A spinal cord neuroprosthesis for locomotor deficits due to Parkinson's disease.

People with late-stage Parkinson's disease (PD) often suffer from debilitating locomotor deficits that are resistant to currently available therapies. To alleviate these deficits, we developed a neuroprosthesis operating in closed loop that targets the dorsal root entry zones innervating lumbosacral segments to reproduce the natural spatiotemporal activation of the lumbosacral spinal cord during walking. We first developed this neuroprosthesis in a non-human primate model that replicates locomotor deficits due to PD. This neuroprosthesis not only alleviated locomotor deficits but also restored skilled walking in this model. We then implanted the neuroprosthesis in a 62-year-old male with a 30-year history of PD who presented with severe gait impairments and frequent falls that were medically refractory to currently available therapies. We found that the neuroprosthesis interacted synergistically with deep brain stimulation of the subthalamic nucleus and dopaminergic replacement therapies to alleviate asymmetry and promote longer steps, improve balance and reduce freezing of gait. This neuroprosthesis opens new perspectives to reduce the severity of locomotor deficits in people with PD.

Electrical spinal cord stimulation must preserve proprioception to enable locomotion in humans with spinal cord injury.

Epidural electrical stimulation (EES) of the spinal cord restores locomotion in animal models of spinal cord injury but is less effective in humans. Here we hypothesized that this interspecies discrepancy is due to interference between EES and proprioceptive information in humans. Computational simulations and preclinical and clinical experiments reveal that EES blocks a significant amount of proprioceptive input in humans, but not in rats. This transient deafferentation prevents modulation of reciprocal inhibitory networks involved in locomotion and reduces or abolishes the conscious perception of leg position. Consequently, continuous EES can only facilitate locomotion within a narrow range of stimulation parameters and is unable to provide meaningful locomotor improvements in humans without rehabilitation. Simulations showed that burst stimulation and spatiotemporal stimulation profiles mitigate the cancellation of proprioceptive information, enabling robust control over motor neuron activity. This demonstrates the importance of stimulation protocols that preserve proprioceptive information to facilitate walking with EES.

Targeted neurotechnology restores walking in humans with spinal cord injury.

Spinal cord injury leads to severe locomotor deficits or even complete leg paralysis. Here we introduce targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation. Using an implanted pulse generator with real-time triggering capabilities, we delivered trains of spatially selective stimulation to the lumbosacral spinal cord with timing that coincided with the intended movement. Within one week, this spatiotemporal stimulation had re-established adaptive control of paralysed muscles during overground walking. Locomotor performance improved during rehabilitation. After a few months, participants regained voluntary control over previously paralysed muscles without stimulation and could walk or cycle in ecological settings during spatiotemporal stimulation. These results establish a technological framework for improving neurological recovery and supporting the activities of daily living after spinal cord injury.

Neural and muscular factors both contribute to plantar-flexor muscle weakness in older fallers.

Plantar-flexor muscles are key muscles in the control of postural sway. Older fallers present lower maximal plantar-flexor performance than older non-fallers; however, the mechanisms underlying this motor impairment remain to be elucidated. This study aimed to determine whether muscular and neural factors are both involved in the lower maximal plantar-flexor performance of older fallers. The maximal voluntary contraction (MVC) torque, resting twitch torque, voluntary activation level (VAL), and electromyographic (EMG) activities for the soleus, gastrocnemius medialis, gastrocnemius lateralis and tibialis anterior during plantar-flexor MVCs were recorded in 23 older non-fallers (age: 83.3 ±â€¯3.9 years) and 25 older fallers (age: 84.0 ±â€¯4.1 years). The maximal plantar-flexor Hoffmann reflex normalized to the maximal motor potential (Hmax/Mmax) was measured to assess the efficacy of spinal transmission from the Ia-afferent fibers to the α-motoneurons. Older fallers presented lower plantar-flexor MVC torque, resting twitch torque, VAL and EMG activity (P < 0.05). No significant differences between older fallers and non-fallers were found for the Hmax/Mmax ratio and dorsi-flexor coactivation. The current findings showed for the first time that both neural and muscular factors associated with the plantar-flexors contributed to the specific alteration of maximal motor performance in older fallers. The lack of a difference in the Hmax/Mmax ratio indicated that the efficacy of spinal transmission from the Ia-afferent fibers to the α-motoneurons was not involved in the lower voluntary muscle activation of older fallers. This suggests that supraspinal centers are likely to be involved in the lower voluntary muscle activation observed in older fallers.

A multidirectional gravity-assist algorithm that enhances locomotor control in patients with stroke or spinal cord injury.

Gait recovery after neurological disorders requires remastering the interplay between body mechanics and gravitational forces. Despite the importance of gravity-dependent gait interactions and active participation for promoting this learning, these essential components of gait rehabilitation have received comparatively little attention. To address these issues, we developed an adaptive algorithm that personalizes multidirectional forces applied to the trunk based on patient-specific motor deficits. Implementation of this algorithm in a robotic interface reestablished gait dynamics during highly participative locomotion within a large and safe environment. This multidirectional gravity-assist enabled natural walking in nonambulatory individuals with spinal cord injury or stroke and enhanced skilled locomotor control in the less-impaired subjects. A 1-hour training session with multidirectional gravity-assist improved locomotor performance tested without robotic assistance immediately after training, whereas walking the same distance on a treadmill did not ameliorate gait. These results highlight the importance of precise trunk support to deliver gait rehabilitation protocols and establish a practical framework to apply these concepts in clinical routine.

A brain-spine interface alleviating gait deficits after spinal cord injury in primates.

Spinal cord injury disrupts the communication between the brain and the spinal circuits that orchestrate movement. To bypass the lesion, brain-computer interfaces have directly linked cortical activity to electrical stimulation of muscles, and have thus restored grasping abilities after hand paralysis. Theoretically, this strategy could also restore control over leg muscle activity for walking. However, replicating the complex sequence of individual muscle activation patterns underlying natural and adaptive locomotor movements poses formidable conceptual and technological challenges. Recently, it was shown in rats that epidural electrical stimulation of the lumbar spinal cord can reproduce the natural activation of synergistic muscle groups producing locomotion. Here we interface leg motor cortex activity with epidural electrical stimulation protocols to establish a brain-spine interface that alleviated gait deficits after a spinal cord injury in non-human primates. Rhesus monkeys (Macaca mulatta) were implanted with an intracortical microelectrode array in the leg area of the motor cortex and with a spinal cord stimulation system composed of a spatially selective epidural implant and a pulse generator with real-time triggering capabilities. We designed and implemented wireless control systems that linked online neural decoding of extension and flexion motor states with stimulation protocols promoting these movements. These systems allowed the monkeys to behave freely without any restrictions or constraining tethered electronics. After validation of the brain-spine interface in intact (uninjured) monkeys, we performed a unilateral corticospinal tract lesion at the thoracic level. As early as six days post-injury and without prior training of the monkeys, the brain-spine interface restored weight-bearing locomotion of the paralysed leg on a treadmill and overground. The implantable components integrated in the brain-spine interface have all been approved for investigational applications in similar human research, suggesting a practical translational pathway for proof-of-concept studies in people with spinal cord injury.

A decision model to predict the risk of the first fall onset.

BACKGROUND: Miscellaneous features from various domains are accepted to be associated with the risk of falling in the elderly. However, only few studies have focused on establishing clinical tools to predict the risk of the first fall onset. A model that would objectively and easily evaluate the risk of a first fall occurrence in the coming year still needs to be built. OBJECTIVES: We developed a model based on machine learning, which might help the medical staff predict the risk of the first fall onset in a one-year time window. PARTICIPANTS/MEASUREMENTS: Overall, 426 older adults who had never fallen were assessed on 73 variables, comprising medical, social and physical outcomes, at t0. Each fall was recorded at a prospective 1-year follow-up. A decision tree was built on a randomly selected training subset of the cohort (80% of the full-set) and validated on an independent test set. RESULTS: 82 participants experienced a first fall during the follow-up. The machine learning process independently extracted 13 powerful parameters and built a model showing 89% of accuracy for the overall classification with 83%-82% of true positive fallers and 96%-61% of true negative non-fallers (training set vs. independent test set). CONCLUSION: This study provides a pilot tool that could easily help the gerontologists refine the evaluation of the risk of the first fall onset and prioritize the effective prevention strategies. The study also offers a transparent framework for future, related investigation that would validate the clinical relevance of the established model by independently testing its accuracy on larger cohort.

Neuromuscular electrical stimulation leads to physiological gains enhancing postural balance in the pre-frail elderly.

Physiological aging leads to a progressive weakening of muscles and tendons, thereby disturbing the ability to control postural balance and consequently increasing exposure to the risks of falls. Here, we introduce a simple and easy-to-use neuromuscular electrical stimulation (NMES) training paradigm designed to alleviate the postural control deficit in the elderly, the first hallmarks of which present as functional impairment. Nine pre-frail older women living in a long-term care facility performed 4 weeks of NMES training on their plantarflexor muscles, and seven nontrained, non-frail older women living at home participated in this study as controls. Participants were asked to perform maximal voluntary contractions (MVC) during isometric plantarflexion in a lying position. Musculo-tendinous (MT) stiffness was assessed before and after the NMES training by measuring the displacement of the MT junction and related tendon force during MVC. In a standing position, the limit of stability (LoS) performance was determined through the maximal forward displacement of the center of foot pressure, and related postural sway parameters were computed around the LoS time gap, a high force requiring task. The NMES training induced an increase in MVC, MT stiffness, and LoS. It significantly changed the dynamics of postural balance as a function of the tendon property changes. The study outcomes, together with a multivariate analysis of investigated variables, highlighted the benefits of NMES as a potential tool in combating neuromuscular weakening in the elderly. The presented training-based strategy is valuable in alleviating some of the adverse functional consequences of aging by directly acting on intrinsic biomechanical and muscular properties whose improvements are immediately transferable into a functional context.

Neuroprosthetic technologies to augment the impact of neurorehabilitation after spinal cord injury.

Spinal cord injury leads to a range of disabilities, including limitations in locomotor activity, that seriously diminish the patients' autonomy and quality of life. Electrochemical neuromodulation therapies, robot-assisted rehabilitation and willpower-based training paradigms restored supraspinal control of locomotion in rodent models of severe spinal cord injury. This treatment promoted extensive and ubiquitous remodeling of spared circuits and residual neural pathways. In four chronic paraplegic individuals, electrical neuromodulation of the spinal cord resulted in the immediate recovery of voluntary leg movements, suggesting that the therapeutic concepts developed in rodent models may also apply to humans. Here, we briefly review previous work, summarize current developments, and highlight impediments to translate these interventions into medical practice to improve functional recovery of spinal-cord-injured individuals.

Effects of total sleep deprivation on the perception of action capabilities.

Changes in a subject's state have been shown to modulate the perceptual update of his or her action capabilities. In parallel, sleep deprivation impairs in cognitive functions. It involves common neural structures that support the perception of successfully achieving a motor task. Thus, the study investigated the effect of 24 h of sleep deprivation on the perception of action capabilities. Twenty-four healthy participants were randomly separated into two groups (control group vs. 24 h sleep deprivation group). Participants in the control group slept at home according to their habitual sleep-wake schedule. The 24-h sleep deprivation group stayed awake in the laboratory. Participants estimated the limit of their maximal height of stepping-over a bar before and after the sleep intervention. These estimations were compared to each participant's actual maximal stepping-over height. Physical performance (measured by maximal voluntary quadriceps contraction and repetitive vertical jumping tests) and perceptual inhibition tests (measured by choice reaction time tasks) were also performed for three sessions at three time points t 0, t +12h, and t +24h with t 0 = 8:00 a.m. for all participants. Participants in the 24-h sleep deprivation group showed impairments in perceived over-stepping performance and impaired cognitive functioning (higher reaction time), while no changes were observed in actual performance in the over-stepping, voluntary quadriceps contraction, or jumping tasks. The cognitive processing of inputs that specify the estimated consequences of motor action is discussed as the main explanation for the inability to successfully update the perception of action capabilities after sleep deprivation.

Postural sway, falls, and cognitive status: a cross-sectional study among older adults.

BACKGROUND: Cognitive impairment-related changes in postural sway increase fall risk among older adults. Better understanding this association could be helpful for fall prevention. OBJECTIVE: To examine the center-of-pressure (COP) velocity association with cognitive status and history of falls, in cognitively healthy individuals (CHI), patients with mild cognitive impairment (MCI), and with mild-to-moderate Alzheimer's disease (MMAD). METHODS: Six hundred and eleven older community-dwellers (77.2 ± 7.9 years; 51.8% men) were separated into CHI, MCI, and MMAD participants. By computing the average absolute maximal velocity (AAMV), the bounding limits of COP velocity dynamics were determined while participants were asked to maintain quiet stance on a force platform with eyes open or with eyes closed. Age, gender, history of falls, body mass index, medications, handgrip strength, Timed Up & Go score were used as covariates. RESULTS: The multivariate ANCOVA, with AAMV in eyes open and eyes closed conditions as dependent variables, showed that the highest AAMVs that bound the COP velocity dynamics of postural sway were associated with cognitive impairment (p = 0.048) (i.e., lowest limits in CHI and MCI as compared with MMAD) and falls (p = 0.033) (i.e., highest limits in fallers). CONCLUSIONS: These findings identified the bounding limits of COP velocity as a hallmark feature of cognitive impairment-related changes in postural sway, in particular for MMAD. This point is of special interest for clinical balance assessment and fall prevention in MMAD patients in order to plan long-term targeted fall-prevention programs.

Gait disturbances as specific predictive markers of the first fall onset in elderly people: a two-year prospective observational study.

Falls are common in the elderly, and potentially result in injury and disability. Thus, preventing falls as soon as possible in older adults is a public health priority, yet there is no specific marker that is predictive of the first fall onset. We hypothesized that gait features should be the most relevant variables for predicting the first fall. Clinical baseline characteristics (e.g., gender, cognitive function) were assessed in 259 home-dwelling people aged 66 to 75 that had never fallen. Likewise, global kinetic behavior of gait was recorded from 22 variables in 1036 walking tests with an accelerometric gait analysis system. Afterward, monthly telephone monitoring reported the date of the first fall over 24 months. A principal components analysis was used to assess the relationship between gait variables and fall status in four groups: non-fallers, fallers from 0 to 6 months, fallers from 6 to 12 months and fallers from 12 to 24 months. The association of significant principal components (PC) with an increased risk of first fall was then evaluated using the area under the Receiver Operator Characteristic Curve (ROC). No effect of clinical confounding variables was shown as a function of groups. An eigenvalue decomposition of the correlation matrix identified a large statistical PC1 (termed "Global kinetics of gait pattern"), which accounted for 36.7% of total variance. Principal component loadings also revealed a PC2 (12.6% of total variance), related to the "Global gait regularity." Subsequent ANOVAs showed that only PC1 discriminated the fall status during the first 6 months, while PC2 discriminated the first fall onset between 6 and 12 months. After one year, any PC was associated with falls. These results were bolstered by the ROC analyses, showing good predictive models of the first fall during the first six months or from 6 to 12 months. Overall, these findings suggest that the performance of a standardized walking test at least once a year is essential for fall prevention.

Postural control and cognitive decline in older adults: position versus velocity implicit motor strategy.

The present study explored the impact of cognitive decline on postural control strategies in older adults with and without cognitive decline from mild cognitive impairment (MCI) to mild-to-moderate Alzheimer disease (MMAD). We hypothesized that the cognitive decline affected the postural control leading to higher bounding limits of COP velocity dynamics. Based on a cross-sectional design, 175 non-faller older adults were recruited in Angers University Hospital, France, including 50 cognitively healthy individuals [CHI] (mean age 76.42 ± 4.84 years; 30% women), 64 age- and body mass index-matched participants with MCI (mean age 77.51 ± 6.32 years; 39% women), and 61 age- and body mass index-matched participants with MMAD (mean age 78.44 ± 3.97 years; 62% women). For all data collection of postural sway, the participants were asked to maintain quiet stance on force platform. The postural test consisted of two trials of quiet stance, with eyes open and with eyes closed. The COP parameters were mean and standard deviation (SD) of position, velocity and average absolute maximal velocity (AAMV) in antero-posterior and medio-lateral directions. Overall, the analysis concerning all COP parameters revealed a significant main effect of cognitive status on velocity-based variables, with post hoc comparisons evidencing that SD velocity and AAMV increased with cognitive impairment. The current findings suggest an active control (or corrective process) of COP velocity dynamics for CHI, whereas MCI and MMAD are affected by COP movements.

Origins of balance disorders during a daily living movement in obese: can biomechanical factors explain everything?

Obese people suffer from postural deficits and are more subject to falls than their lean counterpart. To improve prevention and post-fall rehabilitation programs, it seems important to better understand the posturo-kinetic disorders in daily life situations by determining the contribution of some key factors, mainly morphological characteristics and physical activity level, in the apparition of these disorders. Twelve severe android obese and eight healthy non obese adults performed a reaching task mobilizing the whole body. To further determine the origin of the postural and motor behavior differences, non obese individuals also performed an experimental session with additional constraints which simulated some of the obese morphological characteristics. Impact of the sedentary lifestyle was also studied by dissociation of the obese in two subgroups: physically « active ¼ and physically « inactive ¼. Movement kinetics and kinematics were characterized with an optoelectronic system synchronized to a force platform. The mechanical equilibrium pattern was evaluated through the displacements of the Centre of Mass (CoM) and the centre of foot pressure within the Base of Support (BoS). Results showed that obesity decreased movement speed (≈-23%, p<0.01), strongly increased CoM displacement (≈+30%, p<0.05) and induced an important spatio-temporal desynchronization (≈+40%, p<0.05) of the focal and postural components of the movement during the transition between the descending and ascending movements. The role of some morphological characteristics and of physical activity on obese patients' postural control disorder is discussed and set back in the more general context of overall factors contributing to postural deficits with obesity.

Obesity impact on the attentional cost for controlling posture.

BACKGROUND: This study investigated the effects of obesity on attentional resources allocated to postural control in seating and unipedal standing. METHODS: Ten non obese adults (BMI = 22.4±1.3, age = 42.4±15.1) and 10 obese adult patients (BMI = 35.2±2.8, age = 46.2±19.6) maintained postural stability on a force platform in two postural tasks (seated and unipedal). The two postural tasks were performed (1) alone and (2) in a dual-task paradigm in combination with an auditory reaction time task (RT). Performing the RT task together with the postural one was supposed to require some attentional resources that allowed estimating the attentional cost of postural control. 4 trials were performed in each condition for a total of 16 trials. FINDINGS: (1) Whereas seated non obese and obese patients exhibited similar centre of foot pressure oscillations (CoP), in the unipedal stance only obese patients strongly increased their CoP sway in comparison to controls. (2) Whatever the postural task, the additional RT task did not affect postural stability. (3) Seated, RT did not differ between the two groups. (4) RT strongly increased between the two postural conditions in the obese patients only, suggesting that body schema and the use of internal models was altered with obesity. INTERPRETATION: Obese patients needed more attentional resources to control postural stability during unipedal stance than non obese participants. This was not the case in a more simple posture such as seating. To reduce the risk of fall as indicated by the critical values of CoP displacement, obese patients must dedicate a strong large part of their attentional resources to postural control, to the detriment of non-postural events. Obese patients were not able to easily perform multitasking as healthy adults do, reflecting weakened psycho-motor abilities.