OFF Medication Research Articles

Reaching and stepping respond differently to medication and cueing in Parkinson’s disease

The basal ganglia contribute to internal timekeeping, and dopaminergic medication has been observed to moderate timing deficits associated with Parkinson’s Disease (PD) during single joint movements. However, it is unclear whether similar effects can be observed in multi-joint movements. Twenty-five people with PD and twelve healthy peers performed repetitive reaching and stepping-in-place tasks with and without auditory cues at their self-selected maximal cadence. The PD group was measured ON and OFF medication. Reduced cadence error was found for both groups and tasks when cued, and ON PD exhibited decreased cadence compared to OFF PD. Overall timing variability was no different from controls, but differences were found in estimates of clock and motor variance using the Wing-Kristofferson model of interval timing. A medication and cueing interaction during the reaching task produced increased clock variance in uncued, ON PD. During the stepping task, clock and motor variance of the PD group were unaffected by cues, in contrast to the control group. Serial lag-one correlation was reduced in both groups for cued reaching, but was unaffected by cueing or medication in the PD group when stepping-in-place. These findings suggest that overall timing variability may not capture timing deficits in PD.

Neurophysiological markers of motor compensatory mechanisms in early Parkinson's disease.

Compensatory mechanisms in Parkinson's disease are defined as the changes that the brain uses to adapt to neurodegeneration and progressive dopamine reduction. Motor compensation in early Parkinson's disease could, in part, be responsible for a unilateral onset of clinical motor signs despite the presence of bilateral nigrostriatal degeneration. Although several mechanisms have been proposed for compensatory adaptations in Parkinson's disease, the underlying pathophysiology is unclear. Here, we investigate motor compensation in Parkinson's disease by investigating the relationship between clinical signs, dopamine transporter imaging data and neurophysiological measures of the primary motor cortex (M1), using transcranial magnetic stimulation in presymptomatic and symptomatic hemispheres of patients. In this cross-sectional, multicentre study, we screened 82 individuals with Parkinson's disease. Patients were evaluated clinically in their medication OFF state using standardized scales. Sixteen Parkinson's disease patients with bilateral dopamine transporter deficit in the putamina but unilateral symptoms were included. Twenty-eight sex- and age-matched healthy controls were also investigated. In all participants, we tested cortical excitability using single- and paired-pulse techniques, interhemispheric inhibition and cortical plasticity with paired associative stimulation. Data were analysed with ANOVAs, multiple linear regression and logistic regression models. Individual coefficients of motor compensation were defined in patients based on clinical and imaging data, i.e. the motor compensation coefficient. The motor compensation coefficient includes an asymmetry score to balance motor and dopamine transporter data between the two hemispheres, in addition to a hemispheric ratio accounting for the relative mismatch between the magnitude of motor signs and dopaminergic deficit. In patients, corticospinal excitability and plasticity were higher in the presymptomatic compared with the symptomatic M1. Also, interhemispheric inhibition from the presymptomatic to the symptomatic M1 was reduced. Lower putamen binding was associated with higher plasticity and reduced interhemispheric inhibition in the presymptomatic hemisphere. The motor compensation coefficient distinguished the presymptomatic from the symptomatic hemisphere. Finally, in the presymptomatic hemisphere, a higher motor compensation coefficient was associated with lower corticospinal excitability and interhemispheric inhibition and with higher plasticity. In conclusion, the present study suggests that motor compensation involves M1-striatal networks and intercortical connections becoming more effective with progressive loss of dopaminergic terminals in the putamen. The balance between these motor networks seems to be driven by cortical plasticity.

The Time Course of Changes in Prefrontal Cortex Activity During Walking in People With Parkinson’s Disease

Background Walking abnormalities in people with Parkinson’s disease (PD) are characterized by a shift in locomotor control from healthy automaticity to compensatory, executive control, mainly located in the prefrontal cortex (PFC). Although PFC activity during walking increases in people with PD, the time course of PFC activity during walking and its relationship to clinical or gait characteristics is unknown. Objective To identify the time course of PFC activity during walking in people with PD. To investigate whether clinical or gait variables would explain the PFC activity changes. Methods Thirty-eight people with PD tested OFF medication wore a portable, functional near-infrared spectroscopy (fNIRS) system to record relative PFC activity while walking. Wearable inertial sensors recorded spatiotemporal gait characteristics. Based on the PFC activity (fNIRS) in the late phase of the walking task (final 40 seconds), compared to the early phase (initial 40 seconds), participants were separated into 2 groups: reduced or sustained PFC activity. Results People with PD who reduced PFC activity during walking had less impaired gait (eg, faster gait speed) than those who had a sustained increase in PFC activity (P < .05). Cognitive set-shifting ability explained 18% of the PFC activation in the group with a sustained increase in PFC activity (P = .033). Conclusions The time course of reduction in PFC activity corresponds to less impaired gait performance in people with PD, while a sustained increase in PFC activity is related to worse cognitive flexibility. Reduction in PFC activity while walking may indicate a less impaired, automatic control of walking.

Inter-joint coordination with and without dopaminergic medication in Parkinson’s disease: a case-control study

BackgroundHow the joints exactly move and interact and how this reflects PD-related gait abnormalities and the response to dopaminergic treatment is poorly understood. A detailed understanding of these kinematics can inform clinical management and treatment decisions. The aim of the study was to investigate the influence of different gait speeds and medication on/off conditions on inter-joint coordination, as well as kinematic differences throughout the whole gait cycle in well characterized pwPD.Methods29 controls and 29 PD patients during medication on, 8 of them also during medication off walked a straight walking path in slow, preferred and fast walking speeds. Gait data was collected using optical motion capture system. Kinematics of the hip and knee and coordinated hip-knee kinematics were evaluated using Statistical Parametric Mapping (SPM) and cyclograms (angle-angle plots). Values derived from cyclograms were compared using repeated-measures ANOVA for within group, and ttest for between group comparisons.ResultsPD gait differed from controls mainly by lower knee range of motion (ROM). Adaptation to gait speed in PD was mainly achieved by increasing hip ROM. Regularity of gait was worse in PD but only during preferred speed. The ratios of different speed cyclograms were smaller in the PD groups. SPM analyses revealed that PD participants had smaller hip and knee angles during the swing phase, and PD participants reached peak hip flexion later than controls. Withdrawal of medication showed an exacerbation of only a few parameters.ConclusionsOur findings demonstrate the potential of granular kinematic analyses, including > 1 joint, for disease and treatment monitoring in PD. Our approach can be extended to further mobility-limiting conditions and other joint combinations.Trial registrationThe study is registered in the German Clinical Trials Register (DRKS00022998, registered on 04 Sep 2020).

Trend change analysis of postural balance in Parkinson’s disease discriminates between medication state

BackgroundMaintaining static balance is relevant and common in everyday life and it depends on a correct intersegmental coordination. A change or reduction in postural capacity has been linked to increased risk of falls. People with Parkinson’s disease (pwPD) experience motor symptoms affecting the maintenance of a stable posture. The aim of the study is to understand the intersegmental changes in postural sway and to apply a trend change analysis to uncover different movement strategies between pwPD and healthy adults.MethodsIn total, 61 healthy participants, 40 young (YO), 21 old participants (OP), and 29 pwPD (13 during medication off, PDoff; 23 during medication on, PDon) were included. Participants stood quietly for 10 s as part of the Short Physical Performance Battery. Inertial measurement units (IMU) at the head, sternum, and lumbar region were used to extract postural parameters and a trend change analysis (TCA) was performed to compare between groups.ObjectiveThis study aims to explore the potential application of TCA for the assessment of postural stability using IMUs, and secondly, to employ this analysis within the context of neurological diseases, specifically Parkinson’s disease.ResultsComparison of sensors locations revealed significant differences between head, sternum and pelvis for almost all parameters and cohorts. When comparing PDon and PDoff, the TCA revealed differences that were not seen by any other parameter.ConclusionsWhile all parameters could differentiate between sensor locations, no group differences could be uncovered except for the TCA that allowed to distinguish between the PD on/off. The potential of the TCA to assess disease progression, response to treatment or even the prodromal PD phase should be explored in future studies.Trial registrationThe research procedure was approved by the ethical committee of the Medical Faculty of Kiel University (D438/18). The study is registered in the German Clinical Trials Register (DRKS00022998).

In Parkinson's disease dopaminergic medication and deep brain stimulation of the subthalamic nucleus increase motor, but not reflection and cognitive impulsivity.

Parkinson's disease is associated with increased impulsivity, which can be divided into several domains: motor (consisting of proactive and reactive subdomains), reflection, and cognitive impulsivity. Evidence suggests that both dopaminergic medication and subthalamic nucleus deep brain stimulation can affect impulsivity. Therefore, we set out to investigate the effects of dopaminergic medication and subthalamic nucleus deep brain stimulation on motor, reflection, and cognitive impulsivity in Parkinson's disease patients. Twenty Parkinson's disease patients who underwent subthalamic nucleus deep brain stimulation were tested ON and OFF dopaminergic medication and ON and OFF subthalamic nucleus deep brain stimulation. They performed three different impulsivity tasks: the AX continuous performance task (AX-CPT) to test for motor impulsivity, the Beads task for reflection impulsivity, and the Delay discounting task for cognitive impulsivity. The combination of subthalamic nucleus deep brain stimulation and dopaminergic medication led to an increase in motor impulsivity (p = 0.036), both proactive (p = 0.045) and reactive (p = 0.006). There was no effect of either dopaminergic medication or subthalamic nucleus deep brain stimulation on reflection and cognitive impulsivity. The combination of dopaminergic medication and subthalamic nucleus deep brain stimulation leads to increased motor, but not cognitive or reflection, impulsivity in patients with Parkinson's disease. Both proactive and reactive motor impulsivity were impaired by the combination of dopaminergic medication and subthalamic nucleus deep brain stimulation.

Stride width and postural stability in frontal gait disorders and Parkinson's disease.

Older adults, as well as those with certain neurological disorders, may compensate for poor neural control of postural stability by widening their base of foot support while walking. However, the extent to which this wide-based gait improves postural stability or affects postural control strategies has not been explored. People with idiopathic Parkinson's disease (iPD, n = 72), frontal gait disorders (FGD, n = 16), and healthy older adults (n = 32) performed walking trials at their preferred speed over an 8-m-long, instrumented walkway. People with iPD were tested in their OFF medication state. Analyses of covariance were performed to determine the associations between stride width and measures of lateral stability control. People with FGD exhibited a wide-based gait compared to both healthy older adults and iPD. An increased stride width was associated with an increase in lateral margin of stability in FGD. Unlike healthy older adults or iPD, people with FGD did not externally rotate their feet (toe-out angle) or shift their center of pressure laterally to aid lateral dynamic stability during walking but slowed their gait instead to increase stability. By adopting a slow, wide-based gait, people with FGD take advantage of the passive, pendular mechanics of walking.

Quantifying local field potential dynamics with amplitude and frequency stability between ON and OFF medication and stimulation in Parkinson's disease

Neural oscillations are critical to understanding the synchronisation of neural activities and their relevance to neurological disorders. For instance, the amplitude of beta oscillations in the subthalamic nucleus has gained extensive attention, as it has been found to correlate with medication status and the therapeutic effects of continuous deep brain stimulation in people with Parkinson's disease. However, the frequency stability of subthalamic nucleus beta oscillations, which has been suggested to be associated with dopaminergic information in brain states, has not been well explored. Moreover, the administration of medicine can have inverse effects on changes in frequency and amplitude. In this study, we proposed a method based on the stationary wavelet transform to quantify the amplitude and frequency stability of subthalamic nucleus beta oscillations and evaluated the method using simulation and real data for Parkinson's disease patients. The results suggest that the amplitude and frequency stability quantification has enhanced sensitivity in distinguishing pathological conditions in Parkinson's disease patients. Our quantification shows the benefit of combining frequency stability information with amplitude and provides a new potential feedback signal for adaptive deep brain stimulation.

Clinical and Brain Morphometry Predictors of Deep Brain Stimulation Outcome in Parkinson’s Disease

Subthalamic deep brain stimulation (STN-DBS) is known to improve motor function in advanced Parkinson’s disease (PD) and to enable a reduction of anti-parkinsonian medication. While the levodopa challenge test and disease duration are considered good predictors of STN-DBS outcome, other clinical and neuroanatomical predictors are less established. This study aimed to evaluate, in addition to clinical predictors, the effect of patients’ individual brain topography on DBS outcome. The medical records of 35 PD patients were used to analyze DBS outcomes measured with the following scales: Part III of the Unified Parkinson’s Disease Rating Scale (UPDRS-III) off medication at baseline, and at 6-months during medication off and stimulation on, use of anti-parkinsonian medication (LED), Abnormal Involuntary Movement Scale (AIMS) and Non-Motor Symptoms Questionnaire (NMS-Quest). Furthermore, preoperative brain MRI images were utilized to analyze the brain morphology in relation to STN-DBS outcome. With STN-DBS, a 44% reduction in the UPDRS-III score and a 43% decrease in the LED were observed (p<0.001). Dyskinesia and non-motor symptoms decreased significantly [median reductions of 78,6% (IQR 45,5%) and 18,4% (IQR 32,2%) respectively, p=0.001 – 0.047]. Along with the levodopa challenge test, patients’ age correlated with the observed DBS outcome measured as UPDRS-III improvement (ρ= -0.466 – -0.521, p<0.005). Patients with greater LED decline had lower grey matter volumes in left superior medial frontal gyrus, in supplementary motor area and cingulum bilaterally. Additionally, patients with greater UPDRS-III score improvement had lower grey matter volume in similar grey matter areas. These findings remained significant when adjusted for sex, age, baseline LED and UPDRS scores respectively and for total intracranial volume (p=0.0041- 0.001). However, only the LED decrease finding remained significant when the analyses were further controlled for stimulation amplitude. It appears that along with the clinical predictors of STN-DBS outcome, individual patient topographic differences may influence DBS outcome. Clinical Trial Registration Number: NCT06095245, registration date October 23, 2023, retrospectively registered

Dopamine improves defective cortical and muscular connectivity during bilateral control of gait in Parkinson’s disease

Parkinson’s Disease (PD)-typical declines in gait coordination are possibly explained by weakness in bilateral cortical and muscular connectivity. Here, we seek to determine whether this weakness and consequent decline in gait coordination is affected by dopamine levels. To this end, we compare cortico-cortical, cortico-muscular, and intermuscular connectivity and gait outcomes between body sides in people with PD under ON and OFF medication states, and in older adults. In our study, participants walked back and forth along a 12 m corridor. Gait events (heel strikes and toe-offs) and electrical cortical and muscular activities were measured and used to compute cortico-cortical, cortico-muscular, and intermuscular connectivity (i.e., coherences in the alpha, beta, and gamma bands), as well as features characterizing gait performance (e.g., the step-timing coordination, length, and speed). We observe that people with PD, mainly during the OFF medication, walk with reduced step-timing coordination. Additionally, our results suggest that dopamine intake in PD increases the overall cortico-muscular connectivity during the stance and swing phases of gait. We thus conclude that dopamine corrects defective feedback caused by impaired sensory-information processing and sensory-motor integration, thus increasing cortico-muscular coherences in the alpha bands and improving gait.

Ensemble classifiers fed by functional connectivity during cognitive processing differentiate Parkinson’s disease even being under medication

Brain–computer interface technologies, as a type of human-computer interaction, provide a control ability on machines and intelligent systems via human brain functions without needing physical contact. Moreover, it has a considerable contribution to the detection of cognitive state changes, which gives a clue for neurodegenerative diseases, including Parkinson’s disease (PD), in recent years. Although various studies implemented different machine learning models with several EEG features to detect PD and receive remarkable performances, there is a lack of knowledge on how brain connectivity during a cognitive task contributes to the differentiation of PD, even being under medication. To fill this gap, this study used three ensemble classifiers, which were fed by functional connectivity through cognitive response coherence (CRC) with varying selected features in different frequency bands upon application of the 3-Stimulation auditory oddball paradigm to differentiate PD medication ON and OFF and healthy controls (HC). The results revealed that the most remarkable performances were exhibited in slow frequency bands (delta and theta) in comparison to high frequency and wide range bands, especially in terms of target sounds. Moreover, in the delta band, target CRC distinguishes all groups from each other with accuracy rates of 80% for HC vs PD-OFF, 80% for HC vs PD-ON, and 81% for PD-ON vs PD-OFF. In the theta band, again target sounds were the most distinctive stimuli to classify HCxPD-OFF (80% accuracy), HCxPD-ON (80.5% accuracy) with quite good performances, and PD-ONxPD-OFF (76% accuracy) with acceptable performance. Besides, this study achieved a state-of-the-art performance with an accuracy of 87.5% in classifying PD-ONxPD-OFF via CRC of standard sounds in the delta band. Overall, the findings revealed that brain connectivity contributes to identifying PD and HC as well as the medication state of PD, especially in the slow frequency bands.

Fractal dimensions and machine learning for detection of Parkinson’s disease in resting-state electroencephalography

Parkinson’s disease (PD) is an incurable neurological disorder that degenerates the cerebrospinal nervous system and hinders motor functions. Electroencephalography (EEG) signal analysis can provide reliable information regarding PD conditions. However, EEG is a complex, multichannel, and nonlinear signal with noise that problematizes identifying PD symptoms. A few studies have employed fractal dimension (FD) to extract distinguishing PD features from EEG signals. However, no exploratory study exists, as per our knowledge, on the efficiency of the different FD measures. We aim to conduct a comparative analysis of the various FDs that, as feature extraction measures, can discriminate PD patients who are ON and OFF medication from healthy controls using ML architecture. This study has implemented and analyzed several techniques for segmentation, feature extraction, and ML models. The results show that k-nearest neighbors (KNN) classifier with Higuchi FD and 90% overlap for segmented window delivers the highest accuracies, yielding a mean accuracy of 99.65±0.15%\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$99.65\\pm 0.15\\%$$\\end{document} for PD patients ON medication and 99.45±0.18%\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$99.45\\pm 0.18\\%$$\\end{document} for PD patients OFF medication, respectively. The model accurately identifies the signs of the disease in resting-state EEG with almost equivalent accuracy in both OFF and ON medication patients. To enhance the interpretability in our study, we leveraged XGB’s feature importance to generate brain topographic plots. This integration of explainable AI (XAI) enhanced the transparency and comprehensibility of our model’s classifications. Additionally, a comparison between the performance of FD and a few entropy measures has also been drawn to validate the significance of FD as a superior feature extraction measure. This study contributes to the body of knowledge with an architectural pipeline for detecting PD in resting-state EEG while emphasizing fractal dimension as an effective way of extracting salient features from EEG signals.

Abnormally low sensorimotor α band nonlinearity serves as an effective EEG biomarker of Parkinson's disease.

Biomarkers obtained from the neurophysiological signals of patients with Parkinson's disease (PD) have objective value in assessing their motor condition for effective diagnosis, monitoring, and clinical intervention. Prominent cortical biomarkers of PD have typically been derived from various β band wave features. This study approached the topic from an alternative perspective and attempted to estimate a recently suggested measure representing α band nonlinear autocorrelative memory from a publicly available EEG dataset that involves 15 patients with earlier-stage PD (dopaminergic medication OFF and ON states) and 16 age-matched healthy controls. The cortical nonlinearity was elevated for the PD ON state compared with the OFF state for bilateral sensorimotor channels C3 and C4 (n = 26; P = 0.003). A similar statistical difference was also identified between PD OFF state and healthy subjects (n = 26; P = 0.049). Analysis over all channels revealed that the α band nonlinearity induced upon medication was constrained to sensorimotor regions. The α nonlinearity measure was compared with a well-accepted cortical biomarker of β-γ phase-amplitude coupling (PAC). They were in moderate negative correlation (r = -0.412; P = 0.036) for only healthy subjects, but not for the patients. The nonlinearity measure was found to be insusceptible to the nonstationary variations within the particular data. Our study provides further evidence that the α band nonlinearity measure can serve as a promising cortical biomarker of PD. The suggested measure can be estimated from a noninvasive low-resolution single scalp EEG channel of patients with relatively early-stage PD, who did not yet need to undergo deep brain stimulation operation.NEW & NOTEWORTHY This study suggests a nonlinearity measure that differentiates Parkinson's disease (PD) dopamine OFF-state scalp EEG data from those of dopamine ON-state patients and healthy subjects. Unlike typical PD cortical biomarkers based on β band activity, this metric shows elevation upon dopaminergic medication in the α band. We provide evidence supporting its potential as an early-stage promising PD biomarker that can be estimated from noninvasive EEG recordings with low resolution and SNR.

Validity and reliability of linear encoder muscle power testing in persons with Parkinson's disease

Objective To investigate the construct validity ON medication and the reliability both ON and OFF medication of linear encoder muscle power testing in persons with Parkinson's disease (pwPD). Design A study using baseline data from one randomized controlled trial (study 1) and one cohort study (study 2). Setting University exercise lab. Participants Study 1: 35 healthy controls and 70 pwPD. Study 2: 20 pwPD. Intervention Study 1: baseline data. Study 2: 4 chair rise tests (2 ON and 2 OFF medication), in a randomized order, separated by 4 to 16 days. Main measures Linear encoder data were collected from a chair rise test. Known groups validity and convergent validity (i.e., construct validity) were assessed by comparing peak power between pwPD and healthy controls and associations between peak power and functional performance (i.e., 6-Min Walk Test, Timed Up and Go Test, Six-Spot Step Test), respectively. Reliability was assessed as day-to-day variation and by intraclass correlation coefficients. Results Peak power was comparable between pwPD and healthy controls (−7.2%, p = 0.17), but lower in moderately impaired pwPD compared to mildly impaired pwPD (−27%, p < 0.01) and healthy controls (−23%, p < 0.01). Moderate to strong associations were observed between peak power and functional performance (r2 = 0.44–0.51). Day-to-day variation ON and OFF medication were 1.0 and 1.3 W/kg, respectively, while intraclass correlation coefficients were 0.95 (0.87;0.98) and 0.93 (0.82;0.97), respectively. Conclusion Linear encoder muscle power testing shows inconsistent known groups validity, acceptable convergent validity ON medication, and excellent day-to-day reliability ON and OFF medication in pwPD.

Effects of subthalamic nucleus deep brain stimulation on the speech of Spanish-speaking Parkinson's disease patients during the first year of treatment.

To describe the effects of subthalamic nucleus deep brain stimulation (STN-DBS) on the speech of Spanish-speaking Parkinson's disease (PD) patients during the first year of treatment. The speech measures (SMs): maximum phonation time, acoustic voice measures, speech rate, speech intelligibility measures, and oral diadochokinesis rates of nine Colombian idiopathic PD patients (four females and five males; age = 63 ± 7 years; years of PD = 10 ± 7 years; UPDRS-III = 57 ± 6; H&Y = 2 ± 0.3) were studied in OFF and ON medication states before and every three months during the first year after STN-DBS surgery. Praat software and healthy native listeners' ratings were used for speech analysis. Statistical analysis tried to find significant differences in the SMs during follow-up (Friedman test) and between medication states (Wilcoxon paired test). Also, a pre-surgery variation interval (PSVI) of reference for every participant and SM was calculated to make an individual analysis of post-surgery variation. Non-significative post-surgery or medication state-related differences in the SMs were found. Nevertheless, individually, based on PSVIs, the SMs exhibited: no variation, inconsistent or consistent variation during post-surgery follow-up in different combinations, depending on the medication state. As a group, participants did not have a shared post-surgery pattern of change in any SM. Instead, based on PSVIs, the SMs varied differently in every participant, which suggests that in Spanish-speaking PD patients, the effects of STN-DBS on speech during the first year of treatment could be highly variable.

Evaluating the ability of a predictive vision-based machine learning model to measure changes in gait in response to medication and DBS within individuals with Parkinson’s disease

IntroductionGait impairments in Parkinson’s disease (PD) are treated with dopaminergic medication or deep-brain stimulation (DBS), although the magnitude of the response is variable between individuals. Computer vision-based approaches have previously been evaluated for measuring the severity of parkinsonian gait in videos, but have not been evaluated for their ability to identify changes within individuals in response to treatment. This pilot study examines whether a vision-based model, trained on videos of parkinsonism, is able to detect improvement in parkinsonian gait in people with PD in response to medication and DBS use.MethodsA spatial–temporal graph convolutional model was trained to predict MDS-UPDRS-gait scores in 362 videos from 14 older adults with drug-induced parkinsonism. This model was then used to predict MDS-UPDRS-gait scores on a different dataset of 42 paired videos from 13 individuals with PD, recorded while ON and OFF medication and DBS treatment during the same clinical visit. Statistical methods were used to assess whether the model was responsive to changes in gait in the ON and OFF states.ResultsThe MDS-UPDRS-gait scores predicted by the model were lower on average (representing improved gait; p = 0.017, Cohen’s d = 0.495) during the ON medication and DBS treatment conditions. The magnitude of the differences between ON and OFF state was significantly correlated between model predictions and clinician annotations (p = 0.004). The predicted scores were significantly correlated with the clinician scores (Kendall’s tau-b = 0.301, p = 0.010), but were distributed in a smaller range as compared to the clinician scores.ConclusionA vision-based model trained on parkinsonian gait did not accurately predict MDS-UPDRS-gait scores in a different PD cohort, but detected weak, but statistically significant proportional changes in response to medication and DBS use. Large, clinically validated datasets of videos captured in many different settings and treatment conditions are required to develop accurate vision-based models of parkinsonian gait.

Efficacy and safety aspects of renal denervation in treatment of arterial hypertension: a systematic review and meta-analysis

Abstract Introduction Current guidelines for the management of arterial hypertension 2018 of European Society for Cardiology (ESC) do not recommend use of renal denervation (RDN) (as device-based therapy) for treatment of hypertension except as part of clinical studies. However, in the meantime several randomized sham-controlled clinical trials were designed using second generation radiofrequency (RF) (SPYRAL HTN-OFF MED, SPYRAL HTN-ON MED), ultrasound (RADIANCE-HTN SOLO, RADIANCE-HTN TRIO) or alcohol-mediated renal denervation (TARGET BP-OFF) devices. We aimed to perform a comprehensive meta-analysis from all published and unpublished randomized, sham-controlled clinical trials which explored the effects of renal denervation on blood pressure across different devices. Methods We searched MEDLINE and Embase via OVID@ for eligible trials. Of note, we also included unpublished data from the SPYRAL-ON Extension and TARGET BP OFF trials. Pooling the data from all studies, we explored the efficacy (ambulatory and office systolic and diastolic BP) and safety (all cause death, vascular complication, renal artery stenosis &amp;gt;70%, hypertensive crisis) of RDN. Results Analysis included 9 eligible trials (i.e. SYMPLICITY HTN-3, ReSET, SPYRAL HTN OFF MED, Desch et al., RADIANCE-HTN SOLO, RADIANCE-HTN TRIO, RADIANCE, TARGET BP OFF, SPYRAL HTN ON MED extension) comprising 2,091 patients (Table 1). RDN reduced ambulatory systolic (-3.10 mmHg, 95% CI -4.22, -1.97, p&amp;lt;0.00001) and office systolic (-5.15 mmHg, 95% CI -6.65, -3.66, p&amp;lt;0.00001) BP and ambulatory diastolic (-1.58 mmHg, 95% CI -2.54, -0.63, p=0.001) and office diastolic (-2.74 mmHg, 95% CI -3.65, -1.83, p&amp;lt;0.00001) BP compared with sham groups. There was no difference concerning ambulatory SBP reduction between trials with ON medication design (-2.94 mmHg, p&amp;lt;0.0001) and those with OFF medication design (-3.37 mmHg, p&amp;lt;0.0001) (p for interaction 0.69). Similarly, office SBP reduction was comparable between trials with (-4.38 mmHg, p&amp;lt;0.0001) and without concomitant antihypertensive drugs prescription (-6.27 mmHg, p&amp;lt;0.00001) (p for interaction 0.22). The rate of vascular complications (OR 1.21, 95% CI 0.28, 5.25, p=0.80), renal artery stenosis (OR 1.50, 95% CI 0.06, 36.97, p=0.80), hypertensive crisis (OR 1.39, 95% CI 0.50, 3.92, p=0.53) and all cause death (OR 0.52, 95% CI 0.10, 2.83, p=0.45) was not different between treatment and sham groups. Conclusions RDN is associated with clinically significant reductions in ambulatory and office SBP as compared with sham in the presence and absence of antihypertensive medication. The procedure use was not associated with an excess in safety events compared with sham group.

Medication only improves limb movements while deep brain stimulation improves eye and limb movements during visually-guided reaching in Parkinson's disease.

Antiparkinson medication and subthalamic nucleus deep brain stimulation (STN-DBS), two common treatments of Parkinson's disease (PD), effectively improve skeletomotor movements. However, evidence suggests that these treatments may have differential effects on eye and limb movements, although both movement types are controlled through the parallel basal ganglia loops. Using a task that requires both eye and upper limb movements, we aimed to determine the effects of medication and STN-DBS on eye and upper limb movement performance. Participants performed a visually-guided reaching task. We collected eye and upper limb movement data from participants with PD who were tested both OFF and ON medication (n = 34) or both OFF and ON bilateral STN-DBS while OFF medication (n = 11). We also collected data from older adult healthy controls (n = 14). We found that medication increased saccade latency, while having no effect on reach reaction time (RT). Medication significantly decreased saccade peak velocity, while increasing reach peak velocity. We also found that bilateral STN-DBS significantly decreased saccade latency while having no effect on reach RT, and increased saccade and reach peak velocity. Finally, we found that there was a positive relationship between saccade latency and reach RT, which was unaffected by either treatment. These findings show that medication worsens saccade performance and benefits reaching performance, while STN-DBS benefits both saccade and reaching performance. We explore what the differential beneficial and detrimental effects on eye and limb movements suggest about the potential physiological changes occurring due to treatment.

Differential spatiotemporal gait effects with frequency and dopaminergic modulation in STN-DBS.

The spatiotemporal gait changes in advanced Parkinson's disease (PD) remain a treatment challenge and have variable responses to L-dopa and subthalamic deep brain stimulation (STN-DBS). The purpose of this study was to determine whether low-frequency STN-DBS (LFS; 60 Hz) elicits a differential response to high-frequency STN-DBS (HFS; 180 Hz) in spatiotemporal gait kinematics. Advanced PD subjects with chronic STN-DBS were evaluated in both the OFF and ON medication states with LFS and HFS stimulation. Randomization of electrode contact pairs and frequency conditions was conducted. Instrumented Stand and Walk assessments were carried out for every stimulation/medication condition. LM-ANOVA was employed for analysis. Twenty-two PD subjects participated in the study, with a mean age (SD) of 63.9 years. Significant interactions between frequency (both LFS and HFS) and electrode contact pairs (particularly ventrally located contacts) were observed for both spatial (foot elevation, toe-off angle, stride length) and temporal (foot speed, stance, single limb support (SLS) and foot swing) gait parameters. A synergistic effect was also demonstrated with L-dopa and both HFS and LFS for right SLS, left stance, left foot swing, right toe-off angle, and left arm range of motion. HFS produced significant improvement in trunk and lumbar range of motion compared to LFS. The study provides evidence of synergism of L-dopa and STN-DBS on lower limb spatial and temporal measures in advanced PD. HFS and LFS STN-DBS produced equivalent effects among all other tested lower limb gait features. HFS produced significant trunk and lumbar kinematic improvements.

Amphetamines Improve the Motivation to Invest Effort in Attention-Deficit/Hyperactivity Disorder.

Prevailing frameworks propose that a key feature of attention-deficit/hyperactivity disorder (ADHD) is lower motivation. An important component of motivation is the willingness to engage in cognitively or physically effortful behavior. However, the degree to which effort sensitivity is impaired in ADHD has rarely been tested, and the efficacy of stimulant medication in ameliorating any such impairments is unclear. Here, we tested 20 individuals with ADHD (11 males, 9 females) who were managed with amphetamine-based medication (dexamfetamine, lisdexamfetamine), and 24 controls (8 males, 16 females). Individuals with ADHD were tested over two counterbalanced sessions, ON and OFF their usual amphetamine-based medication. In each session, participants performed an effort-based decision-making task, in which they were required to choose how much cognitive or physical effort they were willing to engage in return for reward. Our results revealed three main findings. First, individuals with ADHD had lower motivation relative to controls to invest effort in both the cognitive and physical domains. Second, amphetamine increased motivation uniformly across both domains. Finally, the net effect of amphetamine treatment was to mostly restore motivation across both domains of effort relative to healthy controls. These data provide clear evidence for a heightened sensitivity to both cognitive and physical effort in ADHD, and reveal the efficacy of amphetamine-based drugs in restoring effort sensitivity to levels similar to controls. These findings confirm the existence of reduced motivational drive in ADHD, and more broadly provide direct causal evidence for a domain-general role of catecholamines in motivating effortful behavior.SIGNIFICANCE STATEMENT A core feature of attention-deficit/hyperactivity disorder (ADHD) is thought to be a heightened aversion to effort. Surprisingly, however, the degree to which effort sensitivity is impaired in ADHD has rarely been tested. More broadly, the relative efficacy of catecholamines in motivating the investment of cognitive and physical effort is unclear. We tested 20 individuals with ADHD ON and OFF amphetamines, and compared their behavior on an effort-based decision-making task to 24 controls. When tested OFF medication, the ADHD group was less cognitively and physically motivated than controls. However, amphetamines led to a comparable increase in motivation across both domains. This demonstrates the efficacy of catecholamines in facilitating domain-general effort, and highlights the broader potential of such drugs to treat disorders of motivation.