Conventional leg prostheses do not convey sensory information about motion or interaction with the ground to aboveknee amputees, thereby reducing confidence and walking speed in the users that is associated with high mental and physical fatigue 1-4 . The lack of physiological feedback from the remaining extremity to the brain also contributes to the generation of phantom limb pain from the missing leg 5,6 . To determine whether neural sensory feedback restoration addresses these issues, we conducted a study with two transfemoral amputees, implanted with four intraneural stimulation electrodes 7 in the remaining tibial nerve (ClinicalTrials. gov identifier NCT03350061). Participants were evaluated while using a neuroprosthetic device consisting of a prosthetic leg equipped with foot and knee sensors. These sensors drive neural stimulation, which elicits sensations of knee motion and the sole of the foot touching the ground. We found that walking speed and self-reported confidence increased while mental and physical fatigue decreased for both participants during neural sensory feedback compared to the no stimulation trials. Furthermore, participants exhibited reduced phantom limb pain with neural sensory feedback. The results from these proof-of-concept cases provide the rationale for larger population studies investigating the clinical utility of neuroprostheses that restore sensory feedback.Despite advances in the development of lower-limb prosthetics 8 , the potential benefits of restoring sensory feedback from such devices to transfemoral (above-knee) or transtibial (below-knee) amputees has not been investigated. Most surgery techniques 9 and noninvasive methods 10-12 to restore sensory feedback have been tested only in transtibial amputations, which produce a less disabling clinical condition than transfemoral amputation 1,3 . Direct neural stimulation through transversal intrafascicular multichannel electrodes (TIMEs) 7 has enabled upper-limb amputees to feel touch sensations from the missing hand and to exploit them for long-term prosthesis control 13,14 . Only F.M.P. designed the study, developed the software and the overall system integration, performed and supervised the experiments, analyzed the data and wrote and reviewed the paper. M.B. performed the surgeries, was responsible for all the clinical aspects of the study and reviewed the manuscript. G.V. developed the software and the overall system integration, performed the experiments, analyzed the data and reviewed the manuscript. V.I. and S. Mazic collected and analyzed the metabolic measurements. P.M. and B.M. collected and analyzed the EEG measurements. P.C. and T.S. developed the TIME electrodes and delivered technical assistance during the implantation and explanation procedures. F.B. and D.B. developed the software and the overall system integration and performed the experiments. N.K. analyzed the data. D.G. and D.A. designed the hardware and embedded software (real-time control) for STIMEP. K.L. and A.A. participated in the experimental design...

Objective: Hand amputation is a highly disabling event, which significantly affects quality of life. An effective hand replacement can be achieved if the user, in addition to motor functions, is provided with the sensations that are naturally perceived while grasping and moving. Intraneural peripheral electrodes have shown promising results toward the restoration of the sense of touch. However, the long-term usability and clinical relevance of intraneural sensory feedback have not yet been clearly demonstrated. Methods: To this aim, we performed a six months clinical study with three trans-radial amputees who received implants of transverse intrafascicular multichannel electrodes (TIMEs) in their median and ulnar nerves. After calibration, electrical stimulation was delivered through the TIMEs connected to artificial sensors in the digits of a prosthesis to generate sensory feedback, which was then used by the subjects while performing different grasping tasks. Results: All the subjects, notwithstanding their important clinical differences, reported stimulationinduced sensations from the phantom hand for the whole duration of the trial. They also successfully integrated the sensory feedback into their motor control strategies while performing experimental tests simulating tasks of real life (with and without the support of vision). Finally, they reported a decrement of their phantom limb pain and a general improvement in mood state. Interpretation: The promising results achieved with all subjects show the feasibility of the use of intraneural stimulation in clinical settings.

Lower limb amputation (LLA) destroys the sensory communication between the brain and the external world during standing and walking. Current prostheses do not restore sensory feedback to amputees, who, relying on very limited haptic information from the stump-socket interaction, are forced to deal with serious issues: the risk of falls, decreased mobility, prosthesis being perceived as an external object (low embodiment), and increased cognitive burden. Poor mobility is one of the causes of eventual device abandonment. Restoring sensory feedback from the missing leg of above-knee (transfemoral) amputees and integrating the sensory feedback into the sensorimotor loop would markedly improve the life of patients. In this study, we developed a leg neuroprosthesis, which provided real-time tactile and emulated proprioceptive feedback to three transfemoral amputees through nerve stimulation. The feedback was exploited in active tasks, which proved that our approach promoted improved mobility, fall prevention, and agility. We also showed increased embodiment of the lower limb prosthesis (LLP), through phantom leg displacement perception and questionnaires, and ease of the cognitive effort during a dual-task paradigm, through electroencephalographic recordings. Our results demonstrate that induced sensory feedback can be integrated at supraspinal levels to restore functional abilities of the missing leg. This work paves the way for further investigations about how the brain interprets different artificial feedback strategies and for the development of fully implantable sensory-enhanced leg neuroprostheses, which could drastically ameliorate life quality in people with disability.