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Individuals with Parkinson's disease (PD) and healthy adults demonstrate similar levels of visuomotor adaptation provided that the distortion is small or introduced gradually, and hence, implicit processes are engaged. Recently, implicit processes underlying visuomotor adaptation in healthy individuals have been proposed to include proprioceptive recalibration (i.e., shifts in one's proprioceptive sense of felt hand position to match the visual estimate of their hand experienced during reaches with altered visual feedback of the hand). In the current study, we asked if proprioceptive recalibration is preserved in PD patients. PD patients tested during their "off" and "on" medication states and age-matched healthy controls reached to visual targets, while visual feedback of their unseen hand was gradually rotated 30° clockwise or translated 4 cm rightwards of their actual hand trajectory. As expected, PD patients and controls produced significant reach aftereffects, indicating visuomotor adaptation after reaching with the gradually introduced visuomotor distortions. More importantly, following visuomotor adaptation, both patients and controls showed recalibration in hand position estimates, and the magnitude of this recalibration was comparable between PD patients and controls. No differences for any measures assessed were observed across medication status (i.e., PD off vs PD on). Results reveal that patients are able to adjust their sensorimotor mappings and recalibrate proprioception following adaptation to a gradually introduced visuomotor distortion, and that dopaminergic intervention does not affect this proprioceptive recalibration. These results suggest that proprioceptive recalibration does not involve striatal dopaminergic pathways and may contribute to the preserved visuomotor adaptation that arises implicitly in PD patients.

Indexación: Scopus. Evidence from small-scale studies indicates that impairments in postural stability are an early and disabling feature of Huntington’s disease (HD) and may be a useful clinical endpoint for disease modifying trials. Larger studies are needed to confirm these preliminary findings and the suitability of postural stability outcomes as clinical endpoints. Static and dynamic postural stability were evaluated in 54 premanifest HD, 36 manifest HD and 45 healthy individuals using the Sensory Organization Test (SOT) and Limits of Stability (LOS) test. Manifest HD displayed significantly lower scores on all SOT conditions and on the SOT composite score and had more falls than healthy and premanifest HD (p < 0.05). Premanifest and manifest HD demonstrated significantly lower endpoint excursion (p < 0.001), maximum excursion (p ≤ 0.001), and directional control (p ≤ 0.004) values than healthy individuals on the LOS test. Deficits in LOS were found to manifest on the left side of premanifest HD. Significant but low associations were observed between UHDRS-TMS, disease burden score, diagnostic confidence level, SOT conditions and SOT composite score. We confirm here that individuals with premanifest and manifest HD display significant impairments in static and dynamic postural stability. Dynamic posturography assessments should be considered as clinical endpoints for future disease modifying trials. © 2018, The Author(s). https://www.nature.com/articles/s41598-018-32924-y

We have recently shown that visuomotor adaptation following reaches with a misaligned cursor not only induces changes in an individual's motor output, but their proprioceptive sense of hand position as well. Long-term changes are seen in motor adaptation; however, very little is known about the retention of changes in felt hand position. We sought to evaluate whether this recalibration in proprioception, following visuomotor adaptation, is sufficiently robust to be retained the following day (~24 h later), and if so, to determine its extent. Visuomotor adaptation was induced by having subjects perform reaches to visual targets using a cursor representing their unseen hand, which had been gradually rotated 45° counterclockwise. Motor adaptation and proprioceptive recalibration were determined by assessing subjects' reach aftereffects and changes in hand bias, respectively. We found that subjects adapted their reaches and recalibrated their sense of hand position following training with a misaligned cursor, as shown in Cressman and Henriques (J Neurophysiol 102:3505-3518, 2009). More importantly, subjects who showed proprioceptive recalibration in the direction of motor adaptation on Day 1 did retain changes in felt hand position and motor adaptation on Day 2. These findings suggest that in addition to motor changes, individuals are capable of retaining sensory changes in proprioception up to 24 h later.

Background Huntington's disease (HD) is associated with neuronal death in basal ganglia circuits important for postural control. Despite evidence of postural instability associated with HD, postural control at the limits of stability has not been investigated in this disease. Objective To use computerized dynamic posturography to measure postural control at the limits of stability during the premanifest and manifest stages of HD. Methods Patients with manifest HD, premanifest gene carriers, and matched controls stood on mechanically locked force plates while viewing a computer screen. The participant's estimated center of gravity was represented on the screen as a cursor along with eight target icons arranged in a circular pattern at the theoretical edge of limits of stability. On each trial, one of the eight targets was highlighted and the participant was instructed to control the cursor by rapidly shifting his/her weight in the direction of the target. Measures included reaction time, movement velocity, endpoint excursion, maximum excursion, and directional control. Results Analysis of variance revealed significant impairment on endpoint excursion, maximum excursion, and directional control (p≤0.001) in the Huntington's disease group, but not in the premanifest gene carrier group as compared to controls. No differences were found on reaction time or movement velocity measures. Group signal to noise ratios also were examined for the measures. Conclusions HD patients, but not premanifest gene carriers, showed impaired postural control at the limits of stability. Impaired performance in HD patients has potential functional consequences including increased risk of falling during weight-shifting activities.

Treatment of Parkinson's disease with dopaminergic agents, such as l-DOPA, is frequently compromised by disabling side effects, particularly dyskinesia and a shortening in duration of antiparkinsonian action. Studies in animal models and anecdotal evidence from a patient with Parkinson's disease show that the illicit drug ecstasy (MDMA) can alleviate these side effects, though with many drawbacks (e.g., psychoactivity). MDMA itself thus has little therapeutic potential. On the basis of known structure-psychoactivity relationships, we designed a series of α-substituted MDMA analogues, one of which, bearing an α-cyclopropyl substituent (UWA-101), enhanced the quality of l-DOPA actions in animal models. Indeed, UWA-101 was more effective than MDMA. Unlike MDMA, UWA-101 did not reduce viability of serotonergic cells, exhibit psychoactive properties, or reduce food intake, and did not substitute for MDMA in drug discrimination assays. UWA-101 displayed a unique receptor/transporter binding profile relative to MDMA, with a >5-fold decrease in affinity for NET and 5-HT(2A) receptors and a 10-fold increase in affinity for DAT. Furthermore, in a functional reuptake assay, UWA-101 inhibited both 5-HT and dopamine reuptake, while having no effect on the reuptake of noradrenaline. UWA-101 is the first selective DAT/SERT inhibitor described with comparable affinities for these two sites. These data identify a new class of therapeutic in Parkinson's disease and highlight the potential benefits of studying illicit drugs that in themselves would never be considered safe for long-term therapy.

Previous studies of Huntington's disease (HD) have reported motor control deficits for selected fine and gross motor skills. However, no studies have metrically assessed postural control in this clinical group when performing motor skills involved in daily living. Therefore, the purpose of the present study was to evaluate and compare postural control of individuals with confirmed Huntington's disease and non-gene carriers when completing three functional postural tasks. Eleven individuals with HD (mean age=47.1 years: UHDRS mean=34.5: mean age of HD onset 34.6 years: mean CAG repeat=44.1) and 17 non-gene carriers (NGC) (mean age=39.2 years: UHDRS mean=0.13: mean CAG repeat=20.5) completed three tests on a force plate interfaced with a computer. The tests were a step up and over an obstacle (SUO) test, a sit-to-stand (STS) test, and a step and turn (ST) test. Selected kinematic and kinetic variables were used to quantify postural control. Data were analyzed using MANOVA procedures and discriminant function analysis. HD patients were significantly slower in completing all three tests (HD SUO=2.3 s vs. NGC SUO=1.6 s; HD STS=0.8 s vs. NGC STS=0.5 s; HD ST=1.7 s vs. NGC ST=0.9 s) and developed less rising force during the step up and over test (HD=25.8% body weight vs. NGC=39.4% body weight) but not for the sit-to-stand test. Additionally, sway velocity of the center of gravity (COG) was significantly higher for HD patients when performing the sit-to-stand (HD=4.1°/s vs. NGC=2.9°/s) and step and turn tests (HD=33.7°/s vs. NGC=21.7°/s). HD patients manifest significant postural control deficits when performing motor skills typical of daily living activities.

Subtle changes in fine motor control have been observed in individuals who carry the Huntington's disease (HD) mutation but have not yet manifested symptoms, referred to as premanifest HD (preHD). However, few studies have examined gross motor impairments in this population. This study sought to examine the role of sensory involvement in maintaining postural stability during the premanifest and manifest stages of HD using computerized dynamic posturography. Eleven HD participants, 22 preHD subdivided into "preHD Near" (5 years from estimated clinical onset) and "preHD Far" (5 years from estimated clinical onset), and 17 nongene carriers (NGC) completed a sensory organization test (SOT) to assess postural control when vestibular, visual, and somatosensory information was systematically degraded. The HD group demonstrated greater postural sway than the NGC and preHD Far groups on all conditions including baseline, and greater postural sway than the preHD Near group when sensory information was manipulated. The preHD Near group showed significantly greater postural sway than the preHD Far group when visual and somatosensory information was degraded and only vestibular information was available and reliable for maintaining postural stability. The results of this study highlight subtle postural deficits in the face of changing sensory conditions in preHD up to 5 years before estimated disease onset. The findings suggest that the SOT may be a highly sensitive indicator of early motor impairment and subsequent phenoconversion to manifest HD in preHD.

Previous studies have shown that both young and older subjects adapt their reaches in response to a visuomotor distortion. It has been suggested that one's continued ability to adapt to a visuomotor distortion with advancing age is due to the preservation of implicit learning mechanisms, where implicit learning mechanisms include processes that realign sensory inputs (i.e. shift one's felt hand position to match the visual representation). The present study examined this proposal by determining if changes in sense of felt hand position (i.e. proprioceptive recalibration) follow visuomotor adaptation in older subjects. As well, we examined the influence of age on proprioceptive recalibration by comparing young and older subjects' estimates of the position at which they felt their hand was aligned with a visual reference marker before and after aiming with a misaligned cursor that was gradually rotated 30 degrees clockwise of the actual hand location. On estimation trials, subjects moved their hand along a robot-generated constrained pathway. At the end of the movement, a reference marker appeared and subjects indicated if their hand was left or right of the marker. Results indicated that all subjects adapted their reaches at a similar rate and to the same extent across the reaching trials. More importantly, we found that both young and older subjects recalibrated proprioception, such that they felt their hand was aligned with a reference marker when it was approximately 6 degrees more left (or counterclockwise) of the marker following reaches with a rotated cursor. The leftward shift in both young and older subjects' estimates was in the same direction and a third of the extent of adapted movement. Given that the changes in the estimate of felt hand position were only a fraction of the changes observed in the reaching movements, it is unlikely that sensory recalibration was the only source driving changes in reaches. Thus, we propose that proprioceptive recalibration combines with adapted sensorimotor mappings to produce changes in reaching movements. From the results of the present study, it is clear that changes in both sensory and motor systems are possible in older adults and could contribute to the preserved visuomotor adaptation.

Reaching with visual feedback that is misaligned with respect to the actual hand’s location leads to changes in reach trajectories (i.e., visuomotor adaptation). Previous studies have also demonstrated that when training to reach with misaligned visual feedback of the hand, the opposite hand also partially adapts, providing evidence of intermanual transfer. Moreover, our laboratory has shown that visuomotor adaptation to a misaligned hand cursor, either translated or rotated relative to the hand, also leads to changes in felt hand position (what we call proprioceptive recalibration), such that subjects’ estimate of felt hand position relative to both visual and non-visual reference markers (e.g., body midline) shifts in the direction of the visuomotor distortion. In the present study, we first determined the extent that motor adaptation to a translated cursor leads to transfer to the opposite hand, and whether this transfer differs across the dominant and non-dominant hands. Second, we looked to establish whether changes in hand proprioception that occur with the trained hand following adaptation also transfer to the untrained hand. We found intermanual motor transfer to the left untrained (non-dominant) hand after subjects trained their right (dominant) hand to reach with translated visual feedback of their hand. Motor transfer from the left trained to the right untrained hand was not observed. Despite finding changes in felt hand position in both trained hands, we did not find similar evidence of proprioceptive recalibration in the right or left untrained hands. Taken together, our results suggest that unlike visuomotor adaptation, proprioceptive recalibration does not transfer between hands and is specific only to the arm exposed to the distortion.

Reaching to targets with misaligned visual feedback of the hand leads to changes in proprioceptive estimates of hand position and reach aftereffects. In such tasks, subjects are able to make use of two error signals: the discrepancy between the desired and actual movement, known as the sensorimotor error signal, and the discrepancy between visual and proprioceptive estimates of hand position, which we refer to as the cross-sensory error signal. We have recently shown that mere exposure to a sensory discrepancy in the absence of goal-directed movement (i.e. no sensorimotor error signal) is sufficient to produce similar changes in felt hand position and reach aftereffects. Here, we sought to determine the extent that this cross-sensory error signal can contribute to proprioceptive recalibration and movement aftereffects by manipulating the magnitude of this signal in the absence of volitional aiming movements. Subjects pushed their hand out along a robot-generated linear path that was gradually rotated clockwise relative to the path of a cursor. On all trials, subjects viewed a cursor that headed directly towards a remembered target while their hand moved out synchronously. After exposure to a 30° rotated hand-cursor distortion, subjects recalibrated their sense of felt hand position and adapted their reaches. However, no additional increases in recalibration or aftereffects were observed following further increases in the cross-sensory error signal (e.g. up to 70°). This is in contrast to our previous study where subjects freely reached to targets with misaligned visual hand position feedback, hence experiencing both sensorimotor and cross-sensory errors, and the distortion magnitude systematically predicted increases in proprioceptive recalibration and reach aftereffects. Given these findings, we suggest that the cross-sensory error signal results in changes to felt hand position which drive partial reach aftereffects, while larger aftereffects that are produced after visuomotor adaptation (and that vary with the size of distortion) are related to the sensorimotor error signal.

Previous studies have demonstrated that after reaching with misaligned visual feedback of the hand, one adapts his or her reaches and partially recalibrates proprioception, such that sense of felt hand position is shifted to match the seen hand position. However, to date, this has only been demonstrated in the right (dominant) hand following reach training with a visuomotor distortion in which the rotated cursor distortion was introduced gradually. As reach adaptation has been shown to differ depending on how the distortion is introduced (gradual vs. abrupt), we sought to examine proprioceptive recalibration following reach training with a cursor that was abruptly rotated 30° clockwise relative to hand motion. Furthermore, because the left and right arms have demonstrated selective advantages when matching visual and proprioceptive targets, respectively, we assessed proprioceptive recalibration in right-handed subjects following training with either the right or the left hand. On average, we observed shifts in felt hand position of approximately 7.6° following training with misaligned visual feedback of the hand, which is consistent with our previous findings in which the distortion was introduced gradually. Moreover, no difference was observed in proprioceptive recalibration across the left and right hands. These findings suggest that proprioceptive recalibration is a robust process that arises symmetrically in the two hands following visuomotor adaptation regardless of the initial magnitude of the error signal.

Reaching with misaligned visual feedback of the hand leads to reach adaptation (motor recalibration) and also results in partial sensory recalibration, where proprioceptive estimates of hand position are changed in a way that is consistent with the visual distortion. The goal of the present study was to explore the relationship between changes in sensory and motor systems by examining these processes following (1) prolonged reach training and (2) training with increasing visuomotor distortions. To examine proprioceptive recalibration, we determined the position at which subjects felt their hand was aligned with a reference marker after completing three blocks of reach training trials with a cursor that was rotated 30° clockwise (CW) for all blocks, or with a visuomotor distortion that was increased incrementally across the training blocks up to 70°CW relative to actual hand motion. On average, subjects adapted their reaches by 16° and recalibrated their sense of felt hand position by 7° leftwards following the first block of reach training trials in which they reached with a cursor that was rotated 30°CW relative to the hand, compared to baseline values. There was no change in these values for the 30° training group across subsequent training blocks. However, subjects training with increasing levels of visuomotor distortion showed increased reach adaptation (up to 34° leftward movement aftereffects) and sensory recalibration (up to 15° leftwards). Analysis of motor and sensory changes following each training block did not reveal any significant correlations, suggesting that the processes underlying motor adaptation and proprioceptive recalibration occur simultaneously yet independently of each other.

Burkitt's lymphoma (BL) is a particularly aggressive cancer that primarily affects African children. Unfortunately, effective and affordable treatment is out of reach of most of the afflicted. The illicit psychoactive drug methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is cytotoxic to BL cell lines, but its low potency, psychoactivity and neurotoxicity preclude consideration as a therapeutic drug candidate. This paper describes the discovery of novel α-aryl analogues of MDMA that lack psychoactivity and reduce BL cell line viability with significantly more potency than the lead compound. Preliminary in vitro studies also indicate that the compounds are non-toxic to a relevant neuronal cell line.