Reward-Based Improvements in Motor Control Are Driven by Multiple Error-Reducing Mechanisms.

Reward has a remarkable ability to invigorate motor behavior, enabling individuals to select and execute actions with greater precision and speed. However, if reward is to be exploited in applied settings, such as rehabilitation, a thorough understanding of its underlying mechanisms is required. In a series of experiments, we first demonstrate that reward simultaneously improves the selection and execution components of a reaching movement. Specifically, reward promoted the selection of the correct action in the presence of distractors, while also improving execution through increased speed and maintenance of accuracy. These results led to a shift in the speed-accuracy functions for both selection and execution. In addition, punishment had a similar impact on action selection and execution, although it enhanced execution performance across all trials within a block, that is, its impact was noncontingent to trial value. Although the reward-driven enhancement of movement execution has been proposed to occur through enhanced feedback control, an untested possibility is that it is also driven by increased arm stiffness, an energy-consuming process that enhances limb stability. Computational analysis revealed that reward led to both an increase in feedback correction in the middle of the movement and a reduction in motor noise near the target. In line with our hypothesis, we provide novel evidence that this noise reduction is driven by a reward-dependent increase in arm stiffness. Therefore, reward drives multiple error-reduction mechanisms which enable individuals to invigorate motor performance without compromising accuracy.SIGNIFICANCE STATEMENT While reward is well-known for enhancing motor performance, how the nervous system generates these improvements is unclear. Despite recent work indicating that reward leads to enhanced feedback control, an untested possibility is that it also increases arm stiffness. We demonstrate that reward simultaneously improves the selection and execution components of a reaching movement. Furthermore, we show that punishment has a similar positive impact on performance. Importantly, by combining computational and biomechanical approaches, we show that reward leads to both improved feedback correction and an increase in stiffness. Therefore, reward drives multiple error-reduction mechanisms which enable individuals to invigorate performance without compromising accuracy. This work suggests that stiffness control plays a vital, and underappreciated, role in the reward-based imporvemenets in motor control.

Reward-driven enhancements in motor control are robust to TMS manipulation.

A wealth of evidence describes the strong positive impact that reward has on motor control at the behavioural level. However, surprisingly little is known regarding the neural mechanisms which underpin these effects, beyond a reliance on the dopaminergic system. In recent work, we developed a task that enabled the dissociation of the selection and execution components of an upper limb reaching movement. Our results demonstrated that both selection and execution are concommitently enhanced by immediate reward availability. Here, we investigate what the neural underpinnings of each component may be. To this end, we aimed to alter the cortical excitability of the ventromedial prefrontal cortex and supplementary motor area using continuous theta-burst transcranial magnetic stimulation (cTBS) in a within-participant design (N = 23). Both cortical areas are involved in determining an individual's sensitivity to reward and physical effort, and we hypothesised that a change in excitability would result in the reward-driven effects on action selection and execution to be altered, respectively. To increase statistical power, participants were pre-selected based on their sensitivity to reward in the reaching task. While reward did lead to enhanced performance during the cTBS sessions and a control sham session, cTBS was ineffective in altering these effects. These results may provide evidence that other areas, such as the primary motor cortex or the premotor area, may drive the reward-based enhancements of motor performance.

What nurses and midwives want: Findings from the national survey on workplace climate and well-being.

AIM: A discussion of the findings from a nationwide study of workplace and well-being issues of Australian nurses and midwives. BACKGROUND: Current discourse only provides a fragmented understanding of a multifaceted nature of working conditions and well-being, necessitating a more holistic investigation to identify critical workplace issues within these professions. DESIGN: Discussion paper. DATA SOURCES: A national survey conducted in July 2016 involving Australian Nursing and Midwifery Federation members. The literature supporting this paper focuses on the nursing and midwifery workforce and studies on attraction and retention issues. IMPLICATIONS FOR NURSING AND MIDWIFERY: Workplace policies and practices in place in health care organizations that are within the control of management are key factors in the negative issues associated with the profession from the survey. Proactive and targeted interventions particularly aimed at salient issues of work intensification, declining engagement, and effective voice mechanisms are needed to address these crucial issues if the attrition of individuals from nursing and midwifery occupations is going to be ameliorated. CONCLUSION: To alleviate workforce issues pushing nurses and midwives to the tipping point of exiting the professions, health care organizations need to take a proactive stance in addressing issues under the control of management.

Purkinje Cell Activity in the Medial and Lateral Cerebellum During Suppression of Voluntary Eye Movements in Rhesus Macaques.

Volitional suppression of responses to distracting external stimuli enables us to achieve our goals. This volitional inhibition of a specific behavior is supposed to be mainly mediated by the cerebral cortex. However, recent evidence supports the involvement of the cerebellum in this process. It is currently not known whether different parts of the cerebellar cortex play differential or synergistic roles in the planning and execution of this behavior. Here, we measured Purkinje cell (PC) responses in the medial and lateral cerebellum in two rhesus macaques during pro- and anti-saccade tasks. During an antisaccade trial, non-human primates (NHPs) were instructed to make a saccadic eye movement away from a target, rather than toward it, as in prosaccade trials. Our data show that the cerebellum plays an important role not only during the execution of the saccades but also during the volitional inhibition of eye movements toward the target. Simple spike (SS) modulation during the instruction and execution periods of pro- and anti-saccades was prominent in PCs of both the medial and lateral cerebellum. However, only the SS activity in the lateral cerebellar cortex contained information about stimulus identity and showed a strong reciprocal interaction with complex spikes (CSs). Moreover, the SS activity of different PC groups modulated bidirectionally in both of regions, but the PCs that showed facilitating and suppressive activity were predominantly associated with instruction and execution, respectively. These findings show that different cerebellar regions and PC groups contribute to goal-directed behavior and volitional inhibition, but with different propensities, highlighting the rich repertoire of the cerebellar control in executive functions.

Effect of Memantine on Prolonging Safe Driving in Early AD: a Pilot Study.

BACKGROUND: To determine the feasibility of conducting an RCT on the potential effectiveness of memantine hydrochloride in prolonging safe driving in mild AD. METHODS: A placebo-controlled, double blind randomized trial was conducted. Forty-three individuals ≥60 with mild AD met screening criteria and were randomized. Driving ability was measured by a standardized on-road driving test. Outcomes were driving capacity at 6 and 12 months and completion of the 12-month intervention. RESULTS: Of 43 participants randomized, 59% of the memantine group and 52% of the placebo group completed the on-road test at 12 months (p = .66). All 13 memantine group participants maintained their driving status at 12 months, whereas only 8 of the 11 placebo group participants did (p = .040, OR = 4.45). CONCLUSIONS: Results provide the framework for designing a rigorous multisite clinical trial of memantine effect on maintaining driving capacity in mild AD.

Single-pulse stimulation of cerebellar nuclei stops epileptic thalamic activity.

BACKGROUND: Epileptic (absence) seizures in the cerebral cortex can be stopped by pharmacological and optogenetic stimulation of the cerebellar nuclei (CN) neurons that innervate the thalamus. However, it is unclear how such stimulation can modify underlying thalamo-cortical oscillations. HYPOTHESIS: Here we tested whether rhythmic synchronized thalamo-cortical activity during absence seizures can be desynchronized by single-pulse optogenetic stimulation of CN neurons to stop seizure activity. METHODS: We performed simultaneous thalamic single-cell and electrocorticographical recordings in awake tottering mice, a genetic model of absence epilepsy, to investigate the rhythmicity and synchronicity. Furthermore, we tested interictally the impact of single-pulse optogenetic CN stimulation on thalamic and cortical recordings. RESULTS: We show that thalamic firing is highly rhythmic and synchronized with cortical spike-and-wave discharges during absence seizures and that this phase-locked activity can be desynchronized upon single-pulse optogenetic stimulation of CN neurons. Notably, this stimulation of CN neurons was more effective in stopping seizures than direct, focal stimulation of groups of afferents innervating the thalamus. During interictal periods, CN stimulation evoked reliable but heterogeneous responses in thalamic cells in that they could show an increase or decrease in firing rate at various latencies, bi-phasic responses with an initial excitatory and subsequent inhibitory response, or no response at all. CONCLUSION: Our data indicate that stimulation of CN neurons and their fibers in thalamus evokes differential effects in its downstream pathways and desynchronizes phase-locked thalamic neuronal firing during seizures, revealing a neurobiological mechanism that may explain how cerebellar stimulation can stop seizures.

A Neuroanatomically Grounded Optimal Control Model of the Compensatory Eye Movement System in Mice.

We present a working model of the compensatory eye movement system in mice. We challenge the model with a data set of eye movements in mice (n =34) recorded in 4 different sinusoidal stimulus conditions with 36 different combinations of frequency (0.1-3.2 Hz) and amplitude (0.5-8°) in each condition. The conditions included vestibular stimulation in the dark (vestibular-ocular reflex, VOR), optokinetic stimulation (optokinetic reflex, OKR), and two combined visual/vestibular conditions (the visual-vestibular ocular reflex, vVOR, and visual suppression of the VOR, sVOR). The model successfully reproduced the eye movements in all conditions, except for minor failures to predict phase when gain was very low. Most importantly, it could explain the interaction of VOR and OKR when the two reflexes are activated simultaneously during vVOR stimulation. In addition to our own data, we also reproduced the behavior of the compensatory eye movement system found in the existing literature. These include its response to sum-of-sines stimuli, its response after lesions of the nucleus prepositus hypoglossi or the flocculus, characteristics of VOR adaptation, and characteristics of drift in the dark. Our model is based on ideas of state prediction and forward modeling that have been widely used in the study of motor control. However, it represents one of the first quantitative efforts to simulate the full range of behaviors of a specific system. The model has two separate processing loops, one for vestibular stimulation and one for visual stimulation. Importantly, state prediction in the visual processing loop depends on a forward model of residual retinal slip after vestibular processing. In addition, we hypothesize that adaptation in the system is primarily adaptation of this model. In other words, VOR adaptation happens primarily in the OKR loop.

The relationship between reinforcement and explicit control during visuomotor adaptation.

The motor system's ability to adapt to environmental changes is essential for maintaining accurate movements. Such adaptation recruits several distinct systems: cerebellar sensory-prediction error learning, success-based reinforcement, and explicit control. Although much work has focused on the relationship between cerebellar learning and explicit control, there is little research regarding how reinforcement and explicit control interact. To address this, participants first learnt a 20° visuomotor displacement. After reaching asymptotic performance, binary, hit-or-miss feedback (BF) was introduced either with or without visual feedback, the latter promoting reinforcement. Subsequently, retention was assessed using no-feedback trials, with half of the participants in each group being instructed to stop aiming off target. Although BF led to an increase in retention of the visuomotor displacement, instructing participants to stop re-aiming nullified this effect, suggesting explicit control is critical to BF-based reinforcement. In a second experiment, we prevented the expression or development of explicit control during BF performance, by either constraining participants to a short preparation time (expression) or by introducing the displacement gradually (development). Both manipulations strongly impaired BF performance, suggesting reinforcement requires both recruitment and expression of an explicit component. These results emphasise the pivotal role explicit control plays in reinforcement-based motor learning.

Superposition Violations in the Compensatory Eye Movement System.

PURPOSE: Compensatory eye movements (CEM) maintain a stable image on the retina by minimizing retinal slip. The optokinetic reflex (OKR) and vestibulo-ocular reflex (VOR) compensate for low and high velocity stimuli, respectively. The OKR system is known to be highly nonlinear. The VOR is generally modeled as a linear system and assumed to satisfy the superposition and homogeneity principles. To probe CEM violation of the superposition principle, we recorded eye movement responses in C57BL/6 mice to sum of sine (SoS) stimulation, a combination of multiple nonharmonic inputs. METHODS: We tested the VOR, OKR, VVOR (visually enhanced VOR), and SVOR (suppressed VOR). We used stimuli containing 0.6 Hz, 0.8 Hz, 1.0 Hz, and 1.9 Hz. Power spectra of SoS stimuli did not yield distortion products. Gains and delays of SoS and single sine (SS) responses were compared to yield relative gains and delays. RESULTS: We find the superposition principle is violated primarily in the OKR, VOR, and SVOR conditions. In OKR, we observed relative gain suppression of the lower SoS stimulus frequency component irrespective of the absolute frequency. Conversely, SVOR and VOR results showed gain enhancement of the lower frequency component and overall decrease in lead. Visually enhanced VOR results showed trends for overall gain suppression and delay decrease. CONCLUSIONS: Compensatory eye movements arguably depend on predictive signals. These results may reflect better prediction for SS stimuli. Natural CEM system stimulation generally involves complex frequency spectra. Use of SoS stimuli is a step toward unravelling the signals that really drive CEM and the predictive algorithms they depend on.

Efficacy, safety, and tolerability of sertraline in patients with late-life depression and comorbid medical illness.

OBJECTIVES: To report on the efficacy, safety, and tolerability of sertraline in the treatment of elderly depres-sed patients with and without comorbid medical illness. SETTING: Multicenter. DESIGN: Randomized, double-blind, placebo-controlled study. PARTICIPANTS: A total of 752 patients aged 60 and older with diagnosis of major depressive disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis. MEASUREMENTS: Outcome measures included the 17-item Hamilton Depression Scale (HAMD); the Clinical Global Depression-Severity/Improvement (CGI-S/CGI-I); efficacy and safety/adverse event assessments; Quality of Life, Enjoyment, and Satisfaction Questionnaire; and the Medical Outcomes Study 36-Item Short-Form Health Status Survey. RESULTS: In the overall sample, sertraline was superior to placebo on all three primary outcome measures, HAMD, and overall clinical severity and change (CGI-S/CGI-I). Furthermore, therapeutic response to sertraline was comparable in those with or without medical comorbidity, and there were no treatment-by-comorbidity group interactions. Sertraline was also associated with a faster time to response than placebo in the comorbid group (P<.006). Sertraline-treated patients in the comorbid group had similar adverse events and discontinuations when compared to those in the noncomorbid group. CONCLUSION: Sertraline was efficacious in reducing depressive symptomatology, regardless of the presence of comorbid medical illness. Sertraline was safe and well tolerated by patients with or without medical illness.

Influence of sex and menopausal status on response, remission, and recurrence in patients with recurrent major depressive disorder treated with venlafaxine extended release or fluoxetine: analysis of data from the PREVENT study.

OBJECTIVE: To evaluate the effects of sex and menopausal status on acute-, continuation-, and maintenance-phase treatment outcomes in patients with recurrent major depressive disorder (MDD). METHOD: This was a secondary analysis of data from the Prevention of Recurrent Episodes of Depression With Venlafaxine for Two Years (PREVENT) trial, a multiphase, multicenter, double-blind study in which adult outpatients with recurrent MDD (by DSM-IV criteria) were randomly assigned to 10 weeks of acute-phase venlafaxine extended release (ER) (75-300 mg/d) or fluoxetine (20-60 mg/d). Patients achieving response or remission had 6 months of continuation-phase treatment. Responding or remitting patients in the venlafaxine ER group were randomly assigned to venlafaxine ER or placebo for 2 consecutive 12-month maintenance phases; fluoxetine-treated patients continued receiving fluoxetine. The outcome measures for this analysis were acute- and continuation-phase response and remission rates (as measured by the 17-item Hamilton Depression Rating Scale) and time to depression recurrence in the maintenance phases according to sex and menopausal status at baseline. RESULTS: The intent-to-treat population comprised 781 patients in the venlafaxine ER group (65% women) and 266 patients in the fluoxetine group (61% women); 64% of all women were premenopausal, and 25% were postmenopausal (5% perimenopausal; not analyzed). At acute-phase end, remission rates in the venlafaxine ER vs fluoxetine groups were 44% vs 47% in men, 51% vs 52% in women, 50% vs 52% in premenopausal women, and 52% vs 55% in postmenopausal women. At continuation-phase end, remission rates in the venlafaxine ER vs fluoxetine groups were 71% vs 74% in men, 72% vs 67% in women, 72% vs 69% in premenopausal women and 71% vs 63% in postmenopausal women. Response rates were consistent with these findings. Based on a Cox proportional hazards model, sex was not a significant predictor of recurrence during the first or second maintenance phase (hazard ratio [HR] = 1.233; P = .3712 and HR = 1.103; P = .8075, respectively), and neither was menopausal status at acute-phase baseline (HR = 0.941; P = .8234 and HR = 0.531; P = .2065, respectively). CONCLUSIONS: In this study of patients with recurrent MDD, treatment outcomes with venlafaxine ER and fluoxetine did not differ on the basis of sex or menopausal status. Our confidence in these findings is limited by the lack of a placebo arm during the acute and continuation phases and by the small sample sizes for subgroup analyses in the maintenance phases. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00046020.