patients, we tried to determine individual vulnerability to STN-DBS-induced personality changes. METHODS: In total, 27 patients and their caregivers participated in our retrospective observational study. They were asked to assess the patients' personality changes with the Iowa Scale of Personality Changes (ISPC) and the patients' premorbid personalities with the Big Five Inventory (BFI). RESULTS: Caregivers reported significant personality changes in the ISPC domains of Executive Disturbance (p = 0.01) and Disturbed Social Behavior (p = 0.02). Most of the ISPC domains were positively correlated with Conscientiousness, while Executive Disturbance was negatively correlated with Neuroticism of the BFI scale. CONCLUSION: Our results show that executive and social functioning are the two most vulnerable domains in patients with PD after STN-DBS, especially in those patients who score higher for neuroticism and lower for conscientiousness on the BFI scale. The results of our study may provide movement disorder specialists with better counseling options and better selection of DBS candidates. Caregivers' perspective might contribute significantly in understanding postoperative personality changes.

Distractibility predicts favourable response of functional tremor to transcranial magnetic stimulation: An electrophysiological study.

BACKGROUND: Generation of functional tremor relies on the structures involved in the control of voluntary movements. The clinical diagnosis is based on the presence of "positive signs", which are expression of cognitive and motor distractibility and reflect functional tremor dependence on explicit motor control. In patients who manifest less distractibility, habitual (implicit) control may be of greater significance. Habitual behaviours are inflexible and difficult to eradicate. OBJECTIVES: To investigate if motor and cognitive distractibility predicts response to treatment with repetitive transcranial magnetic stimulation. METHODS: 21 patients with functional tremor underwent 5-day repeated sessions of continuous theta burst stimulation over primary motor cortex. A battery of tests to provoke positive signs was performed during accelerometry recordings and the total functional tremor accelerometry score was calculated for each patient. Response to treatment was measured as change in tremor amplitude, expressed as total power of the spectra between 1 and 30 Hz. RESULTS: On the group level, cTBS significantly changed postural tremor amplitude (Z = -1.9; p = 0.05), with the median decrease of 40%, IQR (-90-(+24)). There was a positive correlation between the functional tremor accelerometry score and reduction of postural tremor amplitude with treatment (rs = -0.75, p < 10-3). Responders had higher functional tremor accelerometry scores compared to non-responders (p = 0.001). The total functional tremor accelerometry score was a significant predictor of treatment response (OR = 2.8, p = 0.03; 95% CI 1.1; 7.2). CONCLUSIONS: Patients who are more distractible are better candidates for treatment with transcranial magnetic stimulation. The likely explanation is the between-subjects differences on the reliance of functional tremor generation on explicit vs. implicit motor network.

Switching and Combining Device-Aided Therapies in Advanced Parkinson's Disease: A Double Centre Retrospective Study.

BACKGROUND: Device-aided therapies (DAT), such as continuous subcutaneous apomorphine infusion (CSAI), levodopa-carbidopa intestinal gel infusion (LCIG), and deep brain stimulation of the subthalamic nucleus (STN-DBS), have markedly changed the treatment landscape of advanced Parkinson's disease (aPD). In some patients, it is necessary to switch or combine DATs for various reasons. The aim of this retrospective study was to explore the frequency and reasons for switching between or combining DATs in two movement disorders centres in Slovenia and Israel. METHODS: We collected and analysed demographic and clinical data from aPD patients who switched between or combined DATs. Motor and non-motor reasons, adverse events for switching/combining, and their frequency were examined, as was the effect of DAT using the Global Improvement subscale of the Clinical Global Impression Scale, Movement Disorders Society Unified Parkinson's Disease Rating Scale part III, Mini Mental State Examination, and Parkinson's Disease Questionnaire 39. Descriptive statistics and non-parametric tests were used to analyse the data. RESULTS: Of 505 aPD patients treated with DATs at both centres between January 2009 and June 2021, we identified in a total of 30 patients (6%) who either switched DAT (n = 24: 7 LCIG-to-STN-DBS, 1 LCIG-to-CSAI, 5 CSAI-to STN-DBS, 8 CSAI-to-LCIG, 1 STN-DBS-to-LCIG, 1 LCIG-to-CSAI-to-STN-DBS, and 1 STN-DBS-to-CSAI-to-LCIG) or combined DATs (n = 6:5 STN-DBS+LCIG and 1 STN-DBS+CSAI-to-STN-DBS+LCIG). In most of these patients, an inadequate control of motor symptoms was the main reason for switching or combining DATs, but non-motor reasons (related to the disease and/or DAT) were also identified. CONCLUSIONS: Switching between and combining DATs is uncommon, but in some patients brings substantial clinical improvement and should be considered in those who have either inadequate symptom control on DAT treatment or have developed DAT-related complications.

Olfactory evaluation in hospitalised and self-isolated patients with COVID-19: a single-centre experience on 55 cases.

BACKGROUND: Smell loss is a common symptom of COVID-19 infection. Majority of the studies that evaluated olfactory impairment in COVID-19 used questionnaires (subjective smell evaluations) and did not compare the results with objective or semiobjective measures of smell. We performed smell testing in hospitalised and self-isolated patients with COVID-19 and control participants. METHODS: Fifty-five COVID-19 and 44 control participants underwent smell testing, using Burghart Sniffin' Sticks 'Screening 12 Test'. Participants also rated their smelling capability on the numerical scale. Differences between groups and correlation between smell loss and time from acute onset of symptoms were tested, as well as correlation between results of smell test and subjective assessment of smell. RESULTS: Hospitalised patients with COVID-19 correctly determined 6.5/12 odorants compared with 10/12 in the self-isolated and 11/12 in the control group (p<0.001). Hyposmia or anosmia were present in 87.5% of hospitalised and 29.0% of self-isolated patients (p<0.001). The correlation between subjective self-assessment and results of smell testing was non-significant in both groups of patients with COVID-19, while there was a moderate positive correlation (p=0.001, Spearman's correlation coefficient=0.499) in control participants. CONCLUSION: Contrary to some previous reports suggesting that the presence of olfactory loss may predict milder course of disease, our study found that a vast majority of hospitalised patients with COVID-19 had prominent olfactory impairment. The absence of correlation between self-rated and objective smell evaluation in patients with COVID-19 indicates that subjective smell assessment is unreliable.

Bee Venom Does Not Reduce the Risk for Parkinson's Disease: Epidemiological Study among Beekeepers.

BACKGROUND: Based on the promising results from preclinical studies, bee venom has been investigated as a neuroprotective agent in Parkinson's disease. OBJECTIVE: To assess if longstanding exposure to bee venom is associated with decreased risk for Parkinson's disease among beekeepers. METHODS: Questionnaire gathering information about diagnosis of Parkinson's disease and exposure to bee stings was posted to 6500 members of Slovenian beekeepers' organisation. RESULTS: We received 1298 responses (response rate 20.1%). Twenty beekeepers, all older than 60 years, were diagnosed with Parkinson's disease. The prevalence of Parkinson's disease in beekeepers aged ≥60 years was 3.9%, which is above the reported 0.6-1.3% prevalence of PD in this age group in European population. There was no difference in parameters reflecting bee venom exposure between beekeepers with and without Parkinson's disease. CONCLUSIONS: Continuous exposure to bee venom does not affect neurodegeneration to the extent where it could prevent the expression of Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society.

Central nervous system physiology.

This is the second chapter of the series on the use of clinical neurophysiology for the study of movement disorders. It focusses on methods that can be used to probe neural circuits in brain and spinal cord. These include use of spinal and supraspinal reflexes to probe the integrity of transmission in specific pathways; transcranial methods of brain stimulation such as transcranial magnetic stimulation and transcranial direct current stimulation, which activate or modulate (respectively) the activity of populations of central neurones; EEG methods, both in conjunction with brain stimulation or with behavioural measures that record the activity of populations of central neurones; and pure behavioural measures that allow us to build conceptual models of motor control. The methods are discussed mainly in relation to work on healthy individuals. Later chapters will focus specifically on changes caused by pathology.

Asymmetry at Disease Onset Is Not a Predictor of Parkinson's Disease Progression.

BACKGROUND: Even though a significant fraction of Parkinson's disease (PD) patients presents with only minor or no motor asymmetry, the motor symptoms in PD typically start on one side of the body and worse symptoms on the side of the disease onset usually persist long after the disease has become clinically bilateral. The asymmetric presentation of PD has been studied over the years, with some studies showing slower progression in PD subjects with asymmetric disease presentation. In other studies, however, it was not possible to relate the asymmetry to disease progression. OBJECTIVE: The main objective of the present study was to assess the effect of asymmetry at disease onset on disease progression. METHODS: Using the data available in the Parkinson's Progression Markers Initiative (PPMI) database, at baseline, 423 subjects with de-novo PD were included in the study. Instead of dichotomizing the subjects in asymmetric and symmetric, we kept the asymmetry index and the non-motor, disability, and motor progression at one-, three-, and five-year follow-up continuous. Pearson's r correlational analysis and the coefficient of determination R2 were used to correlate asymmetry indices and disease progression. RESULTS: There was no correlation between neither clinically, nor DatSCAN defined asymmetry and non-motor, motor, and disability progression in the de-novo PD subjects with a 5-year follow-up. CONCLUSION: Asymmetry at disease onset does not predict progression of PD. Further studies are needed to investigate whether early detection of asymmetry on clinical grounds could successfully distinguish between PD and symmetric types of atypical parkinsonism in the early stages of the disease.

Long-term effect of bilateral STN-DBS on non-motor symptoms in Parkinson's disease: A four-year observational, prospective study.

BACKGROUND: Several studies have shown beneficial effects of bilateral stimulation of the subthalamic nucleus (STN-DBS) on motor as well as on non-motor symptoms (NMS) up to 36 months post-surgery in advanced Parkinson's disease (PD) patients. We set to explore the long-term effect of STN-DBS on NMS in a four-year follow-up, prospective, observational study. METHODS: Forty patients were enrolled and assessed at baseline. Twenty-eight were followed-up at 6, 12, 24, 36 and 48 months after the operation. The effect of post-operative time on NMS was analyzed by six-level repeated measures ANOVA. In a post-hoc analysis the follow-up scores were compared to baseline using a paired t-test. RESULTS: The following scores stayed improved up to 24 months after surgery, presented as baseline/24 months, p-value (t-test): total Non-Motor Symptoms Scale score (54.0 ± 5.6/44.9 ± 5.0, p = 0.029), Hamilton Anxiety Scale (14.3 ± 1.3/11.3 ± 1.2, p = 0.019) and PDQ39 (53.4 ± 4.5/40.2 ± 2.9, p = 0.012). PD Sleep Scale 2 remained improved throughout the study (17.4 ± 2.0/12.8 ± 1.3 at 48 months, p = 0.032), while Beck Depression Inventory only at six months post-surgery (9.5 ± 1.2/6.7 ± 0.7 at 6 months, p = 0.006). Montreal Cognitive Assessment remained stable up to 24 months and then declined at 36 months (26.3 ± 0.5/25.4 ± 0.5 at 36 months, p = 0.003), Starkstein Apathy Scale deteriorated throughout the study (7.6 ± 0.7/12.7 ± 0.9 at 48 months, p = 0.006). CONCLUSIONS: We observed beneficial effect of STN-DBS in several but not all domains of NMS at least up to 24 months post-op in advanced PD. Further long-term studies on larger cohorts of PD patients and longer follow-up need to be conducted to better understand the long-term effect of STN-DBS on NMS.