Periodic Reporting for period 3 - FeelAgain (Restoring natural feelings from missing or damaged peripheral nervous system by model-driven neuroprosthesis)
Berichtszeitraum: 2021-04-01 bis 2022-09-30
Leg amputees wear commercial prosthetic devices that do not give proper sensory information back to the brain, about the interaction of the device with the ground or its movement. Diabetic patients with peripheral neuropathy suffer the altered information arriving from the periphery to the brain. Amputees, relying on a very limited and uncomfortable haptic information from the stump-socket interaction, face grave impairments: risk of falls, decreased mobility, perception of the prosthesis as an extraneous body (low embodiment) and increased cognitive burden during walking with consequent psychological distress and device abandonments. Diabetic patients suffer neuropathic pain, poor balance and mobility.
Although considerable efforts have focused on developing and controlling sophisticated lower limb prostheses (LLP), few trials have been conducted to restore sensory feedback. After an amputation, the neural pathways between the remaining periphery and the brain are still functional. Peripheral nerve electrical stimulation (PNES) of the sensory fibers proximal to hand amputation can reactivate sensations from the missing extremity in the brain. In case of success, this project would make a huge impact on a scientific and socio-economical aspect. On the basic science side, I will for the fist time, explore if physiologically plausible recruitment of an appropriate portion of proximal residual nerve, through optimized implanted neural interfaces, is amenable to recreate the missing or partial sensation from foot.
We create and validate a computational model of sensory lower limb nerve, comprising receptors and electrical stimulation effects, usable in wide context of neuro-computational science. In the wider scientific context, this project proposes a conceptual and technological framework for model-guided design and use of neuroproshetic devices, together with tailored measurements definition of long-term clinical benefits, which will be commonly used for future devices development. On the socio-economical level, we aim to provide a therapy against neuropathic pain, which today is not available. It would enable the full work reintegration of diabetic and amputee patients for whom working is impossible because of the impairment produced by pain, together with cost savings for a society by elimination of present (inefficient) drug-based treatments. By preventing occurrence of ulcers and consequent tragic events as amputations will be diminished, with obvious societal benefit. Enhancement of the embodiment and confidence in the prosthesis would counteract the phenomenon of abandonment and trigger a revolution in the prosthetics. All these aspects will allow the creation of a new neuromodulation market, which on the one side will guaran- tee new job positions, and on the other side will create a background in Europe for competing with the USA domination in the field. In an historical moment in which neuromodulation technologies are becoming clinical reality (e.g. vagal or cochlear stimulation), the development of a conceptual framework to assist the design of smart technologies become of paramount importance
For the first time, an implant of intrafascicular electrodes into the residual sciatic nerve of diabetics and amputees will be performed. It will last more than a month (chronic) and will allow, by means of an innovative surgery procedure to maximize the efficiency of stimulation (by increasing the number of active sites placed within the fascicles). During clinical trial a carefully designed experiments will enable the measurement of embodiment, pain sup- pression, fall avoidance and walking ability. This metrics will be used to evaluate the impact of the introduction of developed neuroprosthetic intervention and its comparison with others.
This strategy can be summarized in the following 5 objectives:
1. Design and implementation of a computational model of EPNS effects on afferent nervous system
2. Exploitation of the model for the design of the optimal geometry of neural interfaces and stimulation strategies (encoding algorithms)
3. Development of a sensing prosthesis.
4. Development of assessment-interventional tools (AIT) to boost and measure the: neuropathic pain diminishment, the level of embodiment, fall avoidance and walking quality, ulcers prevention, integration of the sensory feedback in the spinal circuitry involved in movement control.
5. Proof-of-concept in a humans model with amputation and diabetic foot.
Although considerable efforts have focused on developing and controlling sophisticated lower limb prostheses (LLP), few trials have been conducted to restore sensory feedback. After an amputation, the neural pathways between the remaining periphery and the brain are still functional. Peripheral nerve electrical stimulation (PNES) of the sensory fibers proximal to hand amputation can reactivate sensations from the missing extremity in the brain. In case of success, this project would make a huge impact on a scientific and socio-economical aspect. On the basic science side, I will for the fist time, explore if physiologically plausible recruitment of an appropriate portion of proximal residual nerve, through optimized implanted neural interfaces, is amenable to recreate the missing or partial sensation from foot.
We create and validate a computational model of sensory lower limb nerve, comprising receptors and electrical stimulation effects, usable in wide context of neuro-computational science. In the wider scientific context, this project proposes a conceptual and technological framework for model-guided design and use of neuroproshetic devices, together with tailored measurements definition of long-term clinical benefits, which will be commonly used for future devices development. On the socio-economical level, we aim to provide a therapy against neuropathic pain, which today is not available. It would enable the full work reintegration of diabetic and amputee patients for whom working is impossible because of the impairment produced by pain, together with cost savings for a society by elimination of present (inefficient) drug-based treatments. By preventing occurrence of ulcers and consequent tragic events as amputations will be diminished, with obvious societal benefit. Enhancement of the embodiment and confidence in the prosthesis would counteract the phenomenon of abandonment and trigger a revolution in the prosthetics. All these aspects will allow the creation of a new neuromodulation market, which on the one side will guaran- tee new job positions, and on the other side will create a background in Europe for competing with the USA domination in the field. In an historical moment in which neuromodulation technologies are becoming clinical reality (e.g. vagal or cochlear stimulation), the development of a conceptual framework to assist the design of smart technologies become of paramount importance
For the first time, an implant of intrafascicular electrodes into the residual sciatic nerve of diabetics and amputees will be performed. It will last more than a month (chronic) and will allow, by means of an innovative surgery procedure to maximize the efficiency of stimulation (by increasing the number of active sites placed within the fascicles). During clinical trial a carefully designed experiments will enable the measurement of embodiment, pain sup- pression, fall avoidance and walking ability. This metrics will be used to evaluate the impact of the introduction of developed neuroprosthetic intervention and its comparison with others.
This strategy can be summarized in the following 5 objectives:
1. Design and implementation of a computational model of EPNS effects on afferent nervous system
2. Exploitation of the model for the design of the optimal geometry of neural interfaces and stimulation strategies (encoding algorithms)
3. Development of a sensing prosthesis.
4. Development of assessment-interventional tools (AIT) to boost and measure the: neuropathic pain diminishment, the level of embodiment, fall avoidance and walking quality, ulcers prevention, integration of the sensory feedback in the spinal circuitry involved in movement control.
5. Proof-of-concept in a humans model with amputation and diabetic foot.
We pioneered a human-machine system whereby prosthetic sensors readouts are translated into the language of the nervous system of three amputees, achieving significant health and functional benefits, as demonstrated during clinical validation. More in detail, we demonstrated that the natural sensory feedback can be restored in above-knee amputees and that it can be exploited by them to improve the use of the leg prosthesis during different ambulation tasks and to promote its integration in their body schema. We designed a neuroprosthetic framework to restore sensory feedback referred on the phantom lower limb of transfemoral amputees and triggered from the bionic leg by stimulating the residual tibial branch of the sciatic nerve through implanted neural interfaces (Petrini et al. STM, 2019).
The neuroprosthesis is constituted by a microprocessor-based lower limb prosthesis equipped with sensors under the foot sole and in the knee, a controlling microcomputer and a stimulating system. The sensors readouts are acquired and recorded by the wearable insole, transimteted to microcomputer, which transduces them in instructions for the neural stimulator. The signals from the insole and prosthetic knee sensors are translated in impulses of current, the language of the human nervous system, which are delivered to the residual peripheral nerve through electrodes, implanted transversally into the nerve itself. This is performed in the real-time (under 50milisec, therefore imperceivable for users). The policy of the biomimetic current injection in the nerve is designed with help of sophisticated computational models which emulate the neurophysiology of the peripheral nerve fibers transmission of the information. Then, nature does the rest: the signals from the residual nerves are conveyed to the brain of the person, which is able to perceive what happens at the prosthesis and to adjust the walking accordingly. The machine and the body are finally re-connected. Our results demonstrate that induced sensory feedback can be integrated at supraspinal levels to restore functional abilities of the missing leg.
Together with the functional outcomes, we assessed the cognitive (brain) integration of the device into the body schema of the subjects through measurements of prosthesis embodiment and cognitive effort while using the artificial leg. We also showed increased embodiment of the lower limb prosthesis, through phantom leg displacement perception and questionnaires, and ease of the cognitive effort during a dual-task paradigm (when patient walked and had to count specific auditory tones) through electroencephalographic (EEG) recordings.
Then, thanks to the full portability and real-time operation of our novel hardware and software system, amputees stepped out form the lab to the ecological environment. The feedback was exploited in active tasks, which proved that our approach promoted mobility over sand, diminished metabolic cost and therefore overall usability fo the device (Petrini et al., Nat Med 2019). Moreover, 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 when neural sensory feedback was provided. 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. These works pave 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.
The bionic leg integrated with the residual peripheral nervous system of amputees, namely computer-brain interface, enables the brain to accept it as the continuation of the natural leg, and this is essential for higher confidence of the users, and a future wide-spread of these technologies.
The neuroprosthesis is constituted by a microprocessor-based lower limb prosthesis equipped with sensors under the foot sole and in the knee, a controlling microcomputer and a stimulating system. The sensors readouts are acquired and recorded by the wearable insole, transimteted to microcomputer, which transduces them in instructions for the neural stimulator. The signals from the insole and prosthetic knee sensors are translated in impulses of current, the language of the human nervous system, which are delivered to the residual peripheral nerve through electrodes, implanted transversally into the nerve itself. This is performed in the real-time (under 50milisec, therefore imperceivable for users). The policy of the biomimetic current injection in the nerve is designed with help of sophisticated computational models which emulate the neurophysiology of the peripheral nerve fibers transmission of the information. Then, nature does the rest: the signals from the residual nerves are conveyed to the brain of the person, which is able to perceive what happens at the prosthesis and to adjust the walking accordingly. The machine and the body are finally re-connected. Our results demonstrate that induced sensory feedback can be integrated at supraspinal levels to restore functional abilities of the missing leg.
Together with the functional outcomes, we assessed the cognitive (brain) integration of the device into the body schema of the subjects through measurements of prosthesis embodiment and cognitive effort while using the artificial leg. We also showed increased embodiment of the lower limb prosthesis, through phantom leg displacement perception and questionnaires, and ease of the cognitive effort during a dual-task paradigm (when patient walked and had to count specific auditory tones) through electroencephalographic (EEG) recordings.
Then, thanks to the full portability and real-time operation of our novel hardware and software system, amputees stepped out form the lab to the ecological environment. The feedback was exploited in active tasks, which proved that our approach promoted mobility over sand, diminished metabolic cost and therefore overall usability fo the device (Petrini et al., Nat Med 2019). Moreover, 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 when neural sensory feedback was provided. 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. These works pave 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.
The bionic leg integrated with the residual peripheral nervous system of amputees, namely computer-brain interface, enables the brain to accept it as the continuation of the natural leg, and this is essential for higher confidence of the users, and a future wide-spread of these technologies.
To best of our knowledge we advanced different aspects of science and technology beyond the state of the art:
- Computational models of lower limb sensory nerves and mechano-nerve transduction are novel and valuable tool for neuroprosthetic design and also for the neuro-scientific purposes.
- We achieved the first up-to-date sensory neuroprosthesis for the highly disabled above-knee amputees
- We executed unique detailed battery of carefully designed assessments for the health and functionality of the neuroprosthesis, which could became the "golden standard" for similar technologies.
Until the end of the project we expect to generalise our finding for the clinically more relevant and also more complicated category of neuropathic patients.
- Computational models of lower limb sensory nerves and mechano-nerve transduction are novel and valuable tool for neuroprosthetic design and also for the neuro-scientific purposes.
- We achieved the first up-to-date sensory neuroprosthesis for the highly disabled above-knee amputees
- We executed unique detailed battery of carefully designed assessments for the health and functionality of the neuroprosthesis, which could became the "golden standard" for similar technologies.
Until the end of the project we expect to generalise our finding for the clinically more relevant and also more complicated category of neuropathic patients.