Neumann’s principle states that all physical properties of a material are bound by its symmetry. While bulk crystals conform to well-defined point and space groups, phenomena at a substrate’s surface could have less apparent symmetry origins. Here we experimentally explore both reciprocal and non-reciprocal types of acoustoelectric effects driven by surface acoustic waves (SAW). The non-reciprocal acoustoelectric voltage is connected to the natural single-phase unidirectional transducer from device engineering. On the other hand, reciprocal acoustoelectric effect exists in certain SAW configurations that are of different symmetry origins. Half of the configurations have a valid reciprocity-preserving symmetry element of either a mirror plane or a two-fold rotational axis that is perpendicular to the substrate surface. The other half of the configurations do not possess a reciprocity-preserving symmetry element of the half-space but relate to the first scenario through an interchange of SAW propagation and the surface normal directions. Here, it is the symmetric construction in the equation of motion, which holds at nanoscale distances, to be responsible for the correspondence between two scenarios and extends the cases of reciprocal SAW states. This correspondence traces its physical origin to the SAW composition of compression and shear waves along two orthogonal directions respectively.

IntroductionPositioning of deep brain stimulation (DBS) leads is paramount for optimizing therapeutic efficacy in Parkinson’s disease (PD) and dystonia. Quantitative determination of lead position remains essential; however, current atlas-based targeting and stereotactic coordinate methods, while informative, limit patient specificity afforded by high-resolution reconstruction and introduce subjective variability.MethodsWe developed a novel pipeline in Unity™ to ingest 7T MRI-based reconstructions of DBS leads within the globus pallidus internus (GPi). Using anatomical landmarks and structure-specific algorithms, the GPi was parcellated into 12 anatomically-based subregions in a semi-automated, reproducible manner. Active contact positions were localized relative to a novel coordinate system developed from a GPi-based bounding box. A novel distance-to-border metric remapped contacts onto a common atlas (PD25) for population comparison against the same contacts mapped onto a common left GPi space using mid-commissural point (MCP) coordinates (Schaltenbrand-Wahren atlas).ResultsFifteen leads from 10 PD subjects were used for ellipsoid fitting of active contact locations, resulting in an elliptical volume of 38.94 mm3 when using MCP coordinates, compared to a volume of 5.08 mm3 with our GPi-specific coordinates. The mean distance-to-ellipse centroid was 3.45 ± 1.57 mm for MCP coordinates and 2.03 ± 0.82 for our GPi-specific coordinates. Our distance-to-border remapping metric yielded mean adjustments of 0.81 mm (y-axis) and 1.61 mm (z-axis). A subset of six GPi active contacts were plotted with post-DBS motor improvement scores, demonstrating the ability to link lead location with clinical outcomes.ConclusionOur novel software provides a quantifiable lead location with respect to the anatomical target, enhancing patient-specific lead localization by avoiding some of the pitfalls of either structure-to-atlas normalization or traditional stereotactic coordinates.

OBJECTIVE:Deep brain stimulation (DBS) modulates neural elements in the target region but can cause involuntary muscle contractions through unintended internal capsule activation. We characterized upper and lower limb motor evoked potentials (MEPs) produced by DBS to determine how stimulation location and orientation affect responses. METHODS:Low-frequency DBS was delivered in the globus pallidus internus (GPi, 17 hemispheres) and subthalamic nucleus (STN, 8 hemispheres). MEPs were identified by stimulus-triggered averaging of surface electromyography (sEMG) from nine contralateral muscles. RESULTS:MEPs were most robust in distal upper limb muscles, with larger magnitudes and higher incidence than proximal or lower limb muscles (p < 0.001). Onset latencies did not differ between GPi and STN targets (p > 0.14). MEP incidence decreased from distal (ring 1) to proximal (ring 4) lead contacts (p < 0.003). A consistent recruitment hierarchy was observed: the thenar muscle was the most sensitive responder. Thenar MEP absence was associated with MEP absence in all other muscles in 96 % of cases.. In GPi, larger MEPs correlated with posterior-medial stimulation and proximity to the posterior border. CONCLUSION:sEMG-recorded MEPs are a robust indicator of stimulation spread to internal capsule and provide the means to observe and quantify unwanted stimulation effects. SIGNIFICANCE:This study establishes a predictable hierarchy of MEPs during deep brain stimulation, identifying distal upper limb muscles, specifically the thenar, as the most sensitive indicators of internal capsule activation. These findings provide a robust physiological framework for quantifying and avoiding stimulation-induced side effects in patients with Parkinson's disease.

OBJECTIVE:People with Parkinson's disease (PD) and rapid eye movement (REM) sleep without atonia (RSWA) often have more severe gait disturbances compared to PD without RSWA. The association between the presence and expression of RSWA and the rate of progression of gait impairment in PD is unknown. This study examined the changes in spatiotemporal gait metrics over 3 years in people with mild-to-moderate PD (median 1.5 years since diagnosis at baseline) with (PD+RSWA, n = 16) and without RSWA (PD-RSWA, n = 14), and matched controls (n = 16). METHODS:Steady-state gait metrics were obtained using a pressure-sensitive walkway at baseline and 3-year follow-up. RSWA scores were measured from electromyographic recordings during video-based polysomnography at baseline. Linear mixed models tested for the effects of visit, group, side (less vs. more affected), and their interactions. In people with PD, Spearman's correlations examined the relationship between baseline RSWA scores and the change in gait metrics. RESULTS:Stride velocity variability was larger in PD+RSWA, compared to PD-RSWA and controls. Spatial and temporal measures of gait significantly worsened in both PD groups over 3 years. The PD+RSWA group showed a significantly larger decrement in step length (p < 0.05; mean = 7.9%) compared to PD-RSWA (2.6%) and controls (2.3%). Variability measures did not change significantly. In PD, the change in stride length correlated with chin RSWA scores at baseline. INTERPRETATION:RWSA in early PD may be a harbinger of a more rapid progression in gait impairment, characterized primarily by a shortening of steps.

Background: While deep brain stimulation (DBS) targeting the ventral intermediate nucleus (VIM) of thalamus or posterior subthalamic area (PSA) can suppress forms of action tremor in people with Essential Tremor, previous studies have suggested postural tremor may respond more robustly than kinetic tremor to DBS. Objectives: In this study, we aimed to more precisely quantify the (1) onset/offset dynamics and (2) steady-state effects of VIM/PSA-DBS on postural and kinetic tremor. Methods: Tremor data from wireless inertial measurement units were collected from 11 participants with ET (20 unilaterally assessed DBS leads). Three postural hold tasks and one kinetic task were performed with stimulation turned off, in 2-min intervals after enabling unilateral DBS at the clinician-optimized DBS setting (15 min), and in 2-min intervals following cessation of DBS (5 min). Results: At baseline, kinetic tremor had significantly higher amplitudes, standard deviation, and frequency than postural tremor (P < 0.001). DBS had a more robust acute effect on postural tremors (54% decrease, P < 0.001), with near immediate tremor suppression in amplitude and standard deviation, but had non-significant improvement of kinetic tremor on the population-level across the wash-in period (34% decrease). Tremor response was not equivalent between wash-in and wash-out timepoints and involved substantial individual variability including task-specific rebound or long wash-out effects. Conclusions: Programming strategies for VIM/PSA-DBS should consider the individual temporal and effect size variability in postural versus kinetic tremor improvement. Improved targeting and programming strategies around VIM and PSA may be necessary to equivalently suppress both postural and kinetic tremors.

Subject-specific computational models of pallidal deep brain stimulation, in conjunction with quantitative measures of forearm rigidity, were used to examine the neural pathways mediating stimulation-induced changes in rigidity in people with Parkinson’s disease. The model uniquely included internal, efferent and adjacent pathways of the basal ganglia. The results demonstrate that reductions in rigidity evoked by deep brain stimulation were principally mediated by the activation of globus pallidus internus efferent pathways.

The thalamus is a centrally located and heterogeneous brain structure that plays a critical role in various sensory, motor, and cognitive processes. However, visualizing the individual subnuclei of the thalamus using conventional MRI techniques is challenging. This difficulty has posed obstacles in targeting specific subnuclei for clinical interventions such as deep brain stimulation (DBS). In this paper, we present DiMANI, a novel method for directly visualizing the thalamic subnuclei using diffusion MRI (dMRI). The DiMANI contrast is computed by averaging, voxelwise, diffusion-weighted volumes enabling the direct distinction of thalamic subnuclei in individuals. We evaluated the reproducibility of DiMANI through multiple approaches. First, we utilized a unique dataset comprising 8 scans of a single participant collected over a 3-year period. Secondly, we quantitatively assessed manual segmentations of thalamic subnuclei for both intra-rater and inter-rater reliability. Thirdly, we qualitatively correlated DiMANI imaging data from several patients with Essential Tremor with the localization of implanted DBS electrodes and clinical observations. Lastly, we demonstrated that DiMANI can provide similar features at 3T and 7T MRI, using varying numbers of diffusion directions. Our results establish that DiMANI is a reproducible and clinically relevant method to directly visualize thalamic subnuclei. This has significant implications for the development of new DBS targets and the optimization of DBS therapy.

BACKGROUND:Postural instability is one of the most disabling motor symptoms of Parkinson's disease (PD) given its association with falls and loss of independence. Previous studies have assessed biomechanical measures of reactive stepping in response to perturbations, showing that individuals with PD exhibit inadequate postural responses to regain balance.RESEARCH QUESTION:Does dopamine replacement therapy normalize step length in response to balance perturbations?METHODS:In this study, we estimated reactive step length, to a postural perturbation, retrospectively from a dataset of frontal plane video using 2D motion tracking and direct linear transform methods. We compared two perturbation methods: support surface translation and shoulder pull (the clinical standard) in 14 individuals with PD and 13 without PD (on and off medication), with and without partial body weight support (BWS). The primary outcome was the length of the first step taken to regain balance after the perturbation analyzed with mixed effects ANOVA, with post hoc analysis of anteroposterior (AP) and mediolateral (ML) components.RESULTS:PD OFF medication exhibited shorter reactive step length compared to PD ON and compared to control groups for the surface translation perturbations, but no significant difference was observed for the shoulder pull perturbations.SIGNIFICANCE:Dopamine replacement therapy affects step length in response to perturbation more robustly for surface translations than for a pull by the shoulders.

BackgroundWhile deep brain stimulation (DBS) therapy can be effective at suppressing tremor in individuals with medication-refractory Essential Tremor, patient outcome variability remains a significant challenge across centers. Proximity of active electrodes to the cerebellothalamic tract (CTT) is likely important in suppressing tremor, but how tremor control and side effects relate to targeting parcellations within the CTT and other pathways in and around the ventral intermediate (VIM) nucleus of thalamus remain unclear.MethodsUsing ultra-high field (7T) MRI, we developed high-dimensional, subject-specific pathway activation models for 23 directional DBS leads. Modeled pathway activations were compared with post-hoc analysis of clinician-optimized DBS settings, paresthesia thresholds, and dysarthria thresholds. Mixed-effect models were utilized to determine how the six parcellated regions of the CTT and how six other pathways in and around the VIM contributed to tremor suppression and induction of side effects.ResultsThe lateral portion of the CTT had the highest activation at clinical settings (p < 0.05) and a significant effect on tremor suppression (p < 0.001). Activation of the medial lemniscus and posterior-medial CTT was significantly associated with severity of paresthesias (p < 0.001). Activation of the anterior-medial CTT had a significant association with dysarthria (p < 0.05).ConclusionsThis study provides a detailed understanding of the fiber pathways responsible for therapy and side effects of DBS for Essential Tremor, and suggests a model-based programming approach will enable more selective activation of lateral fibers within the CTT.

ObjectiveTo characterize how the proximity of deep brain stimulation (DBS) active contact locations relative to the cerebellothalamic tract (CTT) affect clinical outcomes in patients with essential tremor (ET).BackgroundDBS is an effective treatment for refractory ET. However, the role of the CTT in mediating the effect of DBS for ET is not well characterized. 7-Tesla (T) MRI-derived tractography provides a means to measure the distance between the active contact and the CTT more precisely.MethodsA retrospective review was conducted of 12 brain hemispheres in 7 patients at a single center who underwent 7T MRI prior to ventral intermediate nucleus (VIM) DBS lead placement for ET following failed medical management. 7T-derived diffusion tractography imaging was used to identify the CTT and was merged with the post-operative CT to calculate the Euclidean distance from the active contact to the CTT. We collected optimized stimulation parameters at initial programing, 1- and 2-year follow up, as well as a baseline and postoperative Fahn-Tolosa-Marin (FTM) scores.ResultsThe therapeutic DBS current mean (SD) across implants was 1.8 mA (1.8) at initial programming, 2.5 mA (0.6) at 1 year, and 2.9 mA (1.1) at 2-year follow up. Proximity of the clinically-optimized active contact to the CTT was 3.1 mm (1.2), which correlated with lower current requirements at the time of initial programming (R2 = 0.458, p = 0.009), but not at the 1- and 2-year follow up visits. Subjects achieved mean (SD) improvement in tremor control of 77.9% (14.5) at mean follow-up time of 22.2 (18.9) months. Active contact distance to the CTT did not predict post-operative tremor control at the time of the longer term clinical follow up (R2 = -0.073, p = 0.58).ConclusionActive DBS contact proximity to the CTT was associated with lower therapeutic current requirement following DBS surgery for ET, but therapeutic current was increased over time. Distance to CTT did not predict the need for increased current over time, or longer term post-operative tremor control in this cohort. Further study is needed to characterize the role of the CTT in long-term DBS outcomes.

Introduction Evidence suggests that spontaneous beta band (11–35 Hz) oscillations in the basal ganglia thalamocortical (BGTC) circuit are linked to Parkinson’s disease (PD) pathophysiology. Previous studies on neural responses in the motor cortex evoked by electrical stimulation in the subthalamic nucleus have suggested that circuit resonance may underlie the generation of spontaneous and stimulation-evoked beta oscillations in PD. Whether these stimulation-evoked, resonant oscillations are present across PD patients in the internal segment of the globus pallidus (GPi), a primary output nucleus in the BGTC circuit, is yet to be determined. Methods We characterized spontaneous and stimulation-evoked local field potentials (LFPs) in the GPi of four PD patients (five hemispheres) using deep brain stimulation (DBS) leads externalized after DBS implantation surgery. Results Our analyses show that low-frequency (2–4 Hz) stimulation in the GPi evoked long-latency (>50 ms) beta-band neural responses in the GPi in 4/5 hemispheres. We demonstrated that neural sources generating both stimulation-evoked and spontaneous beta oscillations were correlated in their frequency content and spatial localization. Discussion Our results support the hypothesis that the same neuronal population and resonance phenomenon in the BGTC circuit generates both spontaneous and evoked pallidal beta oscillations. These data also support the development of closed-loop control systems that modulate the GPi spontaneous oscillations across PD patients using beta band stimulation-evoked responses.

BACKGROUND:Excessive subthalamic nucleus (STN) β-band (13-35 Hz) synchronized oscillations has garnered interest as a biomarker for characterizing disease state and developing adaptive stimulation systems for Parkinson's disease (PD). OBJECTIVES:To report on a patient with abnormal treatment-responsive modulation in the β-band. METHODS:We examined STN local field potentials from an externalized deep brain stimulation (DBS) lead while assessing PD motor signs in four conditions (OFF, MEDS, DBS, and MEDS+DBS). RESULTS:The patient presented here exhibited a paradoxical increase in β power following administration of levodopa and pramipexole (MEDS), but an attenuation in β power during DBS and MEDS+DBS despite clinical improvement of 50% or greater under all three therapeutic conditions. CONCLUSIONS:This case highlights the need for further study on the role of β oscillations in the pathophysiology of PD and the importance of personalized approaches to the development of β or other biomarker-based DBS closed loop algorithms. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Objective This experiment tested if balance performance differed between a standardized treadmill surface perturbation task and a clinical pull test and was affected by medication or the presence of body weight support in people with Parkinson’s disease (PD). Methods Twenty-seven individuals were tested (14 PD in both ON- and OFF-medication states). Clinical pull test and rapid forward (backward fall) translations of the support surface were applied to induce postural reactions requiring at least 1 step to restore balance. The effects of pull type (clinical vs. treadmill), partial bodyweight support (0 vs 20% body weight) and group (control, PD ON-meds and PD OFF-meds) on reactive stepping as well as practice/learning effect were examined. The number of steps taken and the first step duration were entered in linear repeated-measures mixed-effect models separately. Results The effects of pull type, group, and bodyweight support were all significant in both metrics, as was ON- vs. OFF-medication. A significant interaction term (group x pull type) was found in the first step duration, showing that the group difference was greater in treadmill compared to the clinical pull test. A significant practice effect was also observed within and across testing sessions. Conclusions A standardized treadmill perturbation performed slightly better than the classical pull test in distinguishing between groups, and partial weight support did not substantially degrade the test’s performance to detect the balance deficits in people with PD.

Freezing of gait (FOG) is a particularly debilitating symptom of Parkinson’s disease (PD) and is often refractory to treatment. A striking feature of FOG is that external sensory cues can be used to overcome freezing and improve gait. Local field potentials (LFPs) recorded from the subthalamic nucleus (STN) and globus pallidus (GP) show that beta-band power modulates with gait phase. In the STN, beta-band oscillations are modulated by external cues, but it is unknown if this relationship holds in the globus pallidus (GP). Here we report LFP data recorded from the left GP, using a Medtronic PC + S device, in a 68-year-old man with PD and FOG during treadmill walking. A “stepping stone” task was used during which stepping was cued using visual targets of constant color or targets that unpredictably changed color, requiring a step length adjustment. Gait performance was quantified using measures of treadmill ground reaction forces and center of pressure and body kinematics from video monitoring. Beta-band power (12–30 Hz) and number of freezing episodes were measured. Cues which unpredictably changed color improved FOG more than conventional cues and were associated with greater modulation of beta-band power in phase with gait. This preliminary finding suggests that cueing-induced improvement of FOG may relate to beta-band modulation.

Background: Treadmills provide a safe and convenient way to study the gait of people with Parkinson's disease (PD), but outcome measures derived from treadmill gait may differ from overground walking. Objective: To investigate how the relationships between gait metrics and walking speed vary between overground and treadmill walking in people with PD and healthy controls. Methods: We compared 29 healthy controls to 27 people with PD in the OFF-medication state. Subjects first walked overground on an instrumented gait walkway, then on an instrumented treadmill at 85%, 100% and 115% of their overground walking speed. Average stride length and cadence were computed for each subject in both overground and treadmill walking. Results: Stride length and cadence both differed between overground and treadmill walking. Regressions of stride length and cadence on gait speed showed a log-log relationship for both overground and treadmill gait in both PD and control groups. The difference between the PD and control groups during overground gait was maintained for treadmill gait, not only when treadmill speed matched overground speed, but also with +/- 15% variation in treadmill speed from that value. Significance: These results show that the impact of PD on stride length and cadence and their relationship to gait speed is preserved in treadmill as compared to overground walking. We conclude that a treadmill protocol is suitable for laboratory use in studies of PD gait therapeutics.

Some symptoms treated with Deep Brain Stimulation (DBS) such as gait in Parkinson's disease (PD), are often poorly responsive to DBS. This may be because DBS settings are usually optimized to other symptoms. To test this, we require an efficient, safe optimization algorithm. To develop such a tool, we extend the BayesOpt algorithm whose successful application to DBS settings we previously published [Louie et al 2021 J Neuroeng Rehabil], using, as a test bed, a simulated cost function constructed for biological plausibility, with measurement noise based on experimental data. We found that the SafeOpt algorithm [Sui et al 2015 Proc Machine Learning Res] converged to the optimum as well, and as fast as the BayesOpt algorithm, while avoiding high-cost points much more effectively. In three dimensions, SafeOpt converged in about 30 iterations, which is a feasible number for physical (not simulated) experiments in real patients. Convergence was slower when measurement nose was greater, but this could be overcome by running it for more iterations. The algorithm was relatively robust to misspecification of hyperparameters, and considerably more robust when hyperparameter fitting was incorporated into the algorithm. The algorithm did not perform as well when the quantization of stimulation settings was coarser, suggesting that it will work better with neurostimulators capable of independent current control. Finally, the algorithm was able to cope with a cost function having multiple local minima.

Significance While disorder is an inalienable characteristic of real crystalline materials, the capability of controlling various types of disorder often strongly influences our understanding of science and the advancement of technology. Magnetic spinel represents a class of materials with a pyrochlore-structured sublattice to potentially host three-dimensional spin frustration but is strongly influenced by the inversion disorder of two similarly sized cation species. While it remains challenging to experimentally differentiate these two characteristics, here we mitigate the disorder issue at the crystal growth stage. Our independent control of both stoichiometry and inversion disorder clarifies both magnetism and structure in a spinel oxide of interest for seven decades.

To elucidate the role of the basal ganglia during REM sleep movements in Parkinson's disease (PD) we recorded pallidal neural activity from four PD patients. Unlike desynchronization commonly observed during wakeful movements, beta oscillations (13-35 Hz) synchronized during REM sleep movements; furthermore, high-frequency oscillations (150-350 Hz) synchronized during movement irrespective of sleep-wake states. Our results demonstrate differential engagement of the basal ganglia during REM sleep and awake movements. ### Competing Interest Statement Noam Harel - Consultant and a shareholder for Surgical Information Sciences Inc. Remi Patriat - Consultant for Surgical Information Sciences Inc. Michael Park - Listed faculty for University of Minnesota Educational Partnership with Medtronic, Inc., Minneapolis, MN, Consultant for: Zimmer Biomet, Synerfues, Inc., NeuroOne, Boston Scientific. Grant/Research support from: Medtronic, Inc., Boston Scientific, Abbott, SynerFuse, Inc., and Fasikl, Inc. Jerrold Vitek - Dr. Vitek serves as a consultant for Medtronic, Boston Scientific and Abbott. He also serves on the Executive Advisory Board for Abbott and is a member of the scientific advisory board for Surgical Information Sciences. He has research support through the National Institutes of Health. Joshua Aman - Consultant for Surgical Information Sciences Inc. All other authors have no competing interest to disclose.

SummaryApproaches to control basal ganglia neural activity in real-time are needed to clarify the causal role of 8-35 Hz (“beta band”) oscillatory dynamics in the manifestation of Parkinson’s disease (PD) motor signs. Here, we show that resonant beta oscillations evoked by electrical pulse with precise amplitude and timing can be used to predictably suppress or amplify spontaneous beta band activity in the internal segment of the globus pallidus (GPi) in the human. Using this approach, referred to as closed-loop evoked interference deep brain stimulation (eiDBS), we could suppress or amplify frequencyspecific (16-22 Hz) neural activity in a PD patient. Our results highlight the utility of eiDBS to characterize the role of oscillatory dynamics in PD and other brain conditions, and to develop personalized neuromodulation systems.

To elucidate the role of the basal ganglia during REM sleep movements in Parkinson’s disease (PD) we recorded pallidal neural activity from four PD patients. Unlike desynchronization commonly observed during wakeful movements, beta oscillations (13–35 Hz) synchronized during REM sleep movements; furthermore, high-frequency oscillations (150–350 Hz) synchronized during movement irrespective of sleep-wake states. Our results demonstrate differential engagement of the basal ganglia during REM sleep and awake movements.