Direct activation of zebrafish neurons by ultrasonic stimulation revealed by whole CNS calcium imaging.

OBJECTIVE: Ultrasounds (US) use in neural engineering is so far mainly limited to ablation through high intensity focused ultrasound, but interesting preliminary results show that low intensity low frequency ultrasound could be used instead to modulate neural activity. However, the extent of this modulatory ability of US is still unclear, as in in vivo studies it is hard to disentangle the contribution to neural responses of direct activation of the neuron by US stimulation and indirect activation due either to sensory response to mechanical stimulation associated to US, or to propagation of activity from neighboring areas. Here, we aim to show how to separate the three effects and assess the presence of direct response to US stimulation in zebrafish. APPROACH: We observed in zebrafish larvae brain-wide US-induced activity patterns through calcium imaging microscopy. Sensory response to mechanical stimulation was assessed with a US shield. Activity propagation was assessed with inter-area latency evaluation. MAIN RESULTS: We prove that in selected brain regions the zebrafish's neural response is mainly due to direct activation, later spreading to the other regions. Shielding the neurons from direct US stimulation resulted in a significantly attenuated response, showing that sensory stimulation does not play a prominent role. SIGNIFICANCE: US non-invasive neuromodulatory approach might lead to novel ways to test and control neural activity, and hence to novel neuromodulatory therapies. Future studies will focus on the biophysical structure of directly responsive neurons to capture the mechanisms of US induced activity.

Fascicular nerve stimulation and recording using a novel double-aisle regenerative electrode.

OBJECTIVE: As artificial prostheses become more refined, they are most often used as a therapeutic option for hand amputation. By contrast to extra- or intraneural interfaces, regenerative nerve electrodes are designed to enable electrical interfaces with regrowing axonal bundles of injured nerves, aiming to achieve high selectivity for recording and stimulation. However, most of the developed designs pose an obstacle to the regrowth mechanisms due to low transparency and cause impairment to the nerve regeneration. APPROACH: Here we present the double-aisle electrode, a new type of highly transparent, non-obstructive regenerative electrode. Using a double-side thin-film polyimide planar multi-contact electrode, two nerve fascicles can regenerate without physical impairment through two electrically isolated aisles. MAIN RESULTS: We show that this electrode can be used to selectively record and stimulate fascicles, acutely as well as chronically, and allow regeneration in nerve gaps of several millimeters without impairment. SIGNIFICANCE: This multi-aisle regenerative electrode may be suitable for neuroprosthetic applications, such as prostheses, for the restoration of hand function after amputation or severe nerve injuries.

Long-term usability and bio-integration of polyimide-based intra-neural stimulating electrodes.

Stimulation of peripheral nerves has transiently restored lost sensation and has the potential to alleviate motor deficits. However, incomplete characterization of the long-term usability and bio-integration of intra-neural implants has restricted their use for clinical applications. Here, we conducted a longitudinal assessment of the selectivity, stability, functionality, and biocompatibility of polyimide-based intra-neural implants that were inserted in the sciatic nerve of twenty-three healthy adult rats for up to six months. We found that the stimulation threshold and impedance of the electrodes increased moderately during the first four weeks after implantation, and then remained stable over the following five months. The time course of these adaptations correlated with the progressive development of a fibrotic capsule around the implants. The selectivity of the electrodes enabled the preferential recruitment of extensor and flexor muscles of the ankle. Despite the foreign body reaction, this selectivity remained stable over time. These functional properties supported the development of control algorithms that modulated the forces produced by ankle extensor and flexor muscles with high precision. The comprehensive characterization of the implant encapsulation revealed hyper-cellularity, increased microvascular density, Wallerian degeneration, and infiltration of macrophages within the endoneurial space early after implantation. Over time, the amount of macrophages markedly decreased, and a layer of multinucleated giant cells surrounded by a capsule of fibrotic tissue developed around the implant, causing an enlargement of the diameter of the nerve. However, the density of nerve fibers above and below the inserted implant remained unaffected. Upon removal of the implant, we did not detect alteration of skilled leg movements and only observed mild tissue reaction. Our study characterized the interplay between the development of foreign body responses and changes in the electrical properties of actively used intra-neural electrodes, highlighting functional stability of polyimide-based implants over more than six months. These results are essential for refining and validating these implants and open a realistic pathway for long-term clinical applications in humans.

A three-dimensional self-opening intraneural peripheral interface (SELINE).

OBJECTIVE: In this study we present the development and testing in a rat model of the self-opening neural interface (SELINE), a novel flexible peripheral neural interface. APPROACH: This polyimide-based electrode has a three-dimensional structure that provides an anchorage system to the nerve and confers stability after implant. This geometry has been achieved by means of the plastic deformation of polyimide. Mechanical and electrochemical characterizations have been performed to prove the integrity of the electrode with very good results. Functionality of SELINEs for fascicular stimulation has been tested during in vivo acute experiments in the rat. Chronic implants were made to test the biocompatibility of the device. MAIN RESULTS: Results showed that SELINEs significantly improve mechanical anchorage to the nerve. Stimulation stability is considerably enhanced compared to common planar transversal electrodes and stimulation selectivity is increased for some motor fascicles. Chronic experimental results showed that SELINEs neither produce changes in the fascicular organization of sciatic nerves nor signs of nerve degeneration. SIGNIFICANCE: The presented three-dimensional electrode provides an effective anchorage system to the nervous tissue that can improve the stability of the implant for acute and chronic studies.

Heritability, genetic correlation and linkage to the 9p21.3 region of mixed platelet-leukocyte conjugates in families with and without early myocardial infarction.

BACKGROUND AND AIMS: Variations in mixed platelet-leukocyte conjugate formation in human whole blood could be genetically determined. We quantified platelet and leukocyte activation and interaction in families with or without early myocardial infarction and evaluated their heritability, genetic correlation and linkage to the 9p21.3 region. METHODS AND RESULTS: The study population included 739 subjects (≥ 15 years old) from 54 large pedigrees, 23 with and 31 without familial myocardial infarction. Mixed platelet-leukocyte conjugates and markers of platelet or leukocyte activation (P-selectin, CD11b and L-selectin surface expression) were measured both before and after in vitro blood stimulation with collagen-ADP. All traits had significant genetic components (17.5-65.3% of the phenotypic variability), while shared household effects (0-39.6%) and environmental covariates (0-10.2%) tended to be smaller. Stimulated platelet-polymorphonuclear leukocyte (PMN) and platelet-monocyte conjugates showed the highest linkage to the 9p21.3 region (LOD = 0.94 and 1.33, respectively; empirical p value = 0.017 and 0.009). PMN markers resulted strongly genetically correlated between them in bivariate analysis among pairs of quantitative traits. CONCLUSION: This study supports a genetic regulation of human mixed platelet-leukocyte conjugates.

Activities on PNS neural interfaces for the control of hand prostheses.

The development of interfaces linking the human nervous system with artificial devices is an important area of research. Several groups are working on the development of devices able to restore sensory-motor function in subjects affected by neurological disorders, injuries or amputations. Neural electrodes implanted in peripheral nervous system, and in particular intrafascicular electrodes, seem to be a promising approach for the control of hand prosthesis thanks to the possibility to selectively access motor and sensory fibers for decoding motor commands and delivering sensory feedback. In this paper, activities on the use of PNS interfaces for the control of hand prosthesis are presented. In particular, the design and feasibility study of a self-opening neural interface is presented together with the decoding of ENG signals in one amputee to control a dexterous hand prosthesis.

A new library of HEMET model: Insulin effects on hepatic metabolism.

Prediction and simulation of cell culture behaviour, under different chemical and physical stimuli by a mathematical model, represent an innovative way to create a virtual cell laboratory, where it is possible to perform and optimize experimental protocol, saving time and money. In silico experiments permit to reproduce pathological and physiological situations and make toxicological tests. In this paper we introduce a new library of HEMET (HEpatocyte METabolism) software that allows the insulin effects on hepatic metabolism to be simulated. This new set of nonlinear differential equations, derived from biochemical reactions which involve this pancreatic hormone, allows the catabolites concentration in hepatic cell culture after insulin infusion to be predicted. The validation procedures were carried out using data obtained from specifically designed cell experiments and from literature. A user friendly interface allows to easily change model parameters, rate constants and inputs simulating a wide range of physiological and pathological scenarios.

Intraoperative transesophageal echocardiography during liver transplantation.

OBJECTIVE: To investigate the safety, value, and impact of transesophageal echocardiography during liver transplantation. DESIGN: Retrospective. SETTING: University teaching hospital. PARTICIPANTS AND INTERVENTIONS: The medical records of 346 patients and the videotapes of 100 intraoperative transesophageal echocardiography examinations were reviewed. MEASUREMENTS AND MAIN RESULTS: Transesophageal echocardiography was indicated for intraoperative monitoring in 62 patients, 41 of whom had pertinent findings, and for diagnostic purposes in 38 patients, 14 of whom had the expected diagnosis verified. Thirty-one patients had no intraoperative findings. Information that would not have been detected intraoperatively by other means included intracardiac defects, the potential for transpulmonary air passage, valvular regurgitation, the presence or absence of ventricular dysfunction, and embolization occurring at allograft reperfusion. Unanticipated findings during the initial transesophageal echocardiography examination as well as evaluation of intraoperative events resulted in a major impact on patient management in 11% of patients. Preoperatively, 64 patients had a prothrombin time greater than 14 seconds; 56 had a platelet count less than 100,000/mm3; and 23 had esophageal varices, 7 of whom had not had variceal sclerotherapy. Two patients had a complication possibly caused by transesophageal echocardiography (sinus bradycardia and upper gastrointestinal bleeding). No patient experienced documented variceal hemorrhage, esophageal or gastric perforation, and/or oropharyngeal trauma. CONCLUSIONS: It appears that transesophageal echocardiography can be performed safely in patients undergoing liver transplantation, is efficacious in rapidly disclosing new information and monitoring during periods of hemodynamic instability, and may have a significant impact on intraoperative patient management during liver transplantation.