Differential Responses to Low- and High-Frequency Subthalamic Nucleus Deep Brain Stimulation on Sensor-Measured Components of Bradykinesia in Parkinson's Disease.

INTRODUCTION: The current approach to assessing bradykinesia in Parkinson's Disease relies on the Unified Parkinson's Disease Rating Scale (UPDRS), which is a numeric scale. Inertial sensors offer the ability to probe subcomponents of bradykinesia: motor speed, amplitude, and rhythm. Thus, we sought to investigate the differential effects of high-frequency compared to low-frequency subthalamic nucleus (STN) deep brain stimulation (DBS) on these quantified facets of bradykinesia. METHODS: We recruited advanced Parkinson's Disease subjects with a chronic bilateral subthalamic nucleus (STN) DBS implantation to a single-blind stimulation trial where each combination of medication state (OFF/ON), electrode contacts, and stimulation frequency (60 Hz/180 Hz) was assessed. The Kinesia One sensor system was used to measure upper limb bradykinesia. For each stimulation trial, subjects performed extremity motor tasks. Sensor data were recorded continuously. We identified STN DBS parameters that were associated with improved upper extremity bradykinesia symptoms using a mixed linear regression model. RESULTS: We recruited 22 subjects (6 females) for this study. The 180 Hz STN DBS (compared to the 60 Hz STN DBS) and dopaminergic medications improved all subcomponents of upper extremity bradykinesia (motor speed, amplitude, and rhythm). For the motor rhythm subcomponent of bradykinesia, ventral contacts yielded improved symptom improvement compared to dorsal contacts. CONCLUSION: The differential impact of high- and low-frequency STN DBS on the symptoms of bradykinesia may advise programming for these patients but warrants further investigation. Wearable sensors represent a valuable addition to the armamentarium that furthers our ability to conduct objective, quantitative clinical assessments.

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

Objective: 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. Methods: 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. Results: 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. Conclusion: 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.

Prospective F-18 FDOPA PET Imaging Study in Human PD.

Purpose: We present the findings of our final prospective study submitted to the U.S. Food and Drug Administration (FDA) for New Drug Application (NDA) approval for the use of 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine (F-18 FDOPA) positron emission tomography (PET) imaging for Parkinson's disease (PD). The primary aim was to determine the sensitivity, specificity, and predictive values of F-18 FDOPA PET in parkinsonian patients with respect to clinical standard-of-truth (SOT). Secondary outcomes included the inter-rater reliability, and correlation of quantitative measures for PET with dopaminergic status. Methods: In 68 parkinsonian subjects, F-18 FDOPA PET scan from 80 to 100 min was acquired following a CT scan. Scan images were presented to one expert in F-18 FDOPA image interpretation and two physicians with prior experience in I-123 FPCIT single-photon emission computed tomography image interpretation. Fifty-six subjects completed the study with a follow-up for SOT determination. Image readers were blind to the clinical/quantitative data; SOT clinician was blind to the image data. Results: For 47 of the 56 patients, SOT was in agreement with the PET scan results. For nine patients, SOT suggested dopaminergic deficit, whereas the imaging showed normal uptake. The specificity and positive predictive values are 91% and 92%, respectively, suggesting high probability that those who test positive by the PET scan truly have dopaminergic degeneration. The sensitivity was 73%. Inter-rater agreement was 0.6-0.8 between the different readers. Conclusion: Our prospective study demonstrates high specificity and moderate sensitivity of F-18 FDOPA PET for PD. We received NDA approval in October 2019. Supplementary Information: The online version contains supplementary material available at 10.1007/s13139-022-00748-4.

Dopamine modulates striatal response to reward and punishment in patients with Parkinson's disease: a pharmacological challenge fMRI study.

It is well established that Parkinson's disease leads to impaired learning from reward and enhanced learning from punishment. The administration of dopaminergic medications reverses this learning pattern. However, few studies have investigated the neural underpinnings of these cognitive processes. In this study, using fMRI, we tested a group of Parkinson's disease patients on and off dopaminergic medications and matched healthy individuals. All individuals completed an fMRI cognitive task that dissociates feedback learning from reward versus punishment. The administration of dopaminergic medications attenuated blood oxygen level dependent (BOLD) responses to punishment in the bilateral putamen, in bilateral dorsolateral prefrontal cortex and the left premotor cortex. Further, the administration of dopaminergic medications resulted in a higher ratio of BOLD activity between reward and punishment trials in these brain areas. BOLD activity in these brain areas was significantly correlated with learning from punishment, but not from reward trials. Furthermore, the administration of dopaminergic medications altered BOLD activity in the right insula and ventromedial prefrontal cortex when Parkinson's disease patients were anticipating feedback. These findings are in agreement with a large body of literature indicating that Parkinson's disease is associated with enhanced learning from punishment. However, it was surprising that dopaminergic medications modulated punishment learning as opposed to reward learning, although reward learning has been directly linked to dopaminergic function. We argue that these results might be attributed to both a change in the balance between direct and indirect pathway activation in the basal ganglia as well as the differential activity of D1 versus D2 dopamine receptors.

Increased sensorimotor network activity in DYT1 dystonia: a functional imaging study.

Neurophysiological studies have provided evidence of primary motor cortex hyperexcitability in primary dystonia, but several functional imaging studies suggest otherwise. To address this issue, we measured sensorimotor activation at both the regional and network levels in carriers of the DYT1 dystonia mutation and in control subjects. We used (15)Oxygen-labelled water and positron emission tomography to scan nine manifesting DYT1 carriers, 10 non-manifesting DYT1 carriers and 12 age-matched controls while they performed a kinematically controlled motor task; they were also scanned in a non-motor audio-visual control condition. Within- and between-group contrasts were analysed with statistical parametric mapping. For network analysis, we first identified a normal motor-related activation pattern in a set of 39 motor and audio-visual scans acquired in an independent cohort of 18 healthy volunteer subjects. The expression of this pattern was prospectively quantified in the motor and control scans acquired in each of the gene carriers and controls. Network values for the three groups were compared with ANOVA and post hoc contrasts. Voxel-wise comparison of DYT1 carriers and controls revealed abnormally increased motor activation responses in the former group (P < 0.05, corrected; statistical parametric mapping), localized to the sensorimotor cortex, dorsal premotor cortex, supplementary motor area and the inferior parietal cortex. Network analysis of the normative derivation cohort revealed a significant normal motor-related activation pattern topography (P < 0.0001) characterized by covarying neural activity in the sensorimotor cortex, dorsal premotor cortex, supplementary motor area and cerebellum. In the study cohort, normal motor-related activation pattern expression measured during movement was abnormally elevated in the manifesting gene carriers (P < 0.001) but not in their non-manifesting counterparts. In contrast, in the non-motor control condition, abnormal increases in network activity were present in both groups of gene carriers (P < 0.001). In this condition, normal motor-related activation pattern expression in non-manifesting carriers was greater than in controls, but lower than in affected carriers. In the latter group, measures of normal motor-related activation pattern expression in the audio-visual condition correlated with independent dystonia clinical ratings (r = 0.70, P = 0.04). These findings confirm that overexcitability of the sensorimotor system is a robust feature of dystonia. The presence of elevated normal motor-related activation pattern expression in the non-motor condition suggests that abnormal integration of audio-visual input with sensorimotor network activity is an important trait feature of this disorder. Lastly, quantification of normal motor-related activation pattern expression in individual cases may have utility as an objective descriptor of therapeutic response in trials of new treatments for dystonia and related disorders.