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Yue Ran Sun,1 Sinem B Beylergil,2 Palak Gupta,2,3 Fatema F Ghasia,4 Aasef G Shaikh1– 3 1Department of Neurology, University Hospitals, Case Western Reserve University, Cleveland, OH, USA; 2Neurology Service, Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA; 3Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA; 4Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USACorrespondence: Aasef G Shaikh, Department of Neurology, University Hospitals, Case Western Reserve University, Cleveland, OH, 44022, USA, Tel +1 2167856981, Email axs848@case.eduAbstract: Parkinson’s disease (PD) affects approximately 10 million individuals worldwide. Visual impairments are a common feature of PD. Patients report difficulties with visual scanning, impaired depth perception and spatial navigation, and blurry and double vision. Examination of PD patients reveals abnormal fixational saccades, strabismus, impaired convergence, and abnormal visually-guided saccades. This review aims to describe objective features of abnormal eye movements in PD and to discuss the structures and pathways through which these abnormalities may manifest.Keywords: Parkinson’s disease, eye movement, gaze holding, strabismus, vergence, saccades

Purpose: This study uses eye tracking to investigate how varying fellow eye (FE) contrast during dichoptic video viewing influences eye movement patterns, and their associations with interocular suppression, visual acuity, and stereoacuity deficit in amblyopia., Methods: Eye movements of 27 amblyopic and 8 healthy control participants were recorded during dichoptic viewing of stationary dots and videos with FE contrasts (100%, 50%, 25%, and 10%). Analysis included durations the amblyopic and FE spent in different stimulus regions, fixation switches, and eye deviation, and correlating these with suppression, visual acuity, and stereoacuity., Results: Participants with pronounced suppression, visual acuity, and stereoacuity deficits demonstrated reduced amblyopic eye fixation in the amblyopic eye (AE) region at 100% FE contrast. Lowering FE contrast increased amblyopic eye duration in stimuli presented within the AE region, notably in anisometropic and treated strabismic participants, and strabismic participants exhibiting fixation switches during viewing of dichoptic stationary dots. Even at lower FE contrasts, participants with greater stereoacuity and visual acuity deficits continued to exhibit diminished AE fixation in the AE region. Increased eye deviation was seen in strabismic participants with lowering of FE contrasts., Conclusions: Dichoptic contrast modulation holds promise for reducing suppression with responses varying by amblyopia type and visual function deficits. Larger strabismic angles may hinder binocular benefits of dichoptic treatments. Fixation switches may serve as an indicator of favorable outcomes. Eye tracking is crucial for understanding these dynamics, providing essential insights into visual attention dynamics of the FE and AE, and may serve as a valuable tool in optimization of amblyopia treatments.

Perception of our linear motion - heading - is critical for postural control, gait, and locomotion, and it is impaired in Parkinson's disease (PD). Deep brain stimulation (DBS) has variable effects on vestibular heading perception, depending on the location of the electrodes within the subthalamic nucleus (STN). Here, we aimed to find the anatomical correlates of heading perception in PD. Fourteen PD participants with bilateral STN DBS performed a two-alternative forced-choice discrimination task where a motion platform delivered translational forward movements with a heading angle varying between 0 and 30° to the left or to the right with respect to the straight-ahead direction. Using psychometric curves, we derived the heading discrimination threshold angle of each patient from the response data. We created patient-specific DBS models and calculated the percentages of stimulated axonal pathways that are anatomically adjacent to the STN and known to play a major role in vestibular information processing. We performed correlation analyses to investigate the extent of these white matter tracts' involvement in heading perception. Significant positive correlations were identified between improved heading discrimination for rightward heading and the percentage of activated streamlines of the contralateral hyperdirect, pallido-subthalamic, and subthalamo-pallidal pathways. The hyperdirect pathways are thought to provide top-down control over STN connections to the cerebellum. In addition, STN may also antidromically activate collaterals of hyperdirect pathway that projects to the precerebellar pontine nuclei. In select cases, there was strong activation of the cerebello-thalamic projections, but it was not consistently present in all participants. Large volumetric overlap between the volume of tissue activation and the STN in the left hemisphere positively impacted rightward heading perception. Altogether, the results suggest heavy involvement of basal ganglia cerebellar network in STN-induced modulation of vestibular heading perception in PD., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Cervical dystonia (CD) is the most common form of focal dystonia encountered in the clinic. Approximately one-third of CD patients have co-existing tremor in the head and hands. Assessment of tremor as regular or irregular in context of its oscillation trajectory, frequency, and amplitude is a major clinical challenge and can confound the diagnosis of CD. The misdiagnosis may lead to therapeutic failures, poor quality of life, and poor utilization of medical and financial resources., Methods: We analyzed the largest cohort of CD patients ( n = 3117) available to date, collected from 37 movement disorder centers in North America, Europe, and Asia. We used machine learning to determine what clinical features from clinician reports predicted the presence of tremor as well as its regular or irregular appearance., Results: Out of 3,117 CD patients, 1,367 had neck tremor. The neck tremor was interpreted as irregular in 1,022, regular in 345, and mixed (both irregular and regular) in 442. A feature importance analysis determined that greater severity of CD, longer disease duration, and older age, in descending order, predicted the presence of neck tremor. The probability of neck tremor was reduced if the dystonia affected other body parts in addition to the neck. We also found a significantly heightened risk for developing neck tremor in women. An additional feature importance analysis indicated that increased severity of dystonia affecting other body parts, severity of CD, and prolonged disease duration was associated with a lower likelihood of regular neck tremor while increased age predicted a higher likelihood., Conclusion: Machine learning recognized the most relevant clinical features that can predict concurrent neck tremor and its irregularity in a large multi-center dystonia cohort. These results may facilitate a more accurate description of neck tremor and improved care path in CD., Competing Interests: Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Self-reported diplopia is described in up to one-third of Parkinson's disease (PD) patients., Objective: The purpose of our study was to expand our understanding of the mechanistic underpinnings of diplopia in PD. We hypothesize that the time-based control of eye alignment and increased eye deviation under binocular viewing will be related to the fusion-initiating and fusion-maintaining component deficits of disparity-driven vergence in PD., Methods: We used high-resolution video-oculography to measure eye alignment under binocular and monocular viewing and disparity-driven vergence in 33 PD and 10 age-matched healthy participants. We computed eye deviation and time-based control of eye alignment, occurrence of conjugate saccadic eye movements, latency and gain of vergence (fusion initiation), and variance of eye position at the end of dynamic vergence (fusion maintenance)., Results: We categorized PD subjects into three groups, considering their time-based control of eye alignment as compared to healthy controls in binocular viewing. Group 1 = 45% had good control and spent >80% of the time when the eyes were well-aligned, Group 2 = 26% had intermediate control and spent <80% but greater >5% of the time when the eyes were well-aligned, and Group 3 = 29% had very poor control with increased eye deviation majority of the times (<5% of the time when the eyes were well-aligned). All three groups exhibited greater eye deviation under monocular viewing than controls. PD subjects exhibited fusion-initiating and fusion-maintaining vergence deficits (prolonged latencies, reduced vergence gain, increased variance of fusion-maintaining component) with a greater probability of saccadic movements than controls. Group 2 and Group 3 subjects were more likely to exhibit failure to initiate vergence (>20%) than Group 1 (13%) and controls (0%) trials. No significant difference was found in the Unified Parkinson's Disease Rating Scale (UPDRS-a tool to measure the severity of PD) values between the three PD groups (Group 1 = 33.69 ± 14.22, Group 2 = 38.43 ± 22.61, and Group 3 = 23.44 ± 1, p > 0.05)., Conclusion: The majority of PD subjects within our cohort had binocular dysfunction with increased eye deviation under monocular viewing and disparity-driven vergence deficits. PD subjects with intermediate or poor control of eye deviation under binocular viewing had greater fusion-initiating and fusion-maintaining vergence deficits. The study highlights the importance of assessing binocular dysfunction in PD subjects independent of the severity of motor symptoms., Competing Interests: The author(s) FG declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Gupta, Murray, Beylergil, Jacobs, Kilbane, Shaikh and Ghasia.)

We examined whether conflicting visual and non-visual information leads to gait abnormalities and how the subthalamic deep brain stimulation (STN DBS) influences gait dysfunction in Parkinson's disease (PD). We used a motion capture system to measure the kinematics of the lower limbs during treadmill walking in immersive virtual reality. The visual information provided in the virtual reality paradigm was modulated to create a mismatch between the optic-flow velocity of the visual scene and the walking speed on the treadmill. In each mismatched condition, we calculated the step duration, step length, step phase, step height, and asymmetries. The key finding of our study was that mismatch between treadmill walking speed and the optic-flow velocity did not consistently alter gait parameters in PD. We also found that STN DBS improved the PD gait pattern by changing the stride length and step height. The effects on phase and left/right asymmetry were not statistically significant. The DBS parameters and location also determined its effects on gait. Statistical effects on stride length and step height were noted when the DBS volume of activated tissue (VTA) was in the dorsal aspect of the subthalamus. The statistically significant effects of STN DBS was present when VTA significantly overlapped with MR tractogrphically measured motor and pre-motor hyperdirect pathways. In summary, our results provide novel insight into ways for controlling walking behavior in PD using STN DBS., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Visual spatial dysfunction is not uncommon in Parkinson's disease. We hypothesized that visual search behavior is impaired in Parkinson's disease and the deficits correlate with changes in the amplitudes and frequency of fixational and non-fixational rapid eye movements. We measured eye movements, the horizontal and vertical angular position vectors of the right and left eye using high-resolution video oculography, in the Parkinsonian cohort who viewed a blank scene and pictures with real-life scene. Latter was associated with a task of searching an object hidden in a clutter, either at an expected or an unexpected location. Parkinsonian cohort took longer initial time to reach the region of interest. The ultimate response time was comparable in both Parkinson's disease and their healthy peers. The fixation duration was comparable in two cohorts but there was a trend wise decline for the ones located at unexpected locations. Parkinson's disease participants made more fixational saccades with significantly larger amplitude and less non-fixational saccades with significantly smaller amplitude during blank scene viewing. However, overall scanned area of the blank scene was not affected in Parkinson's disease. The Parkinson's disease participants made less non-fixational saccades with amplitudes comparable to healthy control during the visual search of a target object. Fixational saccades during visual search were larger in Parkinson's disease particularly when target was placed at an unexpected location, but the frequency was unchanged., (Copyright © 2022. Published by Elsevier B.V.)

Postural instability and balance impairment are common in Parkinson's disease (PD). Multiple factors, such as increased tone, bradykinesia, freezing of gait, posture, axial stiffness, and involuntary appendicular movements, can affect balance. The recent studies found that PD patients have abnormal perception of self-motion in vestibular domain. We asked whether measures of balance function, such as perception of one's motion, correlate with specific movement disorders seen in PD. Moving retinal image or self-motion in space triggers the perception of self-motion. We measured one's linear motion (heading) perception when subjects were moved en bloc using a moving platform (vestibular heading). Similar motion perception was generated in the visual domain (visual heading) by having the subjects view a 3D optical flow with immersive virtual reality goggles. During both tasks, the subjects reported the motion direction in the two-alternative-forced-choice paradigm. The accuracy of perceived motion direction was calculated from the responses fitted to the psychometric function curves to estimate how accurately and precisely the subjects can perceive rightward versus leftward motion (i.e., threshold and slope). Response accuracies and psychometric parameters were correlated with the disease duration, disease severity (total Unified Parkinson's Disease Rating Scale-III, UPDRS-III), and tremor, rigidity, axial, gait/posture components of UPRDS-III. We also correlated heading perception with the number of falls and subjective assessment of balance confidence using the Activities-Specific Balance Component (ABC) Scale. Accuracy, threshold, and sensitivity of vestibular heading perception significantly correlated with the disease duration and severity, particularly the tremor. Correlations were stronger for leftward heading perception in the vestibular domain. The visual heading perception was correlated with ABC Scale, especially with its items concerning optic-flow processing. There was asymmetry in leftward versus rightward vestibular heading perception. The level of asymmetry correlated with the axial component of UPDRS-III. Differences in the clinical parameters that correlate with visual versus vestibular heading perception suggest that two heading perception processes have different mechanistic underpinnings. The correlation of discordance between vestibular and visual heading perception with disease severity and duration suggests that visual function can be utilized for balance rehab in PD patients., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background: Spontaneity is a unique feature of the nervous system. One of the fundamentally critical and recognized forms of spontaneous motor activity is witnessed in the visuomotor system. Microsaccades, the miniature spontaneous eye movements, are critical for the visual perception. We hypothesized that microsaccades follow specific temporal patterns that are modulated by the basal ganglia output., Methods: We used high-resolution video-oculography to capture microsaccades in 48 subjects (31 healthy and 17 with Parkinson's disease) when subjects were asked to hold their gaze on a straight-ahead target projected on white background. We analyzed spontaneous discharge patterns of microsaccades., Results: The first analysis considering coefficient of variation in intersaccadic interval distribution demonstrated that microsaccades in Parkinson's disease are more dispersed than the control group. The second analysis scrutinized microsaccades' temporal variability and revealed 3 distinct occurrence patterns: regular rhythmic, clustered, and randomly occurring following a Poisson-like process. The regular pattern was relatively more common in Parkinson's disease. Subthalamic DBS modulated this temporal pattern. The amount of change in the temporal variability depended on the DBS-induced volume of tissue activation and its overlap with the subthalamic nucleus. The third analysis determined the autocorrelations of microsaccades within 2-second time windows. We found that Parkinson's disease altered local temporal organization in microsaccade generation, and DBS had a modulatory effect., Conclusion: The microsaccades occur in 3 temporal patterns. The basal ganglia are one of the modulators of the microsaccade spontaneity., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by North American Neuro-Ophthalmology Society.)

Parkinson's disease (PD) presents with visuospatial impairment and falls. It is critical to understand how subthalamic deep brain stimulation (STN DBS) modulates visuospatial perception. We hypothesized that DBS has different effects on visual and vestibular perception of linear motion (heading), a critical aspect of visuospatial navigation; and such effects are specific to modulated STN location. Two-alternative forced-choice experiments were performed in 14 PD patients with bilateral STN DBS and 19 age-matched healthy controls (HC) during passive en bloc linear motion and 3D optic-flow in immersive virtual reality measured vestibular and visual heading. Objective measure of perception with Weibull psychometric function revealed that PD has significantly lower accuracy [L: 60.71 (17.86)%, R: 74.82 (17.44)%] and higher thresholds [L: 16.68 (12.83), R: 10.09 (7.35)] during vestibular task in both directions compared to HC (p < 0.05). DBS significantly improved vestibular discrimination accuracy [81.40 (14.36)%] and threshold [4.12 (5.87), p < 0.05] in the rightward direction. There were no DBS effects on the slopes of vestibular psychometric curves. Visual heading perception was better than vestibular and it was comparable to HC. There was no significant effect of DBS on visual heading response accuracy or discrimination threshold (p > 0.05). Patient-specific DBS models revealed an association between change in vestibular heading perception and the modulation of the dorsal STN. In summary, DBS may have different effects on vestibular and visual heading perception in PD. These effects may manifest via dorsal STN putatively by its effects on the cerebellum., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Perception of our linear motion, heading, relies on convergence from multiple sensory systems utilizing visual and vestibular signals. Multisensory convergence takes place in the visuo-vestibular areas of the cerebral cortex and posterior cerebellar vermis. Latter closely connected with the inferior olive may malfunction in disorders of olivo-cerebellar hypersynchrony, such as the syndrome of oculopalatal tremor (OPT). We had recently shown an impairment in vestibular heading perception in the subjects with OPT. Here we asked whether the hypersynchrony in the inferior-olive cerebellar circuit also affects the visual perception of heading, and the impairment is coupled with the deficits in vestibular heading perception. Three subjects with OPT and 11 healthy controls performed a two-alternative forced-choice task in two separate experiments; one when they were moved en bloc in a straight-ahead forward direction or at multiple heading angles to the right or the left; and second when under virtual reality goggle they experienced the movement of star cloud leading to the percept of heading straight, left or to the right at the heading angles similar to those utilized in the vestibular task. The resultant psychometric function curves, derived from the two-alternative-forced-choice task, revealed abnormal threshold to perceive heading direction, abnormal sensitivity to the change in heading direction compared to straight ahead, and a bias towards one side. Although the impairment was present in both visual and vestibular heading perception, the deficits were not coupled., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Multisensory integration is critical for resolving ambiguities in isolated sensory systems assuring accurate perception of one's own linear motion, i.e., heading. The vestibular signal, a critical source of information for heading perception, is transformed in appropriate coordinates suitable for multisensory integration-such transformation takes place under cerebellar supervision. Deficiency in cerebellar function due to Purkinje cell loss results in inaccurate multisensory integration and impaired heading perception. Here, we predict that a classic movement disorder, the syndrome of oculopalatal tremor (OPT), also presents with inaccurate heading direction perception. The characteristic feature of oculopalatal tremor is pseudohypertrophic inferior olive that constantly sends spontaneous, hypersynchronous, abnormal, and meaningless signals to the cerebellum. Such malicious olive signal can impair heading perception. We examined vestibular heading perception in 6 individuals with OPT and 9 age-matched healthy controls (HC). We used a two-alternative forced choice task performed during passive en bloc translation. Compared with age-matched HC, OPT group had significantly higher heading direction perception threshold indicating a less sensitive vestibular system to variations in heading direction. Using computational simulations, we show that the addition of the abnormal noise into the cerebellar system results in decreased spatiotemporal tuning behavior of the cerebellar output. Such impairment in spatiotemporal tuning causes reduced ability to perceive heading direction. Hyperactivity in the inferior-olive cerebellar pathway impairs the heading direction perception. We suggest that this impairment stems from abnormal noise into the cerebellum due to hypersynchronized inferior olive., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

The syndrome of oculopalatal tremor (OPT) featuring the olivo-cerebellar hypersychrony leads to disabling pendular nystagmus and palatal myoclonus. This rare disorder provides valuable information about the motor physiology and offers insights into the mechanistic underpinning of common movement disorders. This focused review summarizes the last decade of OPT research from our laboratory and addresses three critical questions: 1) How the disease of inferior olive affects the physiology of motor learning? We discovered that our brain's ability to compensate for the impaired motor command and implement errors to correct future movements could be affected if the cerebellum is occupied in receiving and transmitting the meaningless signal. A complete failure of OPT patients to adapt to change in rapid eye movements (saccades) provided proof of this principle. 2) Whether maladaptive olivo-cerebellar circuit offers insight into the mechanistic underpinning of the common movement disorder, dystonia, characterized by abnormal twisting and turning of the body part. We discovered that the subgroup of patients who had OPT also had dystonia affecting the neck, trunk, limbs, and face. We also found that the subjects who had tremor predominant neck dystonia (without OPT) also had impaired motor learning on a long and short timescale, just like those with OPT. Altogether, our studies focused on dystonia suggested the evidence for the maladaptive olive-cerebellar system. 3) We discovered that the OPT subjects had difficulty in perceiving the direction of their linear forward motion, i.e., heading, suggesting that olivo-cerebellar hypersynchrony also affects perception., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Miniature yoked eye movements, fixational saccades, are critical to counteract visual fading. Fixational saccades are followed by a return saccades forming squarewaves. Present in healthy states, squarewaves, if too many or too big, affect visual stability. Parkinson's disease (PD), where visual deficits are not uncommon, is associated with the squarewaves that are excessive in number or size. Our working hypothesis is that the basal ganglia are at the epicenter of the abnormal fixational saccades and squarewaves in PD; the effects are manifested through their connections to the superior colliculus (affecting saccade frequency and amplitude) and the cerebellum (affecting velocity and amplitude). We predict that the subthalamic deep brain stimulation (DBS) variably affects the amplitude, frequency, and velocity of fixational saccade and that the effect depends on the electrode's proximity or the volume of activated tissue in the subthalamic nucleus' connections with the superior colliculus or the cerebellum. We found that DBS modulated saccade amplitude, frequency, and velocity in 11 PD patients. Although all three parameters were affected, the extent of the effects varied amongst subjects. The modulation was dependent upon the location and size of the electrically activated volume of the subthalamic region., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Background: No clinical trials have been specifically designed to compare medical treatments after surgery in Parkinson's disease (PD)., Objective: Study's objective was to compare the efficacy and safety of levodopa versus dopamine agonist monotherapy after deep brain stimulation (DBS) in PD., Methods: Thirty-five surgical candidates were randomly assigned to receive postoperative monotherapy with either levodopa or dopamine agonist in a randomized, single-blind study. All patients were reevaluated in short- (3 months), mid- (6 months), and long-term (2.5 years) follow-up after surgery. The primary outcome measure was the change in the Non-Motor Symptoms Scale (NMSS) 3 months after surgery. Secondary outcome measures were the percentage of patients maintaining monotherapy, change in motor symptoms, and specific non-motor symptoms (NMS). Analysis was performed primarily in the intention-to-treat population., Results: Randomization did not significantly affect the primary outcome (difference in NMSS between treatment groups was 4.88 [95% confidence interval: -11.78-21.53, P = 0.566]). In short- and mid-term follow-up, monotherapy was safe and feasible in more than half of patients (60% in short- and 51.5% in mid-term follow-up), but it was more often possible for patients on levodopa. The ability to maintain dopamine agonist monotherapy was related to optimal contact location. In the long term, levodopa monotherapy was feasible only in a minority of patients (34.2%), whereas dopamine agonist monotherapy was not tolerated due to worsening of motor conditions or occurrence of impulse control disorders., Conclusions: This trial provides evidence for simplifying pharmacological treatment after functional neurosurgery for PD. The reduction in dopamine receptor agonists should be attempted while monitoring for occurrence of NMSs, such as apathy and sleep disturbances. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Objectives: Parkinson's disease (PD) commonly affects visuospatial navigation causing postural instability and falls. Our overarching aim was to examine the visual and vestibular systems governing visuospatial navigation in PD. We hypothesize that PD affects vestibular and visual motion perception but to a different extent. The effects of PD on motion perception are dependent on the severity of the disease., Methods: The two-alternative-forced-choice task objectively measured the motion perception during two experiments. One experiment examined the vestibular motion perception with en bloc movement of the platform. The second experiment tested the visual motion perception using an immersive virtual reality goggle., Results: We found that accuracy, threshold, and precision of vestibular perception were more impaired in advanced-PD patients compared to those with a mild form of the disease. The parameters also correlated with the disease duration, overall axial motor impairment causing postural instability and falls, and subjective rating of the balance function. Such changes were present but less severe in visual motion perception., Conclusion: We conclude that PD affects motion perception in the visual and vestibular domains in a severity-dependent manner. The impact of the disease in the vestibular domain is more severe compared to the visual domain. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Objective: Subthalamic deep brain stimulation (DBS) is an established therapy for Parkinson's disease. Connectomic DBS modeling is a burgeoning subfield of research aimed at characterizing the axonal connections activated by DBS. This article describes our approach and methods for evolving the StimVision software platform to meet the technical demands of connectomic DBS modeling in the subthalamic region., Materials and Methods: StimVision v2 was developed with Visualization Toolkit (VTK) libraries and integrates four major components: 1) medical image visualization, 2) axonal pathway visualization, 3) electrode positioning, and 4) stimulation calculation., Results: StimVision v2 implemented two key technological advances for connectomic DBS analyses in the subthalamic region. First was the application of anatomical axonal pathway models to patient-specific DBS models. Second was the application of a novel driving-force method to estimate the response of those axonal pathways to DBS. Example simulations with directional DBS electrodes and clinically defined therapeutic DBS settings are presented to demonstrate the general outputs of StimVision v2 models., Conclusions: StimVision v2 provides the opportunity to evaluate patient-specific axonal pathway activation from subthalamic DBS using anatomically detailed pathway models and electrically detailed electric field distributions with interactive adjustment of the DBS electrode position and stimulation parameter settings., (© 2021 International Neuromodulation Society.)

Objective: To assess the clinical manifestations and predictors of different types of tremors in individuals with different types of isolated dystonia., Methods: Clinical manifestations of tremor were assessed in a multicenter, international cross-sectional, cohort study of 2,362 individuals with all types of isolated dystonia (focal, segmental, multifocal, and generalized) recruited through the Dystonia Coalition., Results: Methodical and standardized assessments of all participants in this cohort revealed the overall prevalence of any type of tremor was 53.3%. The prevalence of dystonic tremor varied from 36.9% to 48.4%, depending on criteria used to define it. To identify the factors associated with tremors in dystonia, the data were analyzed by generalized linear modeling and cluster analyses. Generalized linear modeling indicated 2 of the strongest factors associated with tremor included body region affected by dystonia and recruitment center. Tremor was also associated with severity of dystonia and duration of dystonia, but not with sex or race. The cluster analysis distinguished 8 subgroups within the whole cohort; defined largely by body region with dystonia, and secondarily by other clinical characteristics., Conclusion: The large number of cases evaluated by an international team of movement disorder experts facilitated the dissection of several important factors that influence the apparent prevalence and phenomenology of tremor in dystonia. These results are valuable for understanding the many differences reported in prior studies, and for guiding future studies of the nosology of tremor and dystonia., (© 2020 American Academy of Neurology.)

The relationship between two common movement disorders, dystonia and tremor, is controversial. Both deficits have correlates in the network that includes connections between the cerebellum and the basal ganglia. In order to assess the physiological relationship between tremor and dystonia, we measured the activity of 727 pallidal single-neurons during deep brain stimulation surgery in patients with cervical dystonia without head oscillations, cervical dystonia plus jerky oscillations, and cervical dystonia with sinusoidal oscillations. Cluster analyses of spike-train recordings allowed classification of the pallidal activity into burst, pause, and tonic. Burst neurons were more common, and number of spikes within spike and inter-burst intervals was shorter in pure dystonia and jerky oscillation groups compared to the sinusoidal oscillation group. Pause neurons were more common and irregular in pure tremor group compared to pure dystonia and jerky oscillation groups. There was bihemispheric asymmetry in spontaneous firing discharge in pure dystonia and jerky oscillation groups, but not in sinusoidal oscillation group. These results demonstrate that the physiology of pallidal neurons in patients with pure cervical dystonia is similar to those who have cervical dystonia combined with jerky oscillations, but different from those who have cervical dystonia combined with sinusoidal oscillations. These results imply distinct mechanistic underpinnings for different types of head oscillations in cervical dystonia.

Background: The cingulum bundle (CB) has long been a target for psychiatric neurosurgical procedures, but with limited understanding of the brain networks being impacted. Recent advances in human tractography could provide a foundation to better understand the effects of neurosurgical interventions on the CB; however, the reliability of tractography remains in question., Objective: To evaluate the ability of different tractography techniques, derived from typical, human diffusion-weighted imaging (DWI) data, to characterize CB connectivity described in animal models. This will help validate the clinical applicability of tractography, and generate insight on current and future neurosurgical targets for psychiatric disorders., Methods: Connectivity of the CB in 15 healthy human subjects was evaluated using DWI-based tractography, and compared to tract-tracing findings from nonhuman primates. Brain regions of interest were defined to coincide with the animal model. Tractography was performed using 3 techniques (FSL probabilistic, Camino probabilistic, and Camino deterministic). Differences in connectivity were assessed, and the CB segment with the greatest connectivity was determined., Results: Each tractography technique successfully reproduced the animal tracing model with a mean accuracy of 72% (68-75%, P < .05). Additionally, one region of the CB, the rostral dorsal segment, had significantly greater connectivity to associated brain structures than all other CB segments (P < .05)., Conclusion: Noninvasive, in vivo human analysis of the CB, using clinically available DWI for tractography, consistently reproduced the results of an animal tract-tracing model. This suggests that tractography of the CB can be used for clinical applications, which may aid in neurosurgical targeting for psychiatric disorders., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Introduction: Dystonia is often associated with repetitive jerky oscillations (i.e. dystonic tremor), while tremor is characterized by sinusoidal oscillations. We propose two competing predictions for dystonic tremor and sinusoidal tremor relationship. In any given patient, (1) the oscillation could be characterized as either sinusoidal or jerky based on the degree of distortion in the waveforms, (2) the oscillation consists of both sinusoidal and jerky waveforms mixed in a certain proportion that varies among individuals. We objectively test these predictions in patients with cervical dystonia., Methods: We recorded head oscillations in 14 subjects with cervical dystonia using a high-resolution magnetic field search coil system. Distortion in the signal was used as a measure of jerkiness. A hierarchical clustering classified the oscillations based on distortion characteristics., Results: Signal analysis in the frequency domain allowed identification of the components of the waveforms at frequencies other than the fundamental frequency. The distortion from the component at fundamental frequency was present in both low and high frequency range. Based on varying levels of distortions, i.e. jerkiness, the head oscillations were grouped into 4 clusters: one cluster with lowest distortion (sinusoidal waveforms), one cluster with highest distortion (jerky waveforms), and two intermediate clusters - one with distortion at low frequency and another with distortion at high frequency. The distribution of 4 clusters varied across subjects suggesting co-existence of sinusoidal and jerky waveforms., Conclusion: These results support the prediction that jerky and sinusoidal waveforms concur in cervical dystonia. Amount of concurrence varies amongst patients., (Published by Elsevier Ltd.)

Fixational eye movements comprise of fast microsaccades alternating with slow intersaccadic drifts. These physiologic eye movements play an important role in visual perception. Amblyopic patients are known to have fixation instability, particularly of the amblyopic eye. We examined eye movement abnormalities that contribute to this instability. We found that fixation stability is affected by the presence of fusion maldevelopment nystagmus (FMN). However, some amblyopes can have nystagmus without nasally directed slow phases and reversal in direction of the quick phase on ocular occlusion, features seen in FMN. In patients without nystagmus, we found increased amplitude of fixational saccades and inter-saccadic drifts. We categorized amblyopia patients by type (anisometropic, strabismic, or mixed) and eye movement waveform (no nystagmus, nystagmus without FMN, and FMN). We found specific fast and slow eye movement abnormalities of the fellow and amblyopic eye during fellow, amblyopic and both eyes viewing conditions across eye movement waveforms and types of amblyopia. These eye movement abnormalities can serve as biomarkers that can predict the impact of amblyopia as measured by visual acuity and stereopsis. Evaluation of fixational eye movements in amblyopia could be important to diagnose these common eye diseases and predict treatment effectiveness., Competing Interests: The authors declare that the contents of the article are in agreement with the ethics described in http://biblio.unibe.ch/portale/elibrary/BOP/jemr/ethics.html and that there is no conflict of interest regarding the publication of this paper.

Eye movements are frequently considered diagnostic markers indicating involvement of the cerebellum. Impaired amplitude of saccades (saccade dysmetria), impaired gaze holding function (horizontal or downbeat nystagmus), and interrupted (choppy) pursuit are typically considered hallmarks of cerebellar disorders. While saccade dysmetria is a frequently considered abnormality, the velocity of saccades are rarely considered part of the constellation of cerebellar involvement. Reduced saccade velocity, frequently called "slow saccades" are typically seen in a classic disorder of the midbrain called progressive supranuclear palsy. It is also traditionally diagnostic of spinocerebellar ataxia type 2. In addition to its common causes, the slowness of vertical saccades is not rare in cerebellar disorders. Frequently this phenomenology is seen in multisystem involvement that substantially involves the cerebellum. In this review we will first discuss the physiological basis and the biological need for high saccade velocities. In subsequent sections we will discuss disorders of cerebellum that are known to cause slowing of saccades. We will then discuss possible pathology and novel therapeutic strategies., Competing Interests: Kelsey Jensen (kmj53@case.edu), Sinem Balta Beylergil (sxb818@case.edu), Aasef G. Shaikh (aasefshaikh@gmail.com). Neurological Institute, University Hospitals, Cleveland, OH. Department of Neurology, Case Western Reserve University, Cleveland, OH. Neurology Service, Louis Stokes Cleveland VA Medical Center, Cleveland, OH.Not applicable - this is a review paper.This is a review paper, hence not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Postural instability and falls are common causes of morbidity and mortality in the second most prevalent neurodegenerative condition, Parkinson's disease (PD). Poor understanding of balance dysfunction in PD has hampered the development of novel therapeutic measures for postural instability and balance dysfunction. We aimed to determine how the ability to perceive one's own linear motion in the absence of visual cues, i.e., vestibular heading, is affected in PD. We examined vestibular heading function using a two-alternative forced choice task performed on a six-degree-of-freedom motion platform. Sensitivity of the vestibular system to subtle variations in heading direction and systematic errors in accuracy of responses were assessed for each subject using a Gaussian cumulative distribution psychometric function. Compared to healthy subjects, PD presented with higher angular thresholds to detect vestibular heading direction. These results confirm the potential of our study to provide valuable insight to the vestibular system's role in spatial navigation deficits in PD., (© 2019 Elsevier B.V. All rights reserved.)

Background: It has been well-established that both vestibular function and balance degrade with age and that balance degradation contributes to falls. While multiple causes contribute to balance declines, there have been few empirical investigations of the specific sensory contributors to balance that mediate (i.e., explain a significant fraction of) the effect of age on balance., Objective: To determine if vestibular function significantly mediates the effect of age on balance, and to quantify the fraction of any such statistically significant age-effect on balance using previously published vestibular threshold and balance data., Methods: Balance was quantified as complete/incomplete on a standard Romberg 4-condition foam balance test. Vestibular thresholds were determined using standard methods with motion provided by a Moog 6DOF motion platform. Standard mediation analyses were performed to determine if any of the five vestibular thresholds measured (0.2Hz roll tilt and 1Hz roll tilt, yaw rotation, y-translation, and z-translation) significantly mediated the previously reported age-effect on balance., Results: 0.2Hz roll tilt thresholds were found to significantly mediate the relationship between age and balance, whether we considered all subjects or just the subjects above the age of 40 (above which vestibular thresholds increase with age). Depending on the exact age cut-off implemented between 37 and 42 years of age, 0.2Hz roll tilt thresholds explained (mediated) between 33% and 55% of the total age-effect on balance., Conclusion: Vestibular function may mediate approximately 50% of the widely-reported age-effect on balance. If confirmed by future studies, this may provide an opportunity to improve balance (and presumably reduce fall risk) via specific therapies tailored to improve vestibular function., (© 2019 Elsevier B.V. All rights reserved.)

Substance-dependent individuals often lack the ability to adjust decisions flexibly in response to the changes in reward contingencies. Prediction errors (PEs) are thought to mediate flexible decision-making by updating the reward values associated with available actions. In this study, we explored whether the neurobiological correlates of PEs are altered in alcohol dependence. Behavioral, and functional magnetic resonance imaging (fMRI) data were simultaneously acquired from 34 abstinent alcohol-dependent patients (ADP) and 26 healthy controls (HC) during a probabilistic reward-guided decision-making task with dynamically changing reinforcement contingencies. A hierarchical Bayesian inference method was used to fit and compare learning models with different assumptions about the amount of task-related information subjects may have inferred during the experiment. Here, we observed that the best-fitting model was a modified Rescorla-Wagner type model, the "double-update" model, which assumes that subjects infer the knowledge that reward contingencies are anti-correlated, and integrate both actual and hypothetical outcomes into their decisions. Moreover, comparison of the best-fitting model's parameters showed that ADP were less sensitive to punishments compared to HC. Hence, decisions of ADP after punishments were loosely coupled with the expected reward values assigned to them. A correlation analysis between the model-generated PEs and the fMRI data revealed a reduced association between these PEs and the BOLD activity in the dorsolateral prefrontal cortex (DLPFC) of ADP. A hemispheric asymmetry was observed in the DLPFC when positive and negative PE signals were analyzed separately. The right DLPFC activity in ADP showed a reduced correlation with positive PEs. On the other hand, ADP, particularly the patients with high dependence severity, recruited the left DLPFC to a lesser extent than HC for processing negative PE signals. These results suggest that the DLPFC, which has been linked to adaptive control of action selection, may play an important role in cognitive inflexibility observed in alcohol dependence when reinforcement contingencies change. Particularly, the left DLPFC may contribute to this impaired behavioral adaptation, possibly by impeding the extinction of the actions that no longer lead to a reward.