Hyperexcitability of peripheral sensory neurons plays a critical role in the development and maintenance of chronic pain. Pharmacological analgesics used in clinics reduce neuronal activity. They often come with non‐negligible side effects. Optogenetic approaches can modulate neuronal activity and are attracting growing interest for therapeutic uses, but the delivery of light in different parts of the body requires the development of specific optoelectronic interfaces. We designed and produced a microfabricated optoelectronic implant to deliver yellow light (559 nm) onto the sciatic nerve. We have surgically implanted the device in transgenic mice expressing the yellow light‐sensitive inhibitory archaerhodopsin (ArchT) in nociceptive neurons. Yellow light induced a significant reduction in the responses of the nociceptive neurons and curbed the behavioral responses to noxious mechanical and thermal stimuli. Remarkably, the yellow light‐related inhibition did not alter the behavioral responses evoked by innocuous mechanical stimulation or by intense inflammation. The optoelectronic implants showed reliable and reproducible opto‐electrical performance. For stimulation parameters used in vivo (3.3 V, 60–80 mW/mm 2 , 20 s train pulses, 1 Hz, 80% duty‐cycle, and an inter‐train interval of 1 s), limited temperature increase was measured in an environment mimicking neural tissue surrounded by muscle and fat. Similarly, the basal sensitivity of the implanted mice remains comparable to non‐implanted mice, suggesting a safe integration of the soft electronic device. Our study confirmed that optoelectronic implants tailored to the sciatic nerve can provide specific light spectra and intensities at adequate levels for the optogenetic actuator to trigger significant electrophysiological and behavioral responses in pain perception.

Optoelectronic systems can exert precise control over targeted neurons and pathways throughout the brain in untethered animals, but similar technologies for the spinal cord are not well established. In the present study, we describe a system for ultrafast, wireless, closed-loop manipulation of targeted neurons and pathways across the entire dorsoventral spinal cord in untethered mice. We developed a soft stretchable carrier, integrating microscale light-emitting diodes (micro-LEDs), that conforms to the dura mater of the spinal cord. A coating of silicone-phosphor matrix over the micro-LEDs provides mechanical protection and light conversion for compatibility with a large library of opsins. A lightweight, head-mounted, wireless platform powers the micro-LEDs and performs low-latency, on-chip processing of sensed physiological signals to control photo-stimulation in a closed loop. We use the device to reveal the role of various neuronal subtypes, sensory pathways and supraspinal projections in the control of locomotion in healthy and spinal-cord injured mice.

Activation of nociceptor sensory neurons by noxious stimuli both triggers pain and increases capillary permeability and blood flow to produce neurogenic inflammation(1,2), but whether nociceptors also interact with the immune system remains poorly understood. Here we report a neurotechnology for selective epineural optogenetic neuromodulation of nociceptors and demonstrate that nociceptor activation drives both protective pain behavior and inflammation. The wireless optoelectronic system consists of sub-millimeter-scale light-emitting diodes embedded in a soft, circumneural sciatic nerve implant, powered and driven by a miniaturized head-mounted control unit. Photostimulation of axons in freely moving mice that express channelrhodopsin only in nociceptors resulted in behaviors characteristic of pain, reflecting orthodromic input to the spinal cord. It also led to immune reactions in the skin in the absence of inflammation and potentiation of established inflammation, a consequence of the antidromic activation of nociceptor peripheral terminals. These results reveal a link between nociceptors and immune cells, which might have implications for the treatment of inflammation. An optogenetic study shows that activation of pain-triggering sensory neurons induces an immune response.

Aim: Cardiac tissue deformation can modify tissue resistance, membrane capacitance and ion currents, and hence cause arrhythmogenic slow conduction. Our aim was to investigate whether uniaxial strain causes different changes in conduction velocity (θ) when applied parallel vs. perpendicular to impulse propagation. Methods: Cardiomyocyte strands were cultured on stretchable custom microelectrode arrays and θ was determined during steady-state pacing. Uniaxial strain (5%), either parallel to (orthodromic) or perpendicular to (paradromic) propagation, was applied for 1 min and controlled by imaging a grid of markers. The results were analysed in terms of cable theory. Results: Both types of strain induced immediate changes of θ upon application and release. In material coordinates, orthodromic strain decreased θ significantly more (p<0.001) than paradromic strain (2.2±0.5% vs 1.0±0.2% in n=8 mouse cardiomyocyte cultures, 2.3±0.4% vs 0.9±0.5% in n=4 rat cardiomyocyte cultures, respectively). The larger effect of orthodromic strain can be explained by the increase of axial myoplasmic resistance, which is not altered by paradromic strain. Thus, changes in tissue resistance substantially contributed to the changes of θ during strain, in addition to other influences (e.g., stretch-activated channels). Besides these immediate effects, the application of strain also consistently initiated a slow progressive decrease of θ and a slow recovery of θ upon release. Conclusion: Potentially arrhythmogenic changes in cardiac conduction caused by acute stretch do not only depend on the magnitude of strain itself but also on the orientation of strain relative to impulse propagation. This dependence is due to different effects on tissue resistance. MeSH keywords: Action Potentials; Biomechanical Phenomena; Electrophysiologic Techniques, Cardiac; Myocardium; Primary Cell Culture; Silicone Elastomers Buccarello et al. Cardiac conduction under uniaxial strain Page 3

AIM:Cardiac tissue deformation can modify tissue resistance, membrane capacitance and ion currents and hence cause arrhythmogenic slow conduction. Our aim was to investigate whether uniaxial strain causes different changes in conduction velocity (θ) when the principal strain axis is parallel vs perpendicular to impulse propagation.METHODS:Cardiomyocyte strands were cultured on stretchable custom microelectrode arrays, and θ was determined during steady-state pacing. Uniaxial strain (5%) with principal axis parallel (orthodromic) or perpendicular (paradromic) to propagation was applied for 1 minute and controlled by imaging a grid of markers. The results were analysed in terms of cable theory.RESULTS:Both types of strain induced immediate changes of θ upon application and release. In material coordinates, orthodromic strain decreased θ significantly more (P < .001) than paradromic strain (2.2 ± 0.5% vs 1.0 ± 0.2% in n = 8 mouse cardiomyocyte cultures, 2.3 ± 0.4% vs 0.9 ± 0.5% in n = 4 rat cardiomyocyte cultures, respectively). The larger effect of orthodromic strain can be explained by the increase in axial myoplasmic resistance, which is not altered by paradromic strain. Thus, changes in tissue resistance substantially contributed to the changes of θ during strain, in addition to other influences (eg stretch-activated channels). Besides these immediate effects, the application of strain also consistently initiated a slow progressive decrease in θ and a slow recovery of θ upon release.CONCLUSION:Changes in cardiac conduction velocity caused by acute stretch do not only depend on the magnitude of strain but also on its orientation relative to impulse propagation. This dependence is due to different effects on tissue resistance.

Objective. Nerves in the peripheral nervous system (PNS) contain axons with specific motor, somatosensory and autonomic functions. Optogenetics offers an efficient approach to selectively activate axons within the nerve. However, the heterogeneous nature of nerves and their tortuous route through the body create a challenging environment to reliably implant a light delivery interface. Approach. Here, we propose an optical peripheral nerve interface-an optocuff-, so that optogenetic modulation of peripheral nerves become possible in freely behaving mice. Main results. Using this optocuff, we demonstrate orderly recruitment of motor units with epineural optical stimulation of genetically targeted sciatic nerve axons, both in anaesthetized and in awake, freely behaving animals. Behavioural experiments and histology show the optocuff does not damage the nerve thus is suitable for long-term experiments. Significance. These results suggest that the soft optocuff might be a straightforward and efficient tool to support more extensive study of the PNS using optogenetics.

Reference EPFL-CONF-231603View record in Web of Science Record created on 2017-10-09, modified on 2017-10-09

Potentially harmful stimuli are detected at the skin by nociceptor sensory neurons that drive rapid protective withdrawal reflexes and pain. We set out to define, at a millisecond timescale, the relationship between the activity of these sensory neurons and the resultant behavioral output. Brief optogenetic activation of cutaneous nociceptors was found to activate only a single action potential in each fiber. This minimal input was used to determine high-speed behavioral responses in freely behaving mice. The localized stimulus generated widespread dynamic repositioning and alerting sub-second behaviors whose nature and timing depended on the context of the animal and its position, activity, and alertness. Our findings show that the primary response to injurious stimuli is not limited, fixed, or localized, but is dynamic, and that it involves recruitment and gating of multiple circuits distributed throughout the central nervous system at a sub-second timescale to effectively both alert to the presence of danger and minimize risk of harm.

Considerable progress has been made in the last decade in implantable bioelectronic neurosystems. Yet most neural implants are used in acute and tethered experimental conditions. Here, we present a preliminary prototype of a multichannel system for simultaneous peripheral nerve stimulation and neural recording. The system comprises miniaturized electronics with a total volume of less then 1.4cm3 including a 3.7V battery which is expected to last for 94 days of standby operation or 18 hours of continuous recording and stimulation. Data read-out and device configuration are wireless. Visceral nerves in rodents are interfaced with compliant extraneural electrodes. The 100×350μm2 electrodes display a low impedance (1.8kn at 1kHz) with a PEDOT:PSS coating. We validated the prototype in acute experiments by applying electrical stimulation to the aortic depressor nerve (ADN), resulting in effective and reproducible decrease in blood pressure and heart rate. The combination of miniaturized electronics and flexible electrodes makes the presented system a versatile platform for future implantable devices interfacing small peripheral nerves and potentially enables new applications in the field of neuroscience.

Objective: To study neural reflex mechanisms in hypertension and neural disease in small rodent (rats and mice), implantable wireless nerve stimulation and recording system is required. We aim initially at establishing a low power programmable pulse current source for nerve wireless stimulation and recording in small rodent. Design and Method: A low power programmable pulse current source was designed for nerve stimulation. Aortic depressor nerve (AND), a pure afferent nerve of baroreflex sensor located in Aorta, was selected for low power stimulation (3 V/0.1–0.2 mA/200 micro seconds pulse duration at 5/10/20 Hz for 10 seconds) combined with recording intra-arterial blood pressure (BP) and heart rate (HR), and renal sympathetic nerve activity (RSNA) in 10 adult Wistar male rats (BW: 314 ± 2 g). A femoral arterial catheter was implanted in rat. Twenty four hours later, ADN and RSNA were isolated respectively for placement of electrodes. During stimulation on ADN, BP, HR, and RSNA were synchronised recorded. Results: Low power stimulation on ADN at 5, 10, and 20 HZ for 10 s induced significantly dose-response of decreases in SBPs (25 ± 6, 46 ± 9, and 58 ± 9 mmHg, p < 0.01) and HRs (97 ± 17, 132 ± 13, and 193 ± 25 bpm, p < 0.01). RSNA were also decreased during the stimulation (see figure). Conclusions: The results demonstrate that low power programmable pulse current source can be applied to small rodent for studying neural mechanism related diseases, for instance, sympathetic never system involved pharmacotherapy resistant hypertension. The neural low power stimulation profile will be integrated into an implantable wireless nerve stimulating and recording system for small rodent.

Neuroprosthetic devices that interface with the nervous system to restore functional motor activity offer a viable alternative to nerve regeneration, especially in proximal nerve injuries like brachial plexus injuries where muscle atrophy may set in before nerve re-innervation occurs. Prior studies have used control signals from muscle or cortical activity. However, nerve signals are preferred in many cases since they permit more natural and precise control when compared to muscle activity, and can be accessed with much lower risk than cortical activity. Identification of nerve signals that control the appropriate muscles is essential for the development of such a `bionic link'. Here we examine the correlation between muscle and nerve signals responsible for hand grasping in the M. fascicularis. Simultaneous recordings were performed using a 4-channel thin-film longitudinal intra-fascicular electrode (tf-LIFE) and 9 bipolar endomysial muscle electrodes while the animal performed grasping movements. We were able to identify a high degree of correlation (r > 0.6) between nerve signals from the median nerve and movement-dependent muscle activity from the flexor muscles of the forearm, with a delay that corresponded to 25 m/s nerve conduction velocity. The phase of the flexion could be identified using a wavelet approximation of the ENG. This result confirms this approach for a future neuroprosthetic device for the treatment of peripheral nerve injuries.