Intelligibility of speech in Parkinson's disease relies on anatomically segregated subthalamic beta oscillations.

BACKGROUND: Speech impairment is commonly reported in Parkinson's disease and is not consistently improved by available therapies - including deep brain stimulation of the subthalamic nucleus (STN-DBS), which can worsen communication performance in some patients. Improving the outcome of STN-DBS on speech is difficult due to our incomplete understanding of the contribution of the STN to fluent speaking. OBJECTIVE: To assess the relationship between subthalamic neural activity and speech production and intelligibility. METHODS: We investigated bilateral STN local field potentials (LFPs) in nine parkinsonian patients chronically implanted with DBS during overt reading. LFP spectral features were correlated with clinical scores and measures of speech intelligibility. RESULTS: Overt reading was associated with increased beta-low ([1220) Hz) power in the left STN, whereas speech intelligibility correlated positively with beta-high ([2030) Hz) power in the right STN. CONCLUSION: We identified separate contributions from frequency and brain lateralization of the STN in the execution of an overt reading motor task and its intelligibility. This subcortical organization could be exploited for new adaptive stimulation strategies capable of identifying the occurrence of speaking behavior and facilitating its functional execution.

Dermal and cardiac autonomic fiber involvement in Parkinson's disease and multiple system atrophy.

Pathological aggregates of alpha-synuclein in peripheral dermal nerve fibers can be detected in patients with idiopathic Parkinson's disease and multiple system atrophy. This study combines skin biopsy staining for p-alpha-synuclein depositions and radionuclide imaging of the heart with [123I]-metaiodobenzylguanidine to explore peripheral denervation in both diseases. To this purpose, 42 patients with a clinical diagnosis of Parkinson's disease or multiple system atrophy were enrolled. All patients underwent a standardized clinical work-up including neurological evaluation, neurography, and blood samples. Skin biopsies were obtained from the distal and proximal leg, back, and neck for immunofluorescence double labeling with anti-p-alpha-synuclein and anti-PGP9.5. All patients underwent myocardial [123I]-metaiodobenzylguanidine scintigraphy. Dermal p-alpha-synuclein was observed in 47.6% of Parkinson's disease patients and was mainly found in autonomic structures. 81.0% of multiple system atrophy patients had deposits with most of cases in somatosensory fibers. The [123I]-metaiodobenzylguanidine heart-to-mediastinum ratio was lower in Parkinson's disease than in multiple system atrophy patients (1.94 ± 0.63 vs. 2.91 ± 0.96; p < 0.0001). Irrespective of the diagnosis, uptake was lower in patients with than without p-alpha-synuclein in autonomic structures (1.42 ± 0.51 vs. 2.74 ± 0.83; p < 0.0001). Rare cases of Parkinson's disease with p-alpha-synuclein in somatosensory fibers and multiple system atrophy patients with deposits in autonomic structures or both fiber types presented with clinically overlapping features. In conclusion, this study suggests that alpha-synuclein contributes to peripheral neurodegeneration and mediates the impairment of cardiac sympathetic neurons in patients with synucleinopathies. Furthermore, it indicates that Parkinson's disease and multiple system atrophy share pathophysiologic mechanisms of peripheral nervous system dysfunction with a clinical overlap.

Freezing of gait in Parkinson's disease reflects a sudden derangement of locomotor network dynamics.

Freezing of gait is a disabling symptom of Parkinson's disease that causes a paroxysmal inability to generate effective stepping. The underlying pathophysiology has recently migrated towards a dysfunctional supraspinal locomotor network, but the actual network derangements during ongoing gait freezing are unknown. We investigated the communication between the cortex and the subthalamic nucleus, two main nodes of the locomotor network, in seven freely-moving subjects with Parkinson's disease with a novel deep brain stimulation device, which allows on-demand recording of subthalamic neural activity from the chronically-implanted electrodes months after the surgical procedure. Multisite neurophysiological recordings during (effective) walking and ongoing gait freezing were combined with kinematic measurements and individual molecular brain imaging studies. Patients walked in a supervised environment closely resembling everyday life challenges. We found that during (effective) walking, the cortex and subthalamic nucleus were synchronized in a low frequency band (4-13 Hz). In contrast, gait freezing was characterized in every patient by low frequency cortical-subthalamic decoupling in the hemisphere with less striatal dopaminergic innervation. Of relevance, this decoupling was already evident at the transition from normal (effective) walking into gait freezing, was maintained during the freezing episode, and resolved with recovery of the effective walking pattern. This is the first evidence for a decoding of the networked processing of locomotion in Parkinson's disease and suggests that freezing of gait is a 'circuitopathy' related to a dysfunctional cortical-subcortical communication. A successful therapeutic approach for gait freezing in Parkinson's disease should aim at directly targeting derangements of neural network dynamics.

Probabilistic mapping of the antidystonic effect of pallidal neurostimulation: a multicentre imaging study.

Deep brain stimulation of the internal globus pallidus is a highly effective and established therapy for primary generalized and cervical dystonia, but therapeutic success is compromised by a non-responder rate of up to 25%, even in carefully-selected groups. Variability in electrode placement and inappropriate stimulation settings may account for a large proportion of this outcome variability. Here, we present probabilistic mapping data on a large cohort of patients collected from several European centres to resolve the optimal stimulation volume within the pallidal region. A total of 105 dystonia patients with pallidal deep brain stimulation were enrolled and 87 datasets (43 with cervical dystonia and 44 with generalized dystonia) were included into the subsequent 'normative brain' analysis. The average improvement of dystonia motor score was 50.5 ± 30.9% in cervical and 58.2 ± 48.8% in generalized dystonia, while 19.5% of patients did not respond to treatment (<25% benefit). We defined probabilistic maps of anti-dystonic effects by aggregating individual electrode locations and volumes of tissue activated (VTA) in normative atlas space and ranking voxel-wise for outcome distribution. We found a significant relation between motor outcome and the stimulation volume, but not the electrode location per se. The highest probability of stimulation induced motor benefit was found in a small volume covering the ventroposterior globus pallidus internus and adjacent subpallidal white matter. We then used the aggregated VTA-based outcome maps to rate patient individual VTAs and trained a linear regression model to predict individual outcomes. The prediction model showed robustness between the predicted and observed clinical improvement, with an r2 of 0.294 (P < 0.0001). The predictions deviated on average by 16.9 ± 11.6 % from observed dystonia improvements. For example, if a patient improved by 65%, the model would predict an improvement between 49% and 81%. Results were validated in an independent cohort of 10 dystonia patients, where prediction and observed benefit had a correlation of r2 = 0.52 (P = 0.02) and a mean prediction error of 10.3% (±8.9). These results emphasize the potential of probabilistic outcome brain mapping in refining the optimal therapeutic volume for pallidal neurostimulation and advancing computer-assisted planning and programming of deep brain stimulation.

Motor function in Rett syndrome: comparing clinical and parental assessments.

AIM: To describe a new clinical tool, the Rett Syndrome Motor Evaluation Scale (RESMES) and to assess (loco-)motor function in people with Rett syndrome (RTT). METHOD: Formal assessment provided by physicians was followed by parents' direct observation at home using the RESMES. Sixty females (mean [SD] age 12y 5mo [8y 9mo], range 3-40y) with a clinical diagnosis and genetically determined RTT participated in the study. Spearman's/Pearson's coefficients assessed the correlation between the clinicians' and caregivers' evaluations, as well as the correlation of RESMES scores with other scales, namely the Pain Assessment in Advanced Dementia, the Rett Assessment Rating Scale, the Modified Ashworth Scale, and hand function (assessed with a scale of evaluation of purposeful hand function). Scores provided by parents and clinicians were tested statistically by Mann-Whitney U test. RESULTS: Approximately 88% of patients had moderate to severe RTT symptoms and, on average, moderate motor impairment based on the RESMES. RESMES total scores provided by clinicians and caregivers were highly correlated (r=0.91), as were the subscale scores. Postural transition was a critical area of the RESMES, where parents systematically provided lower scores than clinicians, indicating milder degrees of disability. Severity of scoliosis and mutation type emerged as significant predictors of motor function. INTERPRETATION: The RESMES characterized the (loco-)motor impairments of the patients with RTT well. It also showed a close correlation between the evaluations of clinicians and caregivers, with the possible exception of postural transition tasks, which should be carefully addressed in a clinical setting. The type of mutation and presence of scoliosis should be evaluated, as they predicted the ability to walk. WHAT THIS PAPER ADDS: Caregivers at home can reliably assess motor function in Rett syndrome using the Rett Syndrome Motor Evaluation Scale (RESMES). RESMES scores provided by clinicians and parents were highly correlated. The severity of scoliosis and the genetic mutation predicted standing and walking abilities.

FUNCIÓN MOTORA EN EL SÍNDROME DE RETT: COMPARACIÓN DE EVALUACIONES CLÍNICAS Y PARENTALES: OBJETIVO: Describir una nueva herramienta clínica, la Escala de Evaluación Motora del Síndrome de Rett (RESMES) y evaluar la función motora (locomotora) en personas con síndrome. de Rett (RTT). METODO: La evaluación formal proporcionada por los médicos fue seguida por la observación directa de los padres en el hogar utilizando los RESMES. Sesenta mujeres (edad media 12 años 5 meses[DS =8 años 9 meses], rango 3-40 años) con diagnóstico clínico y genético de RTT participaron en el estudio. Los coeficientes de Spearman / Pearson evaluaron la correlación entre las evaluaciones de los médicos y los cuidadores, así como la correlación de las puntuaciones de RESMES con otras escalas, como la Evaluación del Dolor en la Demencia Avanzada (Pain Assessment in Advanced Dementia), la Escala de Calificación de la Evaluación de Rett (Rett Assessment Rating Scale), la Escala de Ashworth modificada y la función de la mano (evaluado con una escala de evaluación de la función voluntaria de la mano). Las puntuaciones proporcionadas por los padres y los clínicos se evaluaron estadísticamente mediante la prueba U de Mann-Whitney. RESULTADOS: Aproximadamente el 88% de los pacientes tenían síntomas de RTT de moderados a severos y, en promedio, una discapacidad motora moderada basada en los puntajes de RESMES. Se encontró una correlación muy alta (r = 0,91) entre los puntajes totales de RESMES proporcionados por los médicos y cuidadores, al igual que los puntajes con las otras escalas. La transición postural fue un área crítica de RESMES, donde los padres proporcionaron sistemáticamente puntuaciones más bajas que los clínicos, lo que indica grados más leves de discapacidad. La gravedad de la escoliosis y el tipo de mutación fueron factores significativamente predictivos de la función motora. INTERPRETACIÓN: Los puntajes de RESMES caracterizaron bien las alteraciones motoras de las pacientes con RTT. Se encontró una estrecha correlación entre las evaluaciones de los médicos y los cuidadores, con la posible excepción de los cambios postural, que deben evaluarse con cuidado en un entorno clínico. Se debe considerar el tipo de mutación y la presencia de escoliosis, ya que predijeron la capacidad de caminar.

FUNÇÃO MOTORA NA SÍNDROME DE RETT: COMPARANDO AVALIAÇÕES CLÍNICAS E DOS PAIS: OBJETIVO: Descrever uma nova ferramenta clínica, a Escala de avaliação motora da síndrome de Rett (RESMES) e avaliar a função (loco)motora em pessoas com síndrome de Rett (RTT). MÉTODO: A avaliação formal por médicos foi seguida por observação direta dos pais em casa usando a RESMES. Sessenta meninas (média [DP] idade 12a 5m [8a 9m], variação 3-40a) com diagnóstico clínico e RTT determinada geneticamente participaram no estudo. Coeficientes de Spearman/Pearson avaliaram a correlação entre avaliações dos clínicos e cuidadores, assim como as correlações dos escores na RESMES com outras escalas: Avaliação da Dor na Demência avançada (Pain Assessment in Advanced Dementia), Escala de Classificação de Rett (Rett Assessment Rating Scale), a Escala de Ashworth Modificada, e função manual (avaliada com uma escala de avaliação da função manual voluntária). Os escores fornecidos pelos pais e clínicos foram testados estatisticamente com o teste de Mann-Whitney U. RESULTADOS: Aproximadamente 88% dos pacientes tinham sintomas de RTT de moderados a severos e, em média, comprometimento motor moderado na RESMES. Os escores totais da RESMES dados pelos clínicos e cuidadores foram altamente correlacionados (r=0,91), assim como os escores das subescalas. Transição postural foi uma área crítica da RESMES, em que pais sistematicamente ponturam mais baixo que os clínicos, indicando graus mais leves de incapacidade. A severidade da escoliose e tipo de mutação emergiram como preditores significativos da função motora. INTERPRETAÇÃO: A RESMES caracterizou bem as deficiências (loco) motoras de pacientes com RTT. Também mostrou correlação próxima entre as avaliações de clínicos e cuidadores, com a possível exceção das tarefas de transição postural, as quais devem ser cuidadosamente abordadas no contexto clínico. O tipo de mutação e presença de escoliose devem ser avaliados, pois predizem a capacidade de andar.

Cortical response to levodopa in Parkinson's disease patients with dyskinesias.

Levodopa-induced dyskinesias are a common and disabling side effect of dopaminergic therapy in Parkinson's disease, but their neural mechanisms in vivo are still poorly understood. Besides striatal pathology, the importance of cortical dysfunction has been increasingly recognized. The supplementary motor area in particular, may have a relevant role in dyskinesias onset given its involvement in endogenously generated actions. The aim of the present study was to investigate the levodopa-related cortical excitability changes along with the emergence of levodopa-induced peak-of-dose dyskinesias in subjects with Parkinson's disease. Thirteen patients without dyskinesias and ten with dyskinesias received 200/50 mg fast-acting oral levodopa/benserazide following overnight withdrawal (12 hr) from their dopaminergic medication. We targeted transcranial magnetic stimulation to the supplementary motor area, ipsilateral to the most dopamine-depleted striatum defined with single-photon emission computed tomography with [123 I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane, and recorded transcranial magnetic stimulation-evoked potentials with high-density electroencephalography before and at 30, 60, and 180 min after levodopa/benserazide intake. Clinical improvement from levodopa/benserazide paralleled the increase in cortical excitability in both groups. Subjects with dyskinesias showed higher fluctuation of cortical excitability in comparison to non-dyskinetic patients, possibly reflecting dyskinetic movements. Together with endogenous brain oscillation, levodopa-related dynamics of brain state could influence the therapeutic response of neuromodulatory interventions.

Dopamine reuptake transporter-single-photon emission computed tomography and transcranial sonography as imaging markers of prediagnostic Parkinson's disease.

OBJECTIVE: The objective of this study was to examine whether prediagnostic features of Parkinson's disease (PD) were associated with changes in dopamine reuptake transporter-single-photon emission computed tomography and transcranial sonography. METHODS: Prediagnostic features of PD (risk estimates, University of Pennsylvania Smell Identification Test, Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire, and finger-tapping scores) were assessed in a large cohort of older U.K. residents. A total of 46 participants were included in analyses of prediagnostic features and MDS-UPDRS scores with the striatal binding ratio on dopamine reuptake transporter-single-photon emission computed tomography and nigral hyperechogenicity on transcranial sonography. RESULTS: The striatal binding ratio was associated with PD risk estimates (P = .040), University of Pennsylvania Smell Identification Test (P = .002), Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire scores (P = .024), tapping speed (P = .024), and MDS-UPDRS motor scores (P = .009). Remotely collected assessments explained 26% of variation in the striatal binding ratio. The inclusion of MDS-UPDRS motor scores did not explain additional variance. The size of the nigral echogenic area on transcranial sonography was associated with risk estimates (P < .001) and MDS-UPDRS scores (P = .03) only. CONCLUSIONS: The dopamine reuptake transporter-single-photon emission computed tomography results correlated with motor and nonmotor features of prediagnostic PD, supporting its potential use as a marker in the prodromal phase of PD. Transcranial sonography results also correlated with risk scores and motor signs. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Progressive gait ataxia following deep brain stimulation for essential tremor: adverse effect or lack of efficacy?

Thalamic deep brain stimulation is a mainstay treatment for severe and drug-refractory essential tremor, but postoperative management may be complicated in some patients by a progressive cerebellar syndrome including gait ataxia, dysmetria, worsening of intention tremor and dysarthria. Typically, this syndrome manifests several months after an initially effective therapy and necessitates frequent adjustments in stimulation parameters. There is an ongoing debate as to whether progressive ataxia reflects a delayed therapeutic failure due to disease progression or an adverse effect related to repeated increases of stimulation intensity. In this study we used a multimodal approach comparing clinical stimulation responses, modelling of volume of tissue activated and metabolic brain maps in essential tremor patients with and without progressive ataxia to disentangle a disease-related from a stimulation-induced aetiology. Ten subjects with stable and effective bilateral thalamic stimulation were stratified according to the presence (five subjects) of severe chronic-progressive gait ataxia. We quantified stimulated brain areas and identified the stimulation-induced brain metabolic changes by multiple 18 F-fluorodeoxyglucose positron emission tomography performed with and without active neurostimulation. Three days after deactivating thalamic stimulation and following an initial rebound of symptom severity, gait ataxia had dramatically improved in all affected patients, while tremor had worsened to the presurgical severity, thus indicating a stimulation rather than disease-related phenomenon. Models of the volume of tissue activated revealed a more ventrocaudal stimulation in the (sub)thalamic area of patients with progressive gait ataxia. Metabolic maps of both patient groups differed by an increased glucose uptake in the cerebellar nodule of patients with gait ataxia. Our data suggest that chronic progressive gait ataxia in essential tremor is a reversible cerebellar syndrome caused by a maladaptive response to neurostimulation of the (sub)thalamic area. The metabolic signature of progressive gait ataxia is an activation of the cerebellar nodule, which may be caused by inadvertent current spread and antidromic stimulation of a cerebellar outflow pathway originating in the vermis. An anatomical candidate could be the ascending limb of the uncinate tract in the subthalamic area. Adjustments in programming and precise placement of the electrode may prevent this adverse effect and help fine-tuning deep brain stimulation to ameliorate tremor without negative cerebellar signs.

Parkinson's disease beyond 20†years.

BACKGROUND: A very limited number of studies report data on the clinical features of Parkinson's disease (PD) 20 years after onset and beyond. OBJECTIVE: To characterise PD 20 years after onset, investigating the impact of age at onset and disease duration on the clinical picture and the predictors of outcomes in patients reaching the 20-year time point. METHODS: We conducted a retrospective, cross-sectional study and a longitudinal study. All case visits of patients with a disease duration ≥20 years (N=401) were stratified by disease duration (20-22, 23-25, ≥26 years) and by age at onset (cut-off, 50 years). Patients with a disease duration of 20-22 years (N=320) were prospectively followed up for a median of 45 months (IQR 23-89) for the new occurrence of fracture, percutaneous endoscopic gastrostomy, institutionalisation, confinement to a wheelchair or bed and death. RESULTS: Older age at onset and longer disease duration were independently associated with a higher prevalence of major motor and non-motor milestones of disease disability (no interaction observed). In the longitudinal study, the most frequent outcomes were death (N=92), confinement to a wheelchair or bed (N=67) and fracture (N=52). Mortality was associated with the gender: male, older age, dysphagia, orthostatic hypotension, postural instability, fractures and institutionalisation. Fracture was associated with postural instability. Predictors of permanent confinement to a wheelchair or bed were older age, postural instability and institutionalisation. Comorbid dementia at the 20-year examination did not predict any of the outcomes. CONCLUSIONS: Age at onset and disease duration are independent determinants of the clinical features of PD beyond 20 years. Non-motor symptoms depend more on age at onset rather than the disease duration itself. Non-levodopa-responsive axial symptoms are the main predictors of all relevant outcomes.

Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.

GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease.

Spontaneous blink-related beta power increase and theta phase reset in subthalamic nucleus of Parkinson patients during walking.

OBJECTIVE: Both blinking and walking are altered in Parkinson's disease and both motor outputs have been shown to be linked in healthy subjects. Additionally, studies suggest an involvement of basal ganglia activity and striatal dopamine in blink generation. We investigated the role of the basal ganglia circuitry on spontaneous blinking and if this role is dependent on movement state and striatal dopamine. METHODS: We analysed subthalamic nucleus (STN) activity in seven chronically implanted patients for deep brain stimulation (DBS) with respect to blinks and movement state (resting state and unperturbed walking). Neurophysiological recordings were combined with individual molecular brain imaging assessing the dopamine reuptake transporter (DAT) density for the left and right striatum separately. RESULTS: We found a significantly higher blink rate during walking compared to resting. The blink rate during walking positively correlated with the DAT density of the left caudate nucleus. During walking only, spontaneous blinking was followed by an increase in the right STN beta power and a bilateral subthalamic phase reset in the low frequencies. The right STN blink-related beta power modulation correlated negatively with the DAT density of the contralateral putamen. The left STN blink-related beta power correlated with the DAT density of the putamen in the less dopamine-depleted hemisphere. Both correlations were specific to the walking condition and to beta power following a blink. CONCLUSION: Our findings show that spontaneous blinking is related to striatal dopamine and has a frequency specific deployment in the STN. This correlation depends on the current movement state such as walking. SIGNIFICANCE: This work indicates that subcortical activity following a motor event as well as the relationship between dopamine and motor events can be dependent on the motor state. Accordingly, disease related changes in brain activity should be assessed during natural movement.

Gait-related beta-gamma phase amplitude coupling in the subthalamic nucleus of parkinsonian patients.

Analysis of coupling between the phases and amplitudes of neural oscillations has gained increasing attention as an important mechanism for large-scale brain network dynamics. In Parkinson's disease (PD), preliminary evidence indicates abnormal beta-phase coupling to gamma-amplitude in different brain areas, including the subthalamic nucleus (STN). We analyzed bilateral STN local field potentials (LFPs) in eight subjects with PD chronically implanted with deep brain stimulation electrodes during upright quiet standing and unperturbed walking. Phase-amplitude coupling (PAC) was computed using the Kullback-Liebler method, based on the modulation index. Neurophysiological recordings were correlated with clinical and kinematic measurements and individual molecular brain imaging studies ([123I]FP-CIT and single-photon emission computed tomography). We showed a dopamine-related increase in subthalamic beta-gamma PAC from standing to walking. Patients with poor PAC modulation and low PAC during walking spent significantly more time in the stance and double support phase of the gait cycle. Our results provide new insights into the subthalamic contribution to human gait and suggest cross-frequency coupling as a gateway mechanism to convey patient-specific information of motor control for human locomotion.

Metformin use is associated with reduced mortality risk in diabetic patients with Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) and type-2 diabetes (T2D) arguably share pathophysiologic mechanisms, resulting in a more severe phenotype and progression and diabetes is currently considered a risk factor of PD. Besides, research suggests antidiabetic therapies as potential disease-modifying strategies. The main aim was to assess the impact of a metformin-inclusive antidiabetic treatment on patient all-cause mortality. METHODS: A nested case-control prospective study including newly diagnosed PD patients reporting the onset of T2D within ±2 years from the onset of PD (n = 159) and matched (1:5; gender, year of PD onset and age at PD onset) non-diabetic cases (n = 795) followed until death or censoring. Patients on a metformin-inclusive treatment regimen were compared to those receiving other oral anti-diabetics (OADs). RESULTS: Among patients with T2D, 123 were treated with a drug regimen containing metformin (alone [65.0%] or in combination with other drugs [35.0%]) and 36 were prescribed other OADs. During a median PD duration of 96 months [IQR, 60-144], 171 patients died. Diabetes was not associated with reduced survival: fully-adjusted HR = 1.19 [95%CI, 0.81-1.76] (P = 0.37). After stratifying for T2D treatment, a metformin-inclusive regimen was not associated with increased risk of death (HR = 1.06 [95%CI, 0.61-1.84]; P = 0.83), while patients receiving other OADs had reduced survival (HR = 1.83 [95%CI, 1.01-3.32]; P = 0.034). CONCLUSIONS: Metformin use was not associated with increased risk of death in diabetic patients with PD reporting concomitant onset of the two diseases. Metformin appears to be a promising disease-modifying therapy given also the preclinical background, low cost and satisfactory safety and tolerability. Further studies are warranted to investigate its impact on disease progression.

Gait Event Prediction Using Surface Electromyography in Parkinsonian Patients.

Gait disturbances are common manifestations of Parkinson's disease (PD), with unmet therapeutic needs. Inertial measurement units (IMUs) are capable of monitoring gait, but they lack neurophysiological information that may be crucial for studying gait disturbances in these patients. Here, we present a machine learning approach to approximate IMU angular velocity profiles and subsequently gait events using electromyographic (EMG) channels during overground walking in patients with PD. We recorded six parkinsonian patients while they walked for at least three minutes. Patient-agnostic regression models were trained on temporally embedded EMG time series of different combinations of up to five leg muscles bilaterally (i.e., tibialis anterior, soleus, gastrocnemius medialis, gastrocnemius lateralis, and vastus lateralis). Gait events could be detected with high temporal precision (median displacement of <50 ms), low numbers of missed events (<2%), and next to no false-positive event detections (<0.1%). Swing and stance phases could thus be determined with high fidelity (median F1-score of ~0.9). Interestingly, the best performance was obtained using as few as two EMG probes placed on the left and right vastus lateralis. Our results demonstrate the practical utility of the proposed EMG-based system for gait event prediction, which allows the simultaneous acquisition of an electromyographic signal to be performed. This gait analysis approach has the potential to make additional measurement devices such as IMUs and force plates less essential, thereby reducing financial and preparation overheads and discomfort factors in gait studies.

Pallidal Recordings in Chronically Implanted Dystonic Patients: Mitigation of Tremor-Related Artifacts.

Low-frequency oscillatory patterns of pallidal local field potentials (LFPs) have been proposed as a physiomarker for dystonia and hold the promise for personalized adaptive deep brain stimulation. Head tremor, a low-frequency involuntary rhythmic movement typical of cervical dystonia, may cause movement artifacts in LFP signals, compromising the reliability of low-frequency oscillations as biomarkers for adaptive neurostimulation. We investigated chronic pallidal LFPs with the PerceptTM PC (Medtronic PLC) device in eight subjects with dystonia (five with head tremors). We applied a multiple regression approach to pallidal LFPs in patients with head tremors using kinematic information measured with an inertial measurement unit (IMU) and an electromyographic signal (EMG). With IMU regression, we found tremor contamination in all subjects, whereas EMG regression identified it in only three out of five. IMU regression was also superior to EMG regression in removing tremor-related artifacts and resulted in a significant power reduction, especially in the theta-alpha band. Pallido-muscular coherence was affected by a head tremor and disappeared after IMU regression. Our results show that the Percept PC can record low-frequency oscillations but also reveal spectral contamination due to movement artifacts. IMU regression can identify such artifact contamination and be a suitable tool for its removal.

Onset and mortality of Parkinson's disease in relation to type II diabetes.

OBJECTIVES: There is growing evidence that Parkinson's disease and diabetes are partially related diseases; however, the association between the two, and the impact of specific treatments, are still unclear. We evaluated the effect of T2D and antidiabetic treatment on age at PD onset and on all-cause mortality. RESEARCH DESIGN AND METHODS: The standardized rate of T2D was calculated for PD patients using the direct method and compared with subjects with essential tremor (ET) and the general Italian population. Age at onset and survival were also compared between patients without T2D (PD-noT2D), patients who developed T2D before PD onset (PD-preT2D) and patients who developed T2D after PD onset (PD-postT2D). RESULTS: We designed a retrospective and prospective study. The T2D standardized ratio of PD (N = 8380) and ET (N = 1032) patients was 3.8% and 6.1%, respectively, while in the Italian general population, the overall prevalence was 5.3%. In PD-preT2D patients, on antidiabetic treatment, the onset of PD was associated with a + 6.2 year delay (p < 0.001) while no difference was observed in PD-postT2D. Occurrence of T2D before PD onset negatively affected prognosis (adjusted hazard ratio = 1.64 [95% CI 1.33-2.02]; p < 0.001), while no effect on survival was found in PD-postT2D subjects (hazard ratio = 0.86, [95% CI 0.53-1.39]; p = 0.54). CONCLUSIONS: T2D, treated with any antidiabetic therapy before PD, is associated with a delay in its onset. Duration of diabetes increases mortality in PD-preT2D, but not in PD-postT2D. These findings prompt further studies on antidiabetic drugs as a potential disease-modifying therapy for PD.

Dopaminergic striatal innervation predicts interlimb transfer of a visuomotor skill.

We investigated whether dopamine influences the rate of adaptation to a visuomotor distortion and the transfer of this learning from the right to the left limb in human subjects. We thus studied patients with Parkinson disease as a putative in vivo model of dopaminergic denervation. Despite normal adaptation rates, patients showed a reduced transfer compared with age-matched healthy controls. The magnitude of the transfer, but not of the adaptation rate, was positively predicted by the values of dopamine-transporter binding of the right caudate and putamen. We conclude that striatal dopaminergic activity plays an important role in the transfer of visuomotor skills.

Adaptive deep brain stimulation: Retuning Parkinson's disease.

A brain-machine interface represents a promising therapeutic avenue for the treatment of many neurologic conditions. Deep brain stimulation (DBS) is an invasive, neuro-modulatory tool that can improve different neurologic disorders by delivering electric stimulation to selected brain areas. DBS is particularly successful in advanced Parkinson's disease (PD), where it allows sustained improvement of motor symptoms. However, this approach is still poorly standardized, with variable clinical outcomes. To achieve an optimal therapeutic effect, novel adaptive DBS (aDBS) systems are being developed. These devices operate by adapting stimulation parameters in response to an input signal that can represent symptoms, motor activity, or other behavioral features. Emerging evidence suggests greater efficacy with fewer adverse effects during aDBS compared with conventional DBS. We address this topic by discussing the basics principles of aDBS, reviewing current evidence, and tackling the many challenges posed by aDBS for PD.