Disentangling Bradykinesia and Rigidity in Parkinson Disease: Evidence from Short- and Long-Term Subthalamic Nucleus Deep Brain Stimulation.

OBJECTIVE: Bradykinesia and rigidity are considered closely related motor signs in Parkinson disease (PD), but recent neurophysiological findings suggest distinct pathophysiological mechanisms. This study aims to examine and compare longitudinal changes in bradykinesia and rigidity in PD patients treated with bilateral subthalamic nucleus deep brain stimulation (STN-DBS). METHODS: In this retrospective cohort study, the clinical progression of appendicular and axial bradykinesia and rigidity was assessed up to 15 years after STN-DBS in the best treatment conditions (ON medication and ON stimulation). The severity of bradykinesia and rigidity was examined using ad hoc composite scores from specific subitems of the Unified Parkinson's Disease Rating Scale motor part (UPDRS-III). Short- and long-term predictors of bradykinesia and rigidity were analyzed through linear regression analysis, considering various preoperative demographic and clinical data, including disease duration and severity, phenotype, motor and cognitive scores (eg, frontal score), and medication. RESULTS: A total of 301 patients were examined before and 1 year after surgery. Among them, 101 and 56 individuals were also evaluated at 10-year and 15-year follow-ups, respectively. Bradykinesia significantly worsened after surgery, especially in appendicular segments (p < 0.001). Conversely, rigidity showed sustained benefit, with unchanged clinical scores compared to preoperative assessment (p > 0.05). Preoperative motor disability (eg, composite scores from the UPDRS-III) predicted short- and long-term outcomes for both bradykinesia and rigidity (p < 0.01). Executive dysfunction was specifically linked to bradykinesia but not to rigidity (p < 0.05). INTERPRETATION: Bradykinesia and rigidity show long-term divergent progression in PD following STN-DBS and are associated with independent clinical factors, supporting the hypothesis of partially distinct pathophysiology. ANN NEUROL 2024.

Interplay between speech and gait variables in Parkinson's disease patients treated with subthalamic nucleus deep brain stimulation: A long-term instrumental assessment.

OBJECTIVE: To evaluate correlations between speech and gait parameters in the long term and under different medication and subthalamic nucleus deep brain stimulation (STN-DBS) conditions in a cohort of advanced Parkinson's disease (PD) patients. METHODS: This observational study included consecutive PD patients treated with bilateral STN-DBS. Axial symptoms were evaluated using a standardized clinical-instrumental approach. Speech and gait were assessed by perceptual and acoustic analyses and by the instrumented Timed Up and Go (iTUG) test, respectively. Disease motor severity was evaluated with the total score and subscores of the Unified Parkinson's Disease Rating Scale (UPDRS) Part III. Different stimulation and drug treatment conditions were assessed: on-stimulation/off-medication, off-stimulation/off-medication, and on-stimulation/on-medication. RESULTS: Twenty-five PD patients with a 5-year median follow-up after surgery (range 3-7 years) were included (18 males; disease duration at surgery: 10.44 [SD 4.62] years; age at surgery: 58.40 [SD 5.73] years). In the off-stimulation/off-medication and on-stimulation/on-medication conditions, patients who spoke louder had also the greater acceleration of the trunk during gait; whereas in the on-stimulation/on-medication condition only, patients with the poorer voice quality were also the worst to perform the sit to stand and gait phases of the iTUG. Conversely, patients with the higher speech rate performed well in the turning and walking phases of the iTUG. CONCLUSIONS: This study underlines the presence of different correlations between treatment effects of speech and gait parameters in PD patients treated with bilateral STN-DBS. This may allow us to better understand the common pathophysiological basis of these alterations and to develop a more specific and tailored rehabilitation approach for axial signs after surgery.

Comparative features and outcomes of major neurological complications of COVID-19.

BACKGROUND AND PURPOSE: The aim of this study was to assess the neurological complications of SARS-CoV-2 infection and compare phenotypes and outcomes in infected patients with and without selected neurological manifestations. METHODS: The data source was a registry established by the European Academy of Neurology during the first wave of the COVID-19 pandemic. Neurologists collected data on patients with COVID-19 seen as in- and outpatients and in emergency rooms in 23 European and seven non-European countries. Prospective and retrospective data included patient demographics, lifestyle habits, comorbidities, main COVID-19 complications, hospital and intensive care unit admissions, diagnostic tests, and outcome. Acute/subacute selected neurological manifestations in patients with COVID-19 were analysed, comparing individuals with and without each condition for several risk factors. RESULTS: By July 31, 2021, 1523 patients (758 men, 756 women, and nine intersex/unknown, aged 16-101 years) were registered. Neurological manifestations were diagnosed in 1213 infected patients (79.6%). At study entry, 978 patients (64.2%) had one or more chronic general or neurological comorbidities. Predominant acute/subacute neurological manifestations were cognitive dysfunction (N = 449, 29.5%), stroke (N = 392, 25.7%), sleep-wake disturbances (N = 250, 16.4%), dysautonomia (N = 224, 14.7%), peripheral neuropathy (N = 145, 9.5%), movement disorders (N = 142, 9.3%), ataxia (N = 134, 8.8%), and seizures (N = 126, 8.3%). These manifestations tended to differ with regard to age, general and neurological comorbidities, infection severity and non-neurological manifestations, extent of association with other acute/subacute neurological manifestations, and outcome. CONCLUSIONS: Patients with COVID-19 and neurological manifestations present with distinct phenotypes. Differences in age, general and neurological comorbidities, and infection severity characterize the various neurological manifestations of COVID-19.

Pallidal and Cortical Oscillations in Freely Moving Patients With Dystonia.

OBJECTIVES: To evaluate the correlation between the pallidal local field potentials (LFPs) activity and the cortical oscillations (at rest and during several motor tasks) in two freely moving patients with generalized dystonia and pallidal deep brain stimulation (DBS). MATERIALS AND METHODS: Two women with isolated generalized dystonia were selected for bilateral globus pallidus internus (GPi) DBS. After the electrodes' implantation, cortical activity was recorded by a portable electroencephalography (EEG) system simultaneously with GPi LFPs activity, during several motor tasks, gait, and rest condition. Recordings were not performed during stimulation. EEG and LFPs signals relative to each specific movement were coupled together and grouped in neck/upper limbs movements and gait. Power spectral density (PSD), EEG-LFP coherence (through envelope of imaginary coherence operator), and 1/f exponent of LFP-PSD background were calculated. RESULTS: In both patients, the pallidal LFPs PSD at rest was characterized by prominent 4-12 Hz activity. Voluntary movements increased activity in the theta (θ) band (4-7 Hz) compared to rest, in both LFPs and EEG signals. Gait induced a drastic raise of θ activity in both patients' pallidal activity, less marked for the EEG signal. A coherence peak within the 8-13 Hz range was found between pallidal LFPs and EEG recorded at rest. CONCLUSIONS: Neck/upper limbs voluntary movements and gait suppressed the GPi-LFPs-cortical-EEG coherence and differently impacted both EEG and LFPs low frequency activity. These findings suggest a selective modulation of the cortico-basal ganglia network activity in dystonia.

Predictors of Long-Term Outcome of Subthalamic Stimulation in Parkinson Disease.

OBJECTIVE: This study was undertaken to identify preoperative predictive factors of long-term motor outcome in a large cohort of consecutive Parkinson disease (PD) patients with bilateral subthalamic nucleus deep brain stimulation (STN-DBS). METHODS: All consecutive PD patients who underwent bilateral STN-DBS at the Grenoble University Hospital (France) from 1993 to 2015 were evaluated before surgery, at 1 year (short-term), and in the long term after surgery. All available demographic variables, neuroimaging data, and clinical characteristics were collected. Preoperative predictors of long-term motor outcome were investigated by performing survival and univariate/multivariate Cox regression analyses. Loss of motor benefit from stimulation in the long term was defined as a reduction of less than 25% in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III scores compared to the baseline off-medication scores. As a secondary objective, potential predictors of short-term motor outcome after STN-DBS were assessed by performing univariate and multivariate linear regression analyses. RESULTS: In the long-term analyses (mean follow-up = 8.4 ± 6.26 years, median = 10 years, range = 1-17 years), 138 patients were included. Preoperative higher frontal score and off-medication MDS-UPDRS part III scores predicted a better long-term motor response to stimulation, whereas the presence of vascular changes on neuroimaging predicted a worse motor outcome. In 357 patients with available 1-year follow-up, preoperative levodopa response, tremor dominant phenotype, baseline frontal score, and off-medication MDS-UPDRS part III scores predicted the short-term motor outcome. INTERPRETATION: Frontal lobe dysfunction, disease severity in the off-medication condition, and the presence of vascular changes on neuroimaging represent the main preoperative clinical predictors of long-term motor STN-DBS effects. ANN NEUROL 2021;89:587-597.

Limbic Serotonergic Plasticity Contributes to the Compensation of Apathy in Early Parkinson's Disease.

BACKGROUND: De novo Parkinson's disease (PD) patients with apathy exhibit prominent limbic serotonergic dysfunction and microstructural disarray. Whether this distinctive lesion profile at diagnosis entails different prognosis remains unknown. OBJECTIVES: To investigate the progression of dopaminergic and serotonergic dysfunction and their relation to motor and nonmotor impairment in PD patients with or without apathy at diagnosis. METHODS: Thirteen de novo apathetic and 13 nonapathetic PD patients were recruited in a longitudinal double-tracer positron emission tomography cohort study. We quantified the progression of presynaptic dopaminergic and serotonergic pathology using [11 C]PE2I for dopamine transporter and [11 C]DASB for serotonin transporter at baseline and 3 to 5 years later, using linear mixed-effect models and mediation analysis to compare the longitudinal evolution between groups for clinical impairment and region-of-interest-based analysis. RESULTS: After the initiation of dopamine replacement therapy, apathy, depression, and anxiety improved at follow-up in patients with apathy at diagnosis (n = 10) to the level of patients without apathy (n = 11). Patients had similar progression of motor impairment, whereas mild impulsive behaviors developed in both groups. Striato-pallidal and mesocorticolimbic presynaptic dopaminergic loss progressed similarly in both groups, as did serotonergic pathology in the putamen, caudate nucleus, and pallidum. Contrastingly, serotonergic innervation selectively increased in the ventral striatum and anterior cingulate cortex in apathetic patients, contributing to the reversal of apathy besides dopamine replacement therapy. CONCLUSION: Patients suffering from apathy at diagnosis exhibit compensatory changes in limbic serotonergic innervation within 5 years of diagnosis, with promising evidence that serotonergic plasticity contributes to the reversal of apathy. The relationship between serotonergic plasticity and dopaminergic treatments warrants further longitudinal investigations. © 2022 International Parkinson and Movement Disorder Society.

Long-term independence and quality of life after subthalamic stimulation in Parkinson disease.

BACKGROUND AND PURPOSE: Studies on long-term nonmotor outcomes of subthalamic nucleus stimulation in Parkinson disease (PD) are scarce. This study reports on very long-term non-motor and motor outcomes in one of the largest cohorts of people with advanced PD, treated for >10 years with subthalamic nucleus stimulation. The main outcome was to document the evolution of independence in activities of daily living. The secondary outcomes were to measure the change in quality of life, as well as non-motor and motor outcomes. METHODS: Patients were studied preoperatively, at 1 year, and beyond 10 years after subthalamic stimulation with an established protocol including motor, non-motor, and neuropsychological assessments. RESULTS: Eighty-five people with PD were included. Independence scores in the off-medication condition (measured with the Schwab & England Activities of Daily Living Scale) as well as quality of life (measured with the Parkinson's Disease Questionnaire [PDQ]-37) remained improved at longest follow-up compared to preoperatively (respectively, p < 0.001, p = 0.015). Cognitive scores, measured with the Mattis Dementia Rating Scale, significantly worsened compared to before and 1 year after surgery (p < 0.001), without significant change in depression, measured with the Beck Depression Inventory. Motor fluctuations, dyskinesias, and off dystonia remained improved at longest follow-up (p < 0.001), with a significant reduction in dopaminergic treatment (45%, p < 0.001). CONCLUSIONS: This study highlights the long-term improvement of subthalamic stimulation on independence and quality of life, despite the progression of disease and the occurrence of levodopa-resistant symptoms.

Short- and long-term outcome and predictors in an international cohort of patients with neuro-COVID-19.

BACKGROUND AND PURPOSE: Despite the increasing number of reports on the spectrum of neurological manifestations of COVID-19 (neuro-COVID), few studies have assessed short- and long-term outcome of the disease. METHODS: This is a cohort study enrolling adult patients with neuro-COVID seen in neurological consultation. Data were collected prospectively or retrospectively in the European Academy of Neurology NEuro-covid ReGistrY ((ENERGY). The outcome at discharge was measured using the modified Rankin Scale and defined as 'stable/improved' if the modified Rankin Scale score was equal to or lower than the pre-morbid score, 'worse' if the score was higher than the pre-morbid score. Status at 6 months was also recorded. Demographic and clinical variables were assessed as predictors of outcome at discharge and 6 months. RESULTS: From July 2020 to March 2021, 971 patients from 19 countries were included. 810 (83.4%) were hospitalized. 432 (53.3%) were discharged with worse functional status. Older age, stupor/coma, stroke and intensive care unit (ICU) admission were predictors of worse outcome at discharge. 132 (16.3%) died in hospital. Older age, cancer, cardiovascular complications, refractory shock, stupor/coma and ICU admission were associated with death. 262 were followed for 6 months. Acute stroke or ataxia, ICU admission and degree of functional impairment at discharge were predictors of worse outcome. 65/221 hospitalized patients (29.4%) and 10/32 non-hospitalized patients (24.4%) experienced persisting neurological symptoms/signs. 10/262 patients (3.8%) developed new neurological complaints during the 6 months of follow-up. CONCLUSIONS: Neuro-COVID is a severe disease associated with worse functional status at discharge, particularly in older subjects and those with comorbidities and acute complications of infection.

Advances in DBS Technology and Novel Applications: Focus on Movement Disorders.

PURPOSE OF REVIEW: Deep brain stimulation (DBS) is an established treatment in several movement disorders, including Parkinson's disease, dystonia, tremor, and Tourette syndrome. In this review, we will review and discuss the most recent findings including but not limited to clinical evidence. RECENT FINDINGS: New DBS technologies include novel hardware design (electrodes, cables, implanted pulse generators) enabling new stimulation patterns and adaptive DBS which delivers potential stimulation tailored to moment-to-moment changes in the patient's condition. Better understanding of movement disorders pathophysiology and functional anatomy has been pivotal for studying the effects of DBS on the mesencephalic locomotor region, the nucleus basalis of Meynert, the substantia nigra, and the spinal cord. Eventually, neurosurgical practice has improved with more accurate target visualization or combined targeting. A rising research domain emphasizes bridging neuromodulation and neuroprotection. Recent advances in DBS therapy bring more possibilities to effectively treat people with movement disorders. Future research would focus on improving adaptive DBS, leading more clinical trials on novel targets, and exploring neuromodulation effects on neuroprotection.

Do neuropsychiatric fluctuations temporally match motor fluctuations in Parkinson's disease?

INTRODUCTION: In Parkinson's disease (PD), non-motor fluctuations (NMFs), especially neuropsychiatric fluctuations, often coexist with motor fluctuations (MFs) but are often under-recognized by physicians and patients. OBJECTIVE: To investigate the relationship between MFs and neuropsychiatric fluctuations in PD. METHODS: PD patients with MFs and NMFs were enrolled. The Parkinson's Kinetigraph (PKG), a wearable device to detect MFs and dyskinesia, was used to confirm and measure MFs. The Neuropsychiatric Fluctuation Scale (NFS), a scale composed by subscores for both the ON and OFF neuropsychiatric states, was used to identify and quantify neuropsychiatric fluctuations. Patients were asked to wear the PKG for six consecutive days to identify the ON and OFF motor periods, and then to fill the NFS during the ON and OFF motor periods for three consecutive days wearing the PKG. The PKG system provided a bradykinesia score (BKS) and a dyskinesia score (DKS). Relations between BKS, DKS, and ON and OFF NFS subscores were analyzed. RESULTS: In 18 PD patients, anxiety, apathy, and depression characterized the OFF condition, whereas self-confidence, competency, and interest in doing things were typically in the ON condition. There was a positive correlation between the BKS and the OFF NFS subscores (p = 0.036, r = 0.51), whereas no correlation was found between the DKS and the ON NFS subscores (p = 0.38, r = 0.22). CONCLUSION: Neuropsychiatric fluctuations temporarily matched the OFF MFs only in the OFF condition. These findings are useful to better manage OFF NMSs and support the need to further investigate associations between non-motor and motor symptoms in PD patients.

Visual Dysfunction of the Superior Colliculus in De Novo Parkinsonian Patients.

OBJECTIVE: The dual hit hypothesis about the pathogenesis of Parkinson disease (PD) suggests that the brainstem is a convergent area for the propagation of pathological α-synuclein from the periphery to the brain. Although brainstem structures are likely to be affected early in the course of the disease, detailed information regarding specific brainstem regions is lacking. The aim of our study was to investigate the function of the superior colliculus, a sensorimotor brainstem structure, in de novo PD patients compared to controls using brain functional magnetic imaging and visual stimulation paradigms. METHODS: De novo PD patients and controls were recruited. PD subjects were imaged before and after starting PD medications. A recently developed functional magnetic resonance imaging protocol was used to stimulate and visualize the superior colliculus and 2 other visual structures: the lateral geniculate nucleus and the primary visual cortex. RESULTS: In the 22 PD patients, there was no modulation of the superior colliculus responses to the luminance contrasts compared to controls. This implies a hypersensitivity to low luminance contrast and abnormal rapid blood oxygenation level-dependent signal saturation to high luminance contrasts. The lateral geniculate nucleus was only modulated by 3 to 9% luminance contrasts compared to controls. No major differences were found in the primary visual cortex between both groups. INTERPRETATION: Our findings suggest that pathological superior colliculus visual responses in de novo PD patients are present early in the course of the disease. Changes in imaging the superior colliculus could play an important role as a preclinical biomarker of the disease. ANN NEUROL 2020;87:533-546.

Pallidal deep brain stimulation for dystonia: a long term study.

BACKGROUND: Pallidal deep brain stimulation (globus pallidus internus (GPi) DBS) is the best therapeutic option for disabling isolated idiopathic (IID) and inherited (INH) dystonia. Acquired dystonia (AD) may also benefit from GPi DBS. Efficacy and safety in the long-term remained to be established. OBJECTIVE: To retrospectively assess long-term clinical outcomes and safety in dystonic patients who underwent GPi DBS. METHODS: Patients were videotaped and assessed preoperatively and postoperatively (1-year and at last available follow-up) using the Burke-Fahn-Marsden Dystonia Rating Scale (motor score (BFMDRS-M); disability score (BFMDRS-D)). RESULTS: Sixty-one patients were included (follow-up 7.9±5.9 years; range 1-20.7). In IID and INH (n=37), the BFMDRS-M improved at first (20.4±24.5; p<0.00001) and last (22.2±18.2; p<0.001) follow-ups compared with preoperatively (50.5±28.0). In AD (n=19), the BFMDRS-M ameliorated at 1-year (40.8±26.5; p<0.02) and late follow-ups (44.3±24.3; p<0.04) compared with preoperatively (52.8±24.2). In INH dystonia with other neurological features (n=4) there was no motor benefit. In IID and INH, the BFMDRS-D improved at 1-year (9.5±7.5; p<0.0002) and late follow-ups (10.4±7.8; p<0.016) compared with preoperatively (13.3±6.9). In AD, the BFMDRS-D reduced at 1-year (12.0±8.1; p<0.01) and late follow-ups (12.7 ±6.1; p=0.2) compared with preoperatively (14.35±5.7). Most adverse events were hardware related. CONCLUSIONS: GPi DBS is an effective and safe treatment in most patients with dystonia.

Spatiotemporal Gait Differences before and after Botulinum Toxin in People with Focal Dystonia: A Pilot Study.

BACKGROUND: The impact of focal dystonia on gait has attracted little attention and remains elusive. Considering the importance of both visual and head control in gait, blepharospasm and cervical dystonia should affect gait. Improvement of cervical/eyelid control following botulinum toxin (BTX) injections would translate into gait changes. OBJECTIVES: To assess gait differences in people with focal dystonia before and after BTX treatment. METHODS: Ten patients with blepharospasm, 10 patients with cervical dystonia, and 20 healthy age- and gender-matched controls were included. Gait was assessed before and 1-month after BTX injections using Biodex Gait Trainer™ 3. Gait velocity, cadence, step length, step asymmetry, and variability of step length were compared between patients and controls, and between the two time-points using non-parametric statistics. RESULTS: At baseline, compared to controls, cervical dystonia patients showed reduced gait velocity, step length, and cadence. After BTX injections, while gait velocity and step length were significantly increased and step length variability reduced, gait parameters still differed between patients and controls. In blepharospasm patients, baseline gait velocity and step length were significantly smaller than in controls. After BTX injections, these gait parameters were significantly increased and variability decreased, so that patients no longer differed from controls. CONCLUSION: Gait differences exist between patients with focal dystonia not directly affecting the lower limbs and healthy controls. These gait abnormalities were improved differently by BTX treatment according to the type of dystonia. These disparities suggest different pathophysiological mechanisms and support the need for changes in rehabilitation routines in cervical dystonia.

Validation of the Italian version of the Movement Disorder Society--Unified Parkinson's Disease Rating Scale.

The Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) has been available in English since 2008. As part of this process, the MDS-UPDRS organizing team developed guidelines for development of official non-English translations. We present here the formal process for completing officially approved non-English versions of the MDS-UPDRS and specifically focus on the first of these versions in Italian. The MDS-UPDRS was translated into Italian and tested in 377 native-Italian speaking PD patients. Confirmatory and exploratory factor analyses determined whether the factor structure for the English-language MDS-UPDRS could be confirmed in data collected using the Italian translation. To be designated an 'Official MDS translation,' the Comparative Fit Index (CFI) had to be ≥0.90 relative to the English-language version. For all four parts of the Italian MDS-UPDRS, the CFI, in comparison with the English-language data, was ≥0.94. Exploratory factor analyses revealed some differences between the two datasets, however these differences were considered to be within an acceptable range. The Italian version of the MDS-UPDRS reaches the criterion to be designated as an Official Translation and is now available for use. This protocol will serve as outline for further validation of this in multiple languages.

Multi-scale and cross-dimensional TMS mapping: A proof of principle in patients with Parkinson's disease and deep brain stimulation.

Introduction: Transcranial magnetic stimulation (TMS) mapping has become a critical tool for exploratory studies of the human corticomotor (M1) organization. Here, we propose to gather existing cutting-edge TMS-EMG and TMS-EEG approaches into a combined multi-dimensional TMS mapping that considers local and whole-brain excitability changes as well as state and time-specific changes in cortical activity. We applied this multi-dimensional TMS mapping approach to patients with Parkinson's disease (PD) with Deep brain stimulation (DBS) of the sub-thalamic nucleus (STN) ON and OFF. Our goal was to identifying one or several TMS mapping-derived markers that could provide unprecedent new insights onto the mechanisms of DBS in movement disorders. Methods: Six PD patients (1 female, mean age: 62.5 yo [59-65]) implanted with DBS-STN for 1 year, underwent a robotized sulcus-shaped TMS motor mapping to measure changes in muscle-specific corticomotor representations and a movement initiation task to probe state-dependent modulations of corticospinal excitability in the ON (using clinically relevant DBS parameters) and OFF DBS states. Cortical excitability and evoked dynamics of three cortical areas involved in the neural control of voluntary movements (M1, pre-supplementary motor area - preSMA and inferior frontal gyrus - IFG) were then mapped using TMS-EEG coupling in the ON and OFF state. Lastly, we investigated the timing and nature of the STN-to-M1 inputs using a paired pulse DBS-TMS-EEG protocol. Results: In our sample of patients, DBS appeared to induce fast within-area somatotopic re-arrangements of motor finger representations in M1, as revealed by mediolateral shifts of corticomuscle representations. STN-DBS improved reaction times while up-regulating corticospinal excitability, especially during endogenous motor preparation. Evoked dynamics revealed marked increases in inhibitory circuits in the IFG and M1 with DBS ON. Finally, inhibitory conditioning effects of STN single pulses on corticomotor activity were found at timings relevant for the activation of inhibitory GABAergic receptors (4 and 20 ms). Conclusion: Taken together, these results suggest a predominant role of some markers in explaining beneficial DBS effects, such as a context-dependent modulation of corticospinal excitability and the recruitment of distinct inhibitory circuits, involving long-range projections from higher level motor centers and local GABAergic neuronal populations. These combined measures might help to identify discriminative features of DBS mechanisms towards deep clinical phenotyping of DBS effects in Parkinson's Disease and in other pathological conditions.

Efficacy and safety of clonidine for the treatment of impulse control disorder in Parkinson's disease: a multicenter, parallel, randomised, double-blind, Phase 2b Clinical trial.

BACKGROUND: Impulse control disorders (ICDs) are frequently encountered in Parkinson's disease (PD). OBJECTIVES: We aimed to assess whether clonidine, an α2-adrenergic receptor agonist, would improve ICDs. METHODS: We conducted a multicentre trial in five movement disorder departments. Patients with PD and ICDs (n = 41) were enrolled in an 8-week, randomised (1:1), double-blind, placebo-controlled study of clonidine (75 µg twice a day). Randomisation and allocation to the trial group were carried out by a central computer system. The primary outcome was the change at 8 weeks in symptom severity using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) score. A reduction of the most elevated subscore of the QUIP-RS of more than 3 points without any increase in the other QUIP-RS dimension defined success. RESULTS: Between 15 May 2019 and 10 September 2021, 19 patients in the clonidine group and 20 patients in the placebo group were enrolled. The proportion difference of success in reducing QUIP-RS at 8 weeks, was 7% (one-sided upper 90% CI 27%) with 42.1% of success in the clonidine group and 35.0% in the placebo group. Compared to patients in the placebo group, patients in the clonidine group experienced a greater reduction in the total QUIP-RS score at 8 weeks (11.0 points vs. 3.6). DISCUSSION: Clonidine was well tolerated but our study was not enough powerful to demonstrate significant superiority compared to placebo in reducing ICDs despite a greater reduction of total QUIP score at 8 weeks. A phase 3 study should be conducted. TRIAL REGISTRATION: The study was registered (NCT03552068) on clinicaltrials.gov on June 11, 2018.

Long-term effects of bilateral subthalamic nucleus deep brain stimulation on gait disorders in Parkinson's disease: a clinical-instrumental study.

OBJECTIVE: To assess the long-term effects of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on gait in a cohort of advanced Parkinson's Disease (PD) patients. METHODS: This observational study included consecutive PD patients treated with bilateral STN-DBS. Different stimulation and drug treatment conditions were assessed: on-stimulation/off-medication, off-stimulation/off-medication, and on-stimulation/on-medication. Each patient performed the instrumented Timed Up and Go test (iTUG). The instrumental evaluation of walking ability was carried out with a wearable inertial sensor containing a three-dimensional (3D) accelerometer, gyroscope, and magnetometer. This device could provide 3D linear acceleration, angular velocity, and magnetic field vector. Disease motor severity was evaluated with the total score and subscores of the Unified Parkinson Disease Rating Scale part III. RESULTS: Twenty-five PD patients with a 5-years median follow-up after surgery (range 3-7) were included (18 men; mean disease duration at surgery 10.44 ± 4.62 years; mean age at surgery 58.40 ± 5.73 years). Both stimulation and medication reduced the total duration of the iTUG and most of its different phases, suggesting a long-term beneficial effect on gait after surgery. However, comparing the two treatments, dopaminergic therapy had a more marked effect in all test phases. STN-DBS alone reduced total iTUG duration, sit-to-stand, and second turn phases duration, while it had a lower effect on stand-to-sit, first turn, forward walking, and walking backward phases duration. CONCLUSIONS: This study highlighted that in the long-term after surgery, STN-DBS may contribute to gait and postural control improvement when used together with dopamine replacement therapy, which still shows a substantial beneficial effect.

Subtle anomaly detection: Application to brain MRI analysis of de novo Parkinsonian patients.

With the advent of recent deep learning techniques, computerized methods for automatic lesion segmentation have reached performances comparable to those of medical practitioners. However, little attention has been paid to the detection of subtle physiological changes caused by evolutive pathologies, such as neurodegenerative diseases. In this work, we leverage deep learning models to detect anomalies in brain diffusion tensor imaging (DTI) parameter maps of recently diagnosed and untreated (de novo) patients with Parkinson's disease (PD). For this purpose, we trained auto-encoders on parameter maps of healthy controls (n = 56) and tested them on those of de novo PD patients (n = 129). We considered large reconstruction errors between the original and reconstructed images to be anomalies that, when quantified, allow discerning between de novo PD patients and healthy controls. The most discriminating brain macro-region was found to be the white matter with a ROC-AUC 68.3 (IQR 5.4) and the best subcortical structure, the GPi (ROC-AUC 62.6 IQR 5.4). Our results indicate that our deep learning-based model can detect potentially pathological regions in de novo PD patients, without requiring any expert delineation. This may enable extracting neuroimaging biomarkers of PD in the future, but further testing on larger cohorts is needed. Such models can be seamlessly extended with additional parameter maps and applied to study the physio-pathology of other neurological diseases.

Effective connectivity in subcortical visual structures in de novo Patients with Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) manifests with the appearance of non-motor symptoms before motor symptoms onset. Among these, dysfunctioning visual structures have recently been reported to occur at early disease stages. OBJECTIVE: This study addresses effective connectivity in the visual network of PD patients. METHODS: Using functional MRI and dynamic causal modeling analysis, we evaluated the connectivity between the superior colliculus, the lateral geniculate nucleus and the primary visual area V1 in de novo untreated PD patients (n = 22). A subset of the PD patients (n = 8) was longitudinally assessed two times at two months and at six months after starting dopaminergic treatment. Results were compared to those of age-matched healthy controls (n = 22). RESULTS: Our results indicate that the superior colliculus drives cerebral activity for luminance contrast processing both in healthy controls and untreated PD patients. The same effective connectivity was observed with neuromodulatory differences in terms of neuronal dynamic interactions. Our main findings were that the modulation induced by luminance contrast changes of the superior colliculus connectivity (self-connectivity and connectivity to the lateral geniculate nucleus) was inhibited in PD patients (effect of contrast: p = 0.79 and p = 0.77 respectively). The introduction of dopaminergic medication in a subset (n = 8) of the PD patients failed to restore the effective connectivity modulation observed in the healthy controls. INTERPRETATION: The deficits in luminance contrast processing in PD was associated with a deficiency in connectivity adjustment from the superior colliculus to the lateral geniculate nucleus and to V1. No differences in cerebral blood flow were observed between controls and PD patients suggesting that the deficiency was at the neuronal level. Administration of a dopaminergic treatment over six months was not able to normalize the observed alterations in inter-regional coupling. These findings highlight the presence of early dysfunctions in primary visual areas, which might be used as early markers of the disease.