Clinical neuroscience and neurotechnology: An amazing symbiosis.

In the last decades, clinical neuroscience found a novel ally in neurotechnologies, devices able to record and stimulate electrical activity in the nervous system. These technologies improved the ability to diagnose and treat neural disorders. Neurotechnologies are concurrently enabling a deeper understanding of healthy and pathological dynamics of the nervous system through stimulation and recordings during brain implants. On the other hand, clinical neurosciences are not only driving neuroengineering toward the most relevant clinical issues, but are also shaping the neurotechnologies thanks to clinical advancements. For instance, understanding the etiology of a disease informs the location of a therapeutic stimulation, but also the way stimulation patterns should be designed to be more effective/naturalistic. Here, we describe cases of fruitful integration such as Deep Brain Stimulation and cortical interfaces to highlight how this symbiosis between clinical neuroscience and neurotechnology is closer to a novel integrated framework than to a simple interdisciplinary interaction.

Preclinical upper limb neurorobotic platform to assess, rehabilitate, and develop therapies.

Numerous neurorehabilitative, neuroprosthetic, and repair interventions aim to address the consequences of upper limb impairments after neurological disorders. Although these therapies target widely different mechanisms, they share the common need for a preclinical platform that supports the development, assessment, and understanding of the therapy. Here, we introduce a neurorobotic platform for rats that meets these requirements. A four-degree-of-freedom end effector is interfaced with the rat's wrist, enabling unassisted to fully assisted execution of natural reaching and retrieval movements covering the entire body workspace. Multimodal recording capabilities permit precise quantification of upper limb movement recovery after spinal cord injury (SCI), which allowed us to uncover adaptations in corticospinal tract neuron dynamics underlying this recovery. Personalized movement assistance supported early neurorehabilitation that improved recovery after SCI. Last, the platform provided a well-controlled and practical environment to develop an implantable spinal cord neuroprosthesis that improved upper limb function after SCI.

Morphological Neural Computation Restores Discrimination of Naturalistic Textures in Trans-radial Amputees.

Humans rely on their sense of touch to interact with the environment. Thus, restoring lost tactile sensory capabilities in amputees would advance their quality of life. In particular, texture discrimination is an important component for the interaction with the environment, but its restoration in amputees has been so far limited to simplified gratings. Here we show that naturalistic textures can be discriminated by trans-radial amputees using intraneural peripheral stimulation and tactile sensors located close to the outer layer of the artificial skin. These sensors exploit the morphological neural computation (MNC) approach, i.e., the embodiment of neural computational functions into the physical structure of the device, encoding normal and shear stress to guarantee a faithful neural temporal representation of stimulus spatial structure. Two trans-radial amputees successfully discriminated naturalistic textures via the MNC-based tactile feedback. The results also allowed to shed light on the relevance of spike temporal encoding in the mechanisms used to discriminate naturalistic textures. Our findings pave the way to the development of more natural bionic limbs.

Decoding Neural Metabolic Markers From the Carotid Sinus Nerve in a Type 2 Diabetes Model.

Recent studies showed that the carotid sinus nerve (CSN) and the sympathetic nervous system (SNS) are overactivated in type 2 diabetes and that restoring the correct CSN neural activity can re-establish the proper metabolism. However, a robust characterization of the relationship between CSN and SNS neural activities and metabolism in type 2 diabetes is still missing. Here, we investigated the relationship between neural activity of CSN and SNS in control rats and in rats with diet-induced type 2 diabetes and the animal condition during metabolic challenges. We found that the diabetic condition can be discriminated on the basis of CSN and SNS neural activities due to a high-frequency shift in both spectra. This shift is suppressed in the SNS in case of CSN denervation, confirming the role of CSN in driving sympathetic overactivation in type 2 diabetes. Interestingly, the Inter-Burst-Intervals (IBIs) calculated from CSN bursts strongly correlate with perturbations in glycaemia levels. This finding, held for both control and diabetic rats, indicates the possibility of detecting metabolic information from neural recordings even in pathological conditions. Our results suggest that CSN activity could serve as a marker to monitor glycaemic alterations and, therefore, it could be used for closed-loop control of CSN neuromodulation. This paves the way to the development of novel and effective bioelectronic therapies for type 2 diabetes.

Detection of movement onset using EMG signals for upper-limb exoskeletons in reaching tasks.

BACKGROUND: To assist people with disabilities, exoskeletons must be provided with human-robot interfaces and smart algorithms capable to identify the user's movement intentions. Surface electromyographic (sEMG) signals could be suitable for this purpose, but their applicability in shared control schemes for real-time operation of assistive devices in daily-life activities is limited due to high inter-subject variability, which requires custom calibrations and training. Here, we developed a machine-learning-based algorithm for detecting the user's motion intention based on electromyographic signals, and discussed its applicability for controlling an upper-limb exoskeleton for people with severe arm disabilities. METHODS: Ten healthy participants, sitting in front of a screen while wearing the exoskeleton, were asked to perform several reaching movements toward three LEDs, presented in a random order. EMG signals from seven upper-limb muscles were recorded. Data were analyzed offline and used to develop an algorithm that identifies the onset of the movement across two different events: moving from a resting position toward the LED (Go-forward), and going back to resting position (Go-backward). A set of subject-independent time-domain EMG features was selected according to information theory and their probability distributions corresponding to rest and movement phases were modeled by means of a two-component Gaussian Mixture Model (GMM). The detection of movement onset by two types of detectors was tested: the first type based on features extracted from single muscles, whereas the second from multiple muscles. Their performances in terms of sensitivity, specificity and latency were assessed for the two events with a leave one-subject out test method. RESULTS: The onset of movement was detected with a maximum sensitivity of 89.3% for Go-forward and 60.9% for Go-backward events. Best performances in terms of specificity were 96.2 and 94.3% respectively. For both events the algorithm was able to detect the onset before the actual movement, while computational load was compatible with real-time applications. CONCLUSIONS: The detection performances and the low computational load make the proposed algorithm promising for the control of upper-limb exoskeletons in real-time applications. Fast initial calibration makes it also suitable for helping people with severe arm disabilities in performing assisted functional tasks.

Six-Month Assessment of a Hand Prosthesis with Intraneural Tactile Feedback.

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 6-month clinical study with 3 transradial 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 subjects, notwithstanding their important clinical differences, reported stimulation-induced 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. ANN NEUROL 2019;85:137-154.

Spatial and Functional Selectivity of Peripheral Nerve Signal Recording With the Transversal Intrafascicular Multichannel Electrode (TIME).

The selection of suitable peripheral nerve electrodes for biomedical applications implies a trade-off between invasiveness and selectivity. The optimal design should provide the highest selectivity for targeting a large number of nerve fascicles with the least invasiveness and potential damage to the nerve. The transverse intrafascicular multichannel electrode (TIME), transversally inserted in the peripheral nerve, has been shown to be useful for the selective activation of subsets of axons, both at inter- and intra-fascicular levels, in the small sciatic nerve of the rat. In this study we assessed the capabilities of TIME for the selective recording of neural activity, considering the topographical selectivity and the distinction of neural signals corresponding to different sensory types. Topographical recording selectivity was proved by the differential recording of CNAPs from different subsets of nerve fibers, such as those innervating toes 2 and 4 of the hindpaw of the rat. Neural signals elicited by sensory stimuli applied to the rat paw were successfully recorded. Signal processing allowed distinguishing three different types of sensory stimuli such as tactile, proprioceptive and nociceptive ones with high performance. These findings further support the suitability of TIMEs for neuroprosthetic applications, by exploiting the transversal topographical structure of the peripheral nerves.

Restoring natural sensory feedback in real-time bidirectional hand prostheses.

Hand loss is a highly disabling event that markedly affects the quality of life. To achieve a close to natural replacement for the lost hand, the user should be provided with the rich sensations that we naturally perceive when grasping or manipulating an object. Ideal bidirectional hand prostheses should involve both a reliable decoding of the user's intentions and the delivery of nearly "natural" sensory feedback through remnant afferent pathways, simultaneously and in real time. However, current hand prostheses fail to achieve these requirements, particularly because they lack any sensory feedback. We show that by stimulating the median and ulnar nerve fascicles using transversal multichannel intrafascicular electrodes, according to the information provided by the artificial sensors from a hand prosthesis, physiologically appropriate (near-natural) sensory information can be provided to an amputee during the real-time decoding of different grasping tasks to control a dexterous hand prosthesis. This feedback enabled the participant to effectively modulate the grasping force of the prosthesis with no visual or auditory feedback. Three different force levels were distinguished and consistently used by the subject. The results also demonstrate that a high complexity of perception can be obtained, allowing the subject to identify the stiffness and shape of three different objects by exploiting different characteristics of the elicited sensations. This approach could improve the efficacy and "life-like" quality of hand prostheses, resulting in a keystone strategy for the near-natural replacement of missing hands.

Continuous decoding of grasping tasks for a prospective implantable cortical neuroprosthesis.

BACKGROUND: In the recent past several invasive cortical neuroprostheses have been developed. Signals recorded from the motor cortex (area MI) have been decoded and used to control computer cursors and robotic devices. Nevertheless, few attempts have been carried out to predict different grips.A Support Vector Machines (SVMs) classifier has been trained for a continuous decoding of four/six grip types using signals recorded in two monkeys from motor neurons of the ventral premotor cortex (area F5) during a reach-to-grasp task. FINDINGS: The results showed that four/six grip types could be extracted with classification accuracy higher than 96% using window width of 75-150 ms. CONCLUSIONS: These results open new and promising possibilities for the development of invasive cortical neural prostheses for the control of reaching and grasping.

Alignment of angular velocity sensors for a vestibular prosthesis.

Vestibular prosthetics transmit angular velocities to the nervous system via electrical stimulation. Head-fixed gyroscopes measure angular motion, but the gyroscope coordinate system will not be coincident with the sensory organs the prosthetic replaces. Here we show a simple calibration method to align gyroscope measurements with the anatomical coordinate system. We benchmarked the method with simulated movements and obtain proof-of-concept with one healthy subject. The method was robust to misalignment, required little data, and minimal processing.

Combined analysis of cortical (EEG) and nerve stump signals improves robotic hand control.

BACKGROUND: Interfacing an amputee's upper-extremity stump nerves to control a robotic hand requires training of the individual and algorithms to process interactions between cortical and peripheral signals. OBJECTIVE: To evaluate for the first time whether EEG-driven analysis of peripheral neural signals as an amputee practices could improve the classification of motor commands. METHODS: Four thin-film longitudinal intrafascicular electrodes (tf-LIFEs-4) were implanted in the median and ulnar nerves of the stump in the distal upper arm for 4 weeks. Artificial intelligence classifiers were implemented to analyze LIFE signals recorded while the participant tried to perform 3 different hand and finger movements as pictures representing these tasks were randomly presented on a screen. In the final week, the participant was trained to perform the same movements with a robotic hand prosthesis through modulation of tf-LIFE-4 signals. To improve the classification performance, an event-related desynchronization/synchronization (ERD/ERS) procedure was applied to EEG data to identify the exact timing of each motor command. RESULTS: Real-time control of neural (motor) output was achieved by the participant. By focusing electroneurographic (ENG) signal analysis in an EEG-driven time window, movement classification performance improved. After training, the participant regained normal modulation of background rhythms for movement preparation (α/ß band desynchronization) in the sensorimotor area contralateral to the missing limb. Moreover, coherence analysis found a restored α band synchronization of Rolandic area with frontal and parietal ipsilateral regions, similar to that observed in the opposite hemisphere for movement of the intact hand. Of note, phantom limb pain (PLP) resolved for several months. CONCLUSIONS: Combining information from both cortical (EEG) and stump nerve (ENG) signals improved the classification performance compared with tf-LIFE signals processing alone; training led to cortical reorganization and mitigation of PLP.

Decoding of grasping information from neural signals recorded using peripheral intrafascicular interfaces.

BACKGROUND: The restoration of complex hand functions by creating a novel bidirectional link between the nervous system and a dexterous hand prosthesis is currently pursued by several research groups. This connection must be fast, intuitive, with a high success rate and quite natural to allow an effective bidirectional flow of information between the user's nervous system and the smart artificial device. This goal can be achieved with several approaches and among them, the use of implantable interfaces connected with the peripheral nervous system, namely intrafascicular electrodes, is considered particularly interesting. METHODS: Thin-film longitudinal intra-fascicular electrodes were implanted in the median and ulnar nerves of an amputee's stump during a four-week trial. The possibility of decoding motor commands suitable to control a dexterous hand prosthesis was investigated for the first time in this research field by implementing a spike sorting and classification algorithm. RESULTS: The results showed that motor information (e.g., grip types and single finger movements) could be extracted with classification accuracy around 85% (for three classes plus rest) and that the user could improve his ability to govern motor commands over time as shown by the improved discrimination ability of our classification algorithm. CONCLUSIONS: These results open up new and promising possibilities for the development of a neuro-controlled hand prosthesis.

A hybrid approach for the control of axonal outgrowth: preliminary simulation results.

The possible control of axonal outgrowth during neural regeneration could be very useful not only from a neurobiological point of view, but also in the field of neural interfaces. In this manuscript, simulations are presented which investigate the possibility of guiding axons by using a hybrid approach based on the combined used of a chemical model and of a genetic algorithm. Microspheres embedding chemical cues on the basis of information provided by a genetic algorithm are placed to impose a desired trajectory on the axons. Two kinds of simulations were carried out: (i) tracking of linear trajectories; (ii) tracking of trajectories, which were reconstructed from real axonal extension. The results achieved during the simulations seem to confirm the possible use of this approach to guide axonal outgrowth, being the obtained trajectories congruent to possible actual situations. Moreover, the model can be easily extended to a three-dimensional environment.

On the identification of sensory information from mixed nerves by using single-channel cuff electrodes.

BACKGROUND: Several groups have shown that the performance of motor neuroprostheses can be significantly improved by detecting specific sensory events related to the ongoing motor task (e.g., the slippage of an object during grasping). Algorithms have been developed to achieve this goal by processing electroneurographic (ENG) afferent signals recorded by using single-channel cuff electrodes. However, no efforts have been made so far to understand the number and type of detectable sensory events that can be differentiated from whole nerve recordings using this approach. METHODS: To this aim, ENG afferent signals, evoked by different sensory stimuli were recorded using single-channel cuff electrodes placed around the sciatic nerve of anesthetized rats. The ENG signals were digitally processed and several features were extracted and used as inputs for the classification. The work was performed on integral datasets, without eliminating any noisy parts, in order to be as close as possible to real application. RESULTS: The results obtained showed that single-channel cuff electrodes are able to provide information on two to three different afferent (proprioceptive, mechanical and nociceptive) stimuli, with reasonably good discrimination ability. The classification performances are affected by the SNR of the signal, which in turn is related to the diameter of the fibers encoding a particular type of neurophysiological stimulus. CONCLUSIONS: Our findings indicate that signals of acceptable SNR and corresponding to different physiological modalities (e.g. mediated by different types of nerve fibers) may be distinguished.

Double nerve intraneural interface implant on a human amputee for robotic hand control.

OBJECTIVES: The principle underlying this project is that, despite nervous reorganization following upper limb amputation, original pathways and CNS relays partially maintain their function and can be exploited for interfacing prostheses. Aim of this study is to evaluate a novel peripheral intraneural multielectrode for multi-movement prosthesis control and for sensory feed-back, while assessing cortical reorganization following the re-acquired stream of data. METHODS: Four intrafascicular longitudinal flexible multielectrodes (tf-LIFE4) were implanted in the median and ulnar nerves of an amputee; they reliably recorded output signals for 4 weeks. Artificial intelligence classifiers were used off-line to analyse LIFE signals recorded during three distinct hand movements under voluntary order. RESULTS: Real-time control of motor output was achieved for the three actions. When applied off-line artificial intelligence reached >85% real-time correct classification of trials. Moreover, different types of current stimulation were determined to allow reproducible and localized hand/fingers sensations. Cortical organization was observed via TMS in parallel with partial resolution of symptoms due to the phantom-limb syndrome (PLS). CONCLUSIONS: tf-LIFE4s recorded output signals in human nerves for 4 weeks, though the efficacy of sensory stimulation decayed after 10 days. Recording from a number of fibres permitted a high percentage of distinct actions to be classified correctly. Reversal of plastic changes and alleviation of PLS represent corollary findings of potential therapeutic benefit. SIGNIFICANCE: This study represents a breakthrough in robotic hand use in amputees.

Control of hand prostheses using peripheral information.

Several efforts have been carried out to enhance dexterous hand prosthesis control by impaired individuals. Choosing which voluntary signal to use for control purposes is a critical element to achieve this goal. This review presents and discusses the recent results achieved by using electromyographic signals, recorded either with surface (sEMG) or intramuscular (iEMG) electrodes, and electroneurographic (ENG) signals. The potential benefits and shortcomings of the different approaches are described with a particular attention to the definition of all the steps required to achieve an effective hand prosthesis control in the different cases. Finally, a possible roadmap in the field is also presented.

Characterization of EMG patterns from proximal arm muscles during object- and orientation-specific grasps.

Reach-to-grasp tasks are composed of several actions that are more and more considered as simultaneously controlled by the central nervous system in a feedforward manner (at least for well-known activities). If this hypothesis is correct, during prehension tasks, the activity of proximal muscles (and not only of the distal ones used to control finger movements) is modulated according to the kind of object to be grasped and its position. This means that different objects could be identified by processing the electromyographic (EMG) signals recorded from proximal muscles. In this paper, specific experiments have been carried out to support this hypothesis in able-bodied subjects. The results achieved seem to confirm this possibility by showing that the activation of proximal muscles can be statistically different for different grip types. This finding supports the hypothesis that proximal and distal muscles are simultaneously controlled during reaching and grasping. Moreover, this kind of information could allow the development of an EMG-based control strategy based on the natural muscular activities selected by the central nervous system.

Development and quantitative performance evaluation of a noninvasive EMG computer interface.

This paper describes a noninvasive electromyography (EMG) signal-based computer interface and a performance evaluation method based on Fitts' law. The EMG signals induced by volitional wrist movements were acquired from four sites in the lower arm to extract users' intentions, and six classes of wrist movements were distinguished using an artificial neural network. Using the developed interface, a user can move the cursor, click buttons, and type text on a computer. The test setup was built to evaluate the developed interface, and the mouse was tested by five volunteers with intact limbs. The performance of the developed computer interface and the mouse was tested at 1.299 and 7.733 b/s, respectively, and these results were compared with the performance of a commercial noninvasive brain signal interface (0.386 b/s). The results show that the developed interface performed better than the commercial interface, but less satisfactorily than a computer mouse. Although some issues remain to be resolved, the developed EMG interface has the potential to help people with motor disabilities to access computers and Internet environments in a natural and intuitive manner.

Motion analysis in cervical dystonia.

OBJECTIVE: To evaluate kinematic features in cervical dystonia (CD) patients by means of a motion analysis system (Fastrack-Polhemus, Colchester VT, USA). DESIGN: Small study sample. SETTING: Ambulatory care. PATIENTS AND PARTICIPANTS: 15 CD patients and 10 healthy subjects. INTERVENTIONS: Not applicable. MEASUREMENTS AND RESULTS: Posture at rest and voluntary movements in both groups. Posture at rest in CD patients was impaired in all planes; only 20% of the patients exhibited complex dystonic patterns at clinical evaluation, whereas more than 90% of them had complex ones at kinematic evaluation. The analysis of voluntary motion revealed a reduced range of voluntary excursion and increased execution time; the impairment was higher when the patients moved their heads towards the anti-dystonic side. CONCLUSIONS: Fastrack system is a sensitive tool in kinematic evaluation of CD, as it provides useful quantitative information on rest position and on motion in CD patients and may consequently improve the management of this disease.