PET Molecular Imaging of Phosphodiesterase 10A: An Early Biomarker of Huntington's Disease Progression.

BACKGROUND: Changes in phosphodiesterase 10A enzyme levels may be a suitable biomarker of disease progression in Huntington's disease. OBJECTIVES: To evaluate phosphodiesterase 10A PET imaging as a biomarker of HD progression using the radioligand, [18 F]MNI-659. METHODS: The cross-sectional study (NCT02061722) included 45 Huntington's disease gene-expansion carriers stratified into four disease stages (early and late premanifest and Huntington's disease stages 1 and 2) and 45 age- and sex-matched healthy controls. The primary analysis compared striatal and pallidal phosphodiesterase 10A availability between Huntington's disease gene-expansion carriers and healthy controls as assessed by [18 F]MNI-659 binding. We assessed changes in phosphodiesterase 10A expression using several PET methodologies and compared with previously proposed measures of Huntington's disease progression (PET imaging of D2/3 receptors and anatomical volume loss on MRI). The longitudinal follow-up study (NCT02956148) continued evaluation of phosphodiesterase 10A availability in 35 Huntington's disease gene-expansion carriers at a mean of 18 months from baseline of the cross-sectional study. RESULTS: Primary analyses revealed that phosphodiesterase 10A availability in caudate, putamen, and globus pallidus was significantly lower in Huntington's disease gene-expansion carriers versus healthy controls across all stages. Striatal and pallidal phosphodiesterase 10A availability progressively declined in the premanifest stages and appeared to plateau between stages 1 and 2. The percentage decline of phosphodiesterase 10A availability measured cross-sectionally between Huntington's disease gene-expansion carriers and healthy controls was greater than that demonstrated by D2/3 receptor availability or volumetric changes. Annualized rates of phosphodiesterase 10A change showed a statistically significant decline between the cross-sectional study and follow-up. CONCLUSIONS: [18 F]MNI-659 PET imaging is a biologically plausible biomarker of Huntington's disease progression that is more sensitive than the dopamine-receptor and volumetric methods currently used. © 2020 International Parkinson and Movement Disorder Society.

Fatigue-Related Changes of Daily Function: Most Promising Measures for the Digital Age.

Background: Fatigue is a prominent symptom in many diseases and is strongly associated with impaired daily function. The measurement of daily function is currently almost always done with questionnaires, which are subjective and imprecise. With the recent advances of digital wearable technologies, novel approaches to evaluate daily function quantitatively and objectively in real-life conditions are increasingly possible. This also creates new possibilities to measure fatigue-related changes of daily function using such technologies. Summary: This review examines which digitally assessable parameters in immune-mediated inflammatory and neurodegenerative diseases may have the greatest potential to reflect fatigue-related changes of daily function. Key Messages: Results of a standardized analysis of the literature reporting about perception-, capacity-, and performance-evaluating assessment tools indicate that changes of the following parameters: physical activity, independence of daily living, social participation, working life, mental status, cognitive and aerobic capacity, and supervised and unsupervised mobility performance have the highest potential to reflect fatigue-related changes of daily function. These parameters thus hold the greatest potential for quantitatively measuring fatigue in representative diseases in real-life conditions, e.g., with digital wearable technologies. Furthermore, to the best of our knowledge, this is a new approach to analysing evidence for the design of performance-based digital assessment protocols in human research, which may stimulate further systematic research in this area.

Autonomous identification of freezing of gait in Parkinson's disease from lower-body segmental accelerometry.

BACKGROUND: We have previously published a technique for objective assessment of freezing of gait (FOG) in Parkinson's disease (PD) from a single shank-mounted accelerometer. Here we extend this approach to evaluate the optimal configuration of sensor placement and signal processing parameters using seven sensors attached to the lumbar back, thighs, shanks and feet. METHODS: Multi-segmental acceleration data was obtained from 25 PD patients performing 134 timed up and go tasks, and clinical assessment of FOG was performed by two experienced raters from video. Four metrics were used to compare objective and clinical measures; the intraclass correlation coefficient (ICC) for number of FOG episodes and the percent time frozen per trial; and the sensitivity and specificity of FOG detection. RESULTS: The seven-sensor configuration was the most robust, scoring highly on all measures of performance (ICC number of FOG 0.75; ICC percent time frozen 0.80; sensitivity 84.3%; specificity 78.4%). A simpler single-shank sensor approach provided similar ICC values and exhibited a high sensitivity to FOG events, but specificity was lower at 66.7%. Recordings from the lumbar sensor offered only moderate agreement with the clinical raters in terms of absolute number and duration of FOG events (likely due to musculoskeletal attenuation of lower-limb 'trembling' during FOG), but demonstrated a high sensitivity (86.2%) and specificity (82.4%) when considered as a binary test for the presence/absence of FOG within a single trial. CONCLUSIONS: The seven-sensor approach was the most accurate method for quantifying FOG, and is best suited to demanding research applications. A single shank sensor provided measures comparable to the seven-sensor approach but is relatively straightforward in execution, facilitating clinical use. A single lumbar sensor may provide a simple means of objective FOG detection given the ubiquitous nature of accelerometers in mobile telephones and other belt-worn devices.

Effects of Galvanic vestibular stimulation on cognitive function.

Although imaging studies suggest activation of cortical areas by vestibular input, there is little evidence of an adverse effect of non-veridical vestibular input on cognitive function. To test the hypothesis that degraded vestibular afferent input adversely affects cognition, we compared performance on a cognitive test battery in a group undergoing suprathreshold bilateral bipolar Galvanic vestibular stimulation (GVS) with a control group receiving no GVS or subthreshold stimulation. The battery consisted of six cognitive tests as follows: reaction time, dual tasking, Stroop, mental rotation, perspective-taking and matching-to-sample, as well as a simple visuomotor (manual tracking) task. Subjects performed the test battery before, during and after suprathreshold GVS exposure or subthreshold stimulation. Suprathreshold GVS significantly increased error rate for the match-to-sample and perspective-taking tasks relative to the subthreshold group, demonstrating a negative effect of non-veridical vestibular input in these specific cognitive tasks. Reaction time, dual tasking, mental rotation and manual tracking were unaffected by GVS exposure. The adverse effect of suprathreshold GVS on perspective taking but not mental rotation is consistent with imaging studies, which have demonstrated that egocentric mental transformations (perspective taking) occur primarily in cortical areas that receive vestibular input (the parietal-temporal junction and superior parietal lobule), whereas object-based transformations (mental rotation) occur in the frontoparietal region. The increased error rate during the match-to-sample task is likely due to interference with hippocampal processing related to spatial memory, as suggested by imaging studies on vestibular patients.

Validation of 24-hour ambulatory gait assessment in Parkinson's disease with simultaneous video observation.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder resulting in motor disturbances that can impact normal gait. Although PD initially responds well to pharmacological treatment, as the disease progresses efficacy often fluctuates over the course of the day, and clinical management would benefit from long-term objective measures of gait. We have previously described a small device worn on the shank that uses acceleration and angular velocity sensors to calculate stride length and identify freezing of gait in PD patients. In this study we extend validation of the gait monitor to 24-h using simultaneous video observation of PD patients. METHODS: A sleep laboratory was adapted to perform 24-hr video monitoring of patients while wearing the device. Continuous video monitoring of a sleep lab, hallway, kitchen and conference room was performed using a 4-camera security system and recorded to hard disk. Subjects (3) wore the gait monitor on the left shank (just above the ankle) for a 24-h period beginning around 5 pm in the evening. Accuracy of stride length measures were assessed at the beginning and end of the 24-h epoch. Two independent observers rated the video logs to identify when subjects were walking or lying down. RESULTS: The mean error in stride length at the start of recording was 0.05 m (SD 0) and at the conclusion of the 24 h epoch was 0.06 m (SD 0.026). There was full agreement between observer coding of the video logs and the output from the gait monitor software; that is, for every video observation of the subject walking there was a corresponding pulse in the monitor data that indicated gait. CONCLUSIONS: The accuracy of ambulatory stride length measurement was maintained over the 24-h period, and there was 100% agreement between the autonomous detection of locomotion by the gait monitor and video observation.

Galvanic vestibular stimulation as an analogue of spatial disorientation after spaceflight.

BACKGROUND: Exposure to microgravity adversely affects performance of astronaut pilots; a review of the first 100 Shuttle missions found that touchdown speed was above specified limits in 20% of landings, in contrast to near ideal performance in preflight high-fidelity Shuttle simulations. Ground-based simulators emphasize spacecraft handling abilities, but do not recreate the effects of extended weightlessness on sensorimotor function. The aim of this study was to validate an analogue of the sensorimotor effects of microgravity using pseudorandom bilateral bipolar galvanic vestibular stimulation (GVS) during Shuttle landing simulations. METHODS: Pilot performance was assessed during simulated Shuttle landings in the Vertical Motion Simulator at NASA Ames Research Center, Moffett Field, CA (used for astronaut pilot training). Subjects (N = 11) flew eight pairs of identical landing profiles (final approach and touchdown), with and without GVS, presented in a pseudorandom order. RESULTS: Touchdown speed was on target (204 kn) without GVS [203.8 kn], but increased significantly during GVS exposure 1208.5 kn] and was at the upper limit (209 kn) of the target range. The adverse effects of GVS on pilot performance were obvious. Unsuccessful (crash) landings increased from 2.3% (2/88) without GVS to 9% (7/88) with GVS. Hard landings, with touchdown speed in the 'red' (unacceptable) range (> 214 kn), almost doubled from 14 (15.9%) without GVS to 27 (30.7%) with GVS. CONCLUSION: GVS was an effective analogue of decrements in postflight Shuttle pilot performance.

Tolerance to extended galvanic vestibular stimulation: optimal exposure for astronaut training.

BACKGROUND: We have developed an analogue of postflight sensorimotor dysfunction in astronauts using pseudorandom galvanic vestibular stimulation (GVS). To date there has been no study of the effects of extended GVS on human subjects and our aim was to determine optimal exposure for astronaut training based on tolerance to intermittent and continuous galvanic stimulation. METHODS: There were 60 subjects who were exposed to a total of 10.5 min of intermittent GVS at a peak current of 3.5 mA or 5 mA. A subset of 24 subjects who tolerated the intermittent stimulus were subsequently exposed to 20-min continuous stimulation at 3.5 mA or 5 mA. RESULTS: During intermittent GVS the large majority of subjects (78.3%) reported no or at most mild motion sickness symptoms, 13.3% reported moderate symptoms, and 8.3% experienced severe nausea and requested termination of the stimulus. During 20-min continuous exposure, 83.3% of subjects reported no or at most mild motion sickness symptoms and 16.7% (all in the 5-mA group) experienced severe nausea. CONCLUSION: Based on these results, we propose two basic modes of GVS application to minimize the incidence of motion sickness: intermittent high (5 mA) amplitude, suited to simulation of intensive operator tasks requiring a high-fidelity analogue of postflight sensorimotor dysfunction such as landing or docking maneuvers; and continuous low (3.5 mA) amplitude stimulation, for longer simulation scenarios such as extra vehicular activity. Our results suggest that neither mode of stimulation would induce motion sickness in the large majority of subjects for up to 20 min exposure.

Long-duration spaceflight adversely affects post-landing operator proficiency.

Performance of astronaut pilots during space shuttle landing was degraded after a few weeks of microgravity exposure, and longer-term exposure has the potential to impact operator proficiency during critical landing and post-landing operations for exploration-class missions. Full-motion simulations of operationally-relevant tasks were utilized to assess the impact of long-duration spaceflight on operator proficiency in a group of 8 astronauts assigned to the International Space Station, as well as a battery of cognitive/sensorimotor tests to determine the underlying cause of any post-flight performance decrements. A ground control group (N = 12) and a sleep restriction cohort (N = 9) were also tested to control for non-spaceflight factors such as lack of practice between pre- and post-flight testing and fatigue. On the day of return after 6 months aboard the space station, astronauts exhibited significant deficits in manual dexterity, dual-tasking and motion perception, and a striking degradation in the ability to operate a vehicle. These deficits were not primarily due to fatigue; performance on the same tasks was unaffected after a 30-h period of sleep restriction. Astronauts experienced a general post-flight malaise in motor function and motion perception, and a lack of cognitive reserve apparent only when faced with dual tasks, which had recovered to baseline by four days after landing.

A functional MRI study of a paced motor activation task to evaluate frontal-subcortical circuit function in bipolar depression.

The primary aim of this functional magnetic resonance imaging (fMRI) study was to test the utility of a paced motor activation task to evaluate frontal-subcortical (FSC) circuit function in bipolar depression. A secondary aim was to determine if utilizing both a motor and cognitive activation paradigm (Stroop) would provide information about the potential role of FSC dysfunction in the cognitive symptoms of bipolar depression. Analysis of the control group (n=15) alone revealed that the motor task activated FSC structures. Comparison of the control to bipolar group (n=14) revealed significant differences between the groups in striatum as well as cortical areas with FSC connections in response to the non-dominant-hand motor task. In response to the Stroop, there were significant differences between the groups in portions of the bilateral posterior cingulate and occipital cortex, but not in FSC structures. While these results must be considered preliminary, this work supports further studies of paced motor tasks to probe FSC function. Further, it suggests that the use of both a cognitive and motor task in the same study provides useful information about brain function. Finally, it supports the literature implicating FSC circuit abnormalities in bipolar disorder.

New models of frontal-subcortical skeletomotor circuit pathology in tardive dyskinesia.

Tardive dyskinesia (TD) is a hyperkinetic movement disorder that can occur as a side effect of treatment with antipsychotic medications. Because antipsychotics block the D2 family of dopamine receptors in the striatum, it has long been suspected this blockade contributes to the development of TD. Specifically, increased sensitivity of the dopamine receptors following chronic blockade has been thought to result in abnormal functioning of the frontal-subcortical (FSC) skeletomotor circuit and the symptoms of TD. However, this hypothesis remains unproven. In recent years, substantial research has focused on the basal ganglia and FSC circuits. This research has resulted in the development of the focused selection model of skeletomotor circuit function. This hypothesis provides a compelling model of neurocircuit abnormalities in TD. A greater understanding of the neuropathology of TD may lead to the development of better treatment and prevention strategies for this disorder. Furthermore, this information may contribute to a more complete understanding of normal skeletomotor circuit function and the role of circuit pathology in numerous neuropsychiatric conditions.

Pre-adaptation to noisy Galvanic vestibular stimulation is associated with enhanced sensorimotor performance in novel vestibular environments.

Performance on a visuomotor task in the presence of novel vestibular stimulation was assessed in nine healthy subjects. Four subjects had previously been adapted to 120 min exposure to noisy Galvanic vestibular stimulation (GVS) over 12 weekly sessions of 10 min; the remaining five subjects had never experienced GVS. Subjects were seated in a flight simulator and asked to null the roll motion of a visual bar presented on a screen using a joystick. Both the visual bar and the simulator cabin were moving in roll with a pseudorandom (sum of sines) waveform that were uncorrelated. The cross correlation coefficient, which ranges from 1 (identical waveforms) to 0 (unrelated waveforms), was calculated for the ideal (perfect nulling of bar motion) and actual joystick input waveform for each subject. The cross correlation coefficient for the GVS-adapted group (0.90 [SD 0.04]) was significantly higher (t[8] = 3.162; p = 0.013) than the control group (0.82 [SD 0.04]), suggesting that prior adaptation to GVS was associated with an enhanced ability to perform the visuomotor task in the presence of novel vestibular noise.

Central adaptation to repeated galvanic vestibular stimulation: implications for pre-flight astronaut training.

Healthy subjects (N = 10) were exposed to 10-min cumulative pseudorandom bilateral bipolar Galvanic vestibular stimulation (GVS) on a weekly basis for 12 weeks (120 min total exposure). During each trial subjects performed computerized dynamic posturography and eye movements were measured using digital video-oculography. Follow up tests were conducted 6 weeks and 6 months after the 12-week adaptation period. Postural performance was significantly impaired during GVS at first exposure, but recovered to baseline over a period of 7-8 weeks (70-80 min GVS exposure). This postural recovery was maintained 6 months after adaptation. In contrast, the roll vestibulo-ocular reflex response to GVS was not attenuated by repeated exposure. This suggests that GVS adaptation did not occur at the vestibular end-organs or involve changes in low-level (brainstem-mediated) vestibulo-ocular or vestibulo-spinal reflexes. Faced with unreliable vestibular input, the cerebellum reweighted sensory input to emphasize veridical extra-vestibular information, such as somatosensation, vision and visceral stretch receptors, to regain postural function. After a period of recovery subjects exhibited dual adaption and the ability to rapidly switch between the perturbed (GVS) and natural vestibular state for up to 6 months.

Temporal Characteristics of High-Frequency Lower-Limb Oscillation during Freezing of Gait in Parkinson's Disease.

A cardinal feature of freezing of gait (FOG) is high frequency (3-8 Hz) oscillation of the legs, and this study aimed to quantify the temporal pattern of lower-body motion prior to and during FOG. Acceleration data was obtained from sensors attached to the back, thighs, shanks, and feet in 14 Parkinson's disease patients performing timed-up-and-go tasks, and clinical assessment of FOG was performed by two experienced raters from video. A total of 23 isolated FOG events, defined as occurring at least 5 s after gait initiation and with no preceding FOG, were identified from the clinical ratings. The corresponding accelerometer records were analyzed within a 4 s window centered at the clinical onset of freezing. FOG-related high-frequency oscillation (an increase in power in the 3-8 Hz band >3 SD from baseline) followed a distal to proximal onset pattern, appearing at the feet, shanks, thighs, and then back over a period of 250 ms. Peak power tended to decrease as the focus of oscillation moved from feet to back. There was a consistent delay (mean 872 ms) between the onset of high frequency oscillation at the feet and clinical onset of FOG. We infer that FOG is characterized by high frequency oscillation at the feet, which progresses proximally and is mechanically damped at the torso.

Clinical assessment of freezing of gait in Parkinson's disease from computer-generated animation.

The current 'gold standard' for clinical evaluation of freezing of gait (FOG) in Parkinson's disease (PD) is determination of the number of FOG episodes from video by independent raters. We have previously described a robust technique for objective FOG assessment from lower-limb acceleration. However, there is no existing method for validation of autonomous FOG measures in the absence of video documentation. In this study we compared the results of clinical evaluation of FOG from computer-generated animations (derived from body-mounted inertial sensors) during a timed up and go test with the 'gold standard' of clinical video assessment, utilizing a cohort of 10 experienced raters from four PD centers. Agreement between the 10 clinical observers for scoring of FOG from computer animations was more robust for the relative duration of freeze events (percent time frozen; intraclass correlation coefficient of 0.65) than number of FOG episodes, and was comparable with clinical evaluation of the patient from video (intraclass correlation coefficient 0.73). This result suggests that percent time frozen should be considered (along with number of FOG events) to better convey FOG severity. The ability of clinical observers to quantify FOG from computer-generated animation derived from lower-limb motion data provides a potential approach to validation of accelerometry-based FOG identification outside of the clinic.

A comparison of clinical and objective measures of freezing of gait in Parkinson's disease.

Freezing of gait, a paroxysmal motor block, is common in the latter stages of Parkinson's disease. The current 'gold standard' of assessing the severity of freezing is based on clinical identification (by up to 3 raters) of the number of episodes from video. The aims of this study were to systematically assess this 'gold standard' across multiple Parkinson's disease centers, and to compare these clinical ratings with objective measures derived from lower limb acceleration data. Video recordings were acquired during a timed up-and-go task from 10 Parkinson's disease patients (with a clinical history of freezing) in the 'off' state. Patients were instrumented with accelerometers on the lateral aspect of each shank. Ten experienced clinicians were recruited from four Parkinson's disease centers to independently assess the videos for number and duration of freezing events. The reliability of clinical video assessment for number of freezing events was moderate (intraclass correlation coefficient 0.63). Percent time frozen (cumulative duration of freezing episodes/total duration of the walking task) demonstrated stronger agreement between raters (0.73). Agreement of accelerometry-derived measures of freezing severity with mean clinician ratings was strong for number of episodes (0.78) and very strong for percent time frozen (0.93). The results demonstrate the viability of objective measures of freezing, and that percent time frozen is a more reliable metric of severity than number of freezing events for both clinical and objective measures. The large variability between clinicians suggests that caution should be used when comparing subjective ratings across centers.

Absolute distance perception to locations off the ground plane.

Using vision, humans can accurately judge distances to locations on the ground surface up to distances of at least 20 m. Most theories of depth perception assume that this ability is associated with the fact that we live in a terrestrial world in which locations of interest often appear on the ground and for which feedback about distance is often available from nonvisual sources such as walking. Much less is known about the ability of humans to judge absolute distances to locations other than on or supported by the ground plane beyond a few meters, at which point binocular stereo provides at best limited information about distance scaling. We show that one commonly used action measure for probing absolute distance perception exhibits accurate performance, even for targets located on the ceiling of a large room. We follow this with evidence that distance to ceiling locations is recovered with a mechanism that depends, at least in part, on the angle from the line of sight to the target location and a gravity-based frame of reference.

The influence of complex action knowledge on representations of novel graspable objects: evidence from functional magnetic resonance imaging.

The influence of action knowledge associated with novel objects was investigated using functional magnetic resonance imaging. Participants were trained on complex actions associated with novel objects ("tools") and had experience manipulating other visually similar novel objects ("shapes"). During scanning, participants viewed, imagined grasping, and imagined using the objects. Based on previous neuroimaging and neuropsychological findings, our primary goal was to examine frontal and parietal regions subserving action representations associated with visual objects, namely the left inferior parietal lobule (IPL), the left ventral premotor cortex (VPM) and the presupplementary motor cortex (pre-SMA). We predicted differences between the tool and shape stimuli, modulated also by task demands. In viewing, we found greater effect sizes in the left VPM and IPL for tools versus shapes. In grasping, there was similar activation with both object types. The largest differences existed in using, in which greater effect sizes were found for tools versus shapes in left IPL and pre-SMA, and marginally in the left VPM. We suggest that representations of tools extend beyond classically defined affordances and recruit processing about both graspability and known action plans in tasks involving visual memory, motor imagery, and motor execution.