Comparison of Responses to DCN vs. VCN Stimulation in a Mouse Model of the Auditory Brainstem Implant (ABI).

The auditory brainstem implant (ABI) is an auditory neuroprosthesis that provides hearing to deaf patients by electrically stimulating the cochlear nucleus (CN) of the brainstem. Whether such stimulation activates one or the other of the CN's two major subdivisions is not known. Here, we demonstrate clear response differences from the stimulation of the dorsal (D) vs. ventral (V) subdivisions of the CN in a mouse model of the ABI with a surface-stimulating electrode array. For the DCN, low levels of stimulation evoked multiunit responses in the inferior colliculus (IC) that were unimodally distributed with early latencies (avg. peak latency of 3.3 ms). However, high levels of stimulation evoked a bimodal distribution with the addition of a late latency response peak (avg. peak latency of 7.1 ms). For the VCN, in contrast, electrical stimulation elicited multiunit responses that were usually unimodal and had a latency similar to the DCN's late response. Local field potentials (LFP) from the IC showed components that correlated with early and late multiunit responses. Surgical cuts to sever the output of the DCN, the dorsal acoustic stria (DAS), gave insight into the origin of these early and late responses. Cuts eliminated early responses but had little-to-no effect on late responses. The early responses thus originate from cells that project through the DAS, such as DCN's pyramidal and giant cells. Late responses likely arise from the spread of stimulation from a DCN-placed electrode array to the VCN and could originate in bushy and/or stellate cells. In human ABI users, the spread of stimulation in the CN may result in abnormal response patterns that could hinder performance.

Viscoelastic surface electrode arrays to interface with viscoelastic tissues.

Living tissues are non-linearly elastic materials that exhibit viscoelasticity and plasticity. Man-made, implantable bioelectronic arrays mainly rely on rigid or elastic encapsulation materials and stiff films of ductile metals that can be manipulated with microscopic precision to offer reliable electrical properties. In this study, we have engineered a surface microelectrode array that replaces the traditional encapsulation and conductive components with viscoelastic materials. Our array overcomes previous limitations in matching the stiffness and relaxation behaviour of soft biological tissues by using hydrogels as the outer layers. We have introduced a hydrogel-based conductor made from an ionically conductive alginate matrix enhanced with carbon nanomaterials, which provide electrical percolation even at low loading fractions. Our combination of conducting and insulating viscoelastic materials, with top-down manufacturing, allows for the fabrication of electrode arrays compatible with standard electrophysiology platforms. Our arrays intimately conform to the convoluted surface of the heart or brain cortex and offer promising bioengineering applications for recording and stimulation.

MRI-Compatible and Conformal Electrocorticography Grids for Translational Research.

Intraoperative electrocorticography (ECoG) captures neural information from the surface of the cerebral cortex during surgeries such as resections for intractable epilepsy and tumors. Current clinical ECoG grids come in evenly spaced, millimeter-sized electrodes embedded in silicone rubber. Their mechanical rigidity and fixed electrode spatial resolution are common shortcomings reported by the surgical teams. Here, advances in soft neurotechnology are leveraged to manufacture conformable subdural, thin-film ECoG grids, and evaluate their suitability for translational research. Soft grids with 0.2 to 10 mm electrode pitch and diameter are embedded in 150 µm silicone membranes. The soft grids are compatible with surgical handling and can be folded to safely interface hidden cerebral surface such as the Sylvian fold in human cadaveric models. It is found that the thin-film conductor grids do not generate diagnostic-impeding imaging artefacts (<1 mm) nor adverse local heating within a standard 3T clinical magnetic resonance imaging scanner. Next, the ability of the soft grids to record subdural neural activity in minipigs acutely and two weeks postimplantation is validated. Taken together, these results suggest a promising future alternative to current stiff electrodes and may enable the future adoption of soft ECoG grids in translational research and ultimately in clinical settings.

Dimensional scaling of thin-film stimulation electrode systems in translational research.

Objective.Electrical stimulation of biological tissue is an established technique in research and clinical practice that uses implanted electrodes to deliver electrical pulses for a variety of therapies. Significant research currently explores new electrode system technologies and stimulation protocols in preclinical models, aiming at both improving the electrode performance and confirming therapeutic efficacy. Assessing the scalability of newly proposed electrode technology and their use for tissue stimulation remains, however, an open question.Approach.We propose a simplified electrical model that formalizes the dimensional scaling of stimulation electrode systems. We use established equations describing the electrode impedance, and apply them to the case of stimulation electrodes driven by a voltage-capped pulse generator.Main results.We find a hard, intrinsic upward scalability limit to the electrode radius that largely depends on the conductor technology. We finally provide a simple analytical formula predicting the maximum size of a stimulation electrode as a function of the stimulation parameters and conductor resistance.Significance.Our results highlight the importance of careful geometrical and electrical designs of electrode systems based on novel thin-film technologies and that become particularly relevant for their translational implementation with electrode geometries approaching clinical human size electrodes and interfacing with voltage-capped neurostimulation systems.

Neuroprosthetic baroreflex controls haemodynamics after spinal cord injury.

Spinal cord injury (SCI) induces haemodynamic instability that threatens survival1-3, impairs neurological recovery4,5, increases the risk of cardiovascular disease6,7, and reduces quality of life8,9. Haemodynamic instability in this context is due to the interruption of supraspinal efferent commands to sympathetic circuits located in the spinal cord10, which prevents the natural baroreflex from controlling these circuits to adjust peripheral vascular resistance. Epidural electrical stimulation (EES) of the spinal cord has been shown to compensate for interrupted supraspinal commands to motor circuits below the injury11, and restored walking after paralysis12. Here, we leveraged these concepts to develop EES protocols that restored haemodynamic stability after SCI. We established a preclinical model that enabled us to dissect the topology and dynamics of the sympathetic circuits, and to understand how EES can engage these circuits. We incorporated these spatial and temporal features into stimulation protocols to conceive a clinical-grade biomimetic haemodynamic regulator that operates in a closed loop. This 'neuroprosthetic baroreflex' controlled haemodynamics for extended periods of time in rodents, non-human primates and humans, after both acute and chronic SCI. We will now conduct clinical trials to turn the neuroprosthetic baroreflex into a commonly available therapy for people with SCI.

Three-Dimensional Surface Reconstruction of the Human Cochlear Nucleus: Implications for Auditory Brain Stem Implant Design.

Objective The auditory brain stem implant (ABI) is a neuroprosthesis placed on the surface of the cochlear nucleus (CN) to provide hearing sensations in children and adults who are not candidates for cochlear implantation. Contemporary ABI arrays are stiff and do not conform to the curved brain stem surface. Recent advancements in microfabrication techniques have enabled the development of flexible surface arrays, but these have only been applied in animal models. Herein, we measure the surface curvature of the human CN and adjoining regions to assist in the design and placement of next-generation conformable clinical ABI arrays. Three-dimensional (3D) reconstructions from ultrahigh T1-weighted brain magnetic resonance imaging (MRI) sequences and histologic reconstructions based on postmortem adult human brain stem specimens were used. Design This is a retrospective review of radiologic data and postmortem histologic axial sections. Setting This is set at the tertiary referral center. Participants Data were acquired from healthy adults. Main Outcome Measures The main outcome measures are principal curvature values (Kmin and Kmax) and global radius of curvature. Results The CN was successfully extracted and rendered as a 3D surface in all cases. Significant curvatures of the CN in both histologic and radiographic reconstructions were found with global radius of curvature ranging from 2.08 to 8.5 mm. In addition, local curvature analysis revealed that the surface is highly complex. Conclusion Detailed rendering of the human CN is feasible using histology and 3D MRI reconstruction and highlights complex surface topography that is not recapitulated by contemporary stiff ABI arrays.

Human Cochlear Nucleus on 7 Tesla Diffusion Tensor Imaging: Insights Into Micro-anatomy and Function for Auditory Brainstem Implant Surgery.

OBJECTIVE: The cochlear nucleus (CN) is the target of the auditory brainstem implant (ABI). Most ABI candidates have Neurofibromatosis Type 2 (NF2) and distorted brainstem anatomy from bilateral vestibular schwannomas. The CN is difficult to characterize as routine structural MRI does not resolve detailed anatomy. We hypothesize that diffusion tensor imaging (DTI) enables both in vivo localization and quantitative measurements of CN morphology. STUDY DESIGN: We analyzed 7 Tesla (T) DTI images of 100 subjects (200 CN) and relevant anatomic structures using an MRI brainstem atlas with submillimetric (50 µm) resolution. SETTING: Tertiary referral center. PATIENTS: Young healthy normal hearing adults. INTERVENTION: Diagnostic. MAIN OUTCOME MEASURES: Diffusion scalar measures such as fractional anisotropy (FA), mean diffusivity (MD), mode of anisotropy (Mode), principal eigenvectors of the CN, and the adjacent inferior cerebellar peduncle (ICP). RESULTS: The CN had a lamellar structure and ventral-dorsal fiber orientation and could be localized lateral to the inferior cerebellar peduncle (ICP). This fiber orientation was orthogonal to tracts of the adjacent ICP where the fibers run mainly caudal-rostrally. The CN had lower FA compared to the medial aspect of the ICP (0.44 ±â€Š0.09 vs. 0.64 ±â€Š0.08, p < 0.001). CONCLUSIONS: 7T DTI enables characterization of human CN morphology and neuronal substructure. An ABI array insertion vector directed more caudally would better correspond to the main fiber axis of CN. State-of-the-art DTI has implications for ABI preoperative planning and future image guidance-assisted placement of the electrode array.

Soft, Implantable Bioelectronic Interfaces for Translational Research.

The convergence of materials science, electronics, and biology, namely bioelectronic interfaces, leads novel and precise communication with biological tissue, particularly with the nervous system. However, the translation of lab-based innovation toward clinical use calls for further advances in materials, manufacturing and characterization paradigms, and design rules. Herein, a translational framework engineered to accelerate the deployment of microfabricated interfaces for translational research is proposed and applied to the soft neurotechnology called electronic dura mater, e-dura. Anatomy, implant function, and surgical procedure guide the system design. A high-yield, silicone-on-silicon wafer process is developed to ensure reproducible characteristics of the electrodes. A biomimetic multimodal platform that replicates surgical insertion in an anatomy-based model applies physiological movement, emulates therapeutic use of the electrodes, and enables advanced validation and rapid optimization in vitro of the implants. Functionality of scaled e-dura is confirmed in nonhuman primates, where epidural neuromodulation of the spinal cord activates selective groups of muscles in the upper limbs with unmet precision. Performance stability is controlled over 6 weeks in vivo. The synergistic steps of design, fabrication, and biomimetic in vitro validation and in vivo evaluation in translational animal models are of general applicability and answer needs in multiple bioelectronic designs and medical technologies.

Microstructured thin-film electrode technology enables proof of concept of scalable, soft auditory brainstem implants.

Auditory brainstem implants (ABIs) provide sound awareness to deaf individuals who are not candidates for the cochlear implant. The ABI electrode array rests on the surface of the cochlear nucleus (CN) in the brainstem and delivers multichannel electrical stimulation. The complex anatomy and physiology of the CN, together with poor spatial selectivity of electrical stimulation and inherent stiffness of contemporary multichannel arrays, leads to only modest auditory outcomes among ABI users. Here, we hypothesized that a soft ABI could enhance biomechanical compatibility with the curved CN surface. We developed implantable ABIs that are compatible with surgical handling, conform to the curvature of the CN after placement, and deliver efficient electrical stimulation. The soft ABI array design relies on precise microstructuring of plastic-metal-plastic multilayers to enable mechanical compliance, patterning, and electrical function. We fabricated soft ABIs to the scale of mouse and human CN and validated them in vitro. Experiments in mice demonstrated that these implants reliably evoked auditory neural activity over 1 month in vivo. Evaluation in human cadaveric models confirmed compatibility after insertion using an endoscopic-assisted craniotomy surgery, ease of array positioning, and robustness and reliability of the soft electrodes. This neurotechnology offers an opportunity to treat deafness in patients who are not candidates for the cochlear implant, and the design and manufacturing principles are broadly applicable to implantable soft bioelectronics throughout the central and peripheral nervous system.

Auditory brainstem stimulation with a conformable microfabricated array elicits responses with tonotopically organized components.

Auditory brainstem implants (ABIs) restore hearing to deaf individuals not eligible for cochlear implants. Speech comprehension in ABI users is generally poor compared to that of cochlear implant users, and side effects are common. The poor performance may result from activating broad areas and multiple neuronal populations of the cochlear nucleus, however detailed studies of the responses to surface stimulation of the cochlear nucleus are lacking. A conformable electrode array was microfabricated to fit on the rat's dorsal cochlear nucleus (DCN). It hosts 20 small electrodes (each 100 µm diam.). The array was tested by recording evoked potentials and neural activity along the tonotopic axis of the inferior colliculus (IC). Almost all bipolar electrode pairs elicited responses, in some cases with an even, or relatively constant, pattern of thresholds and supra-threshold measures along the long axis of the array. This pattern suggests that conformable arrays can provide relatively constant excitation along the surface of the DCN and thus might decrease the ABI side effects caused by spread of high current to adjacent structures. We also examined tonotopic patterns of the IC responses. Compared to sound-evoked responses, electrically-evoked response mappings had less tonotopic organization and were broader in width. They became more tonotopic when the evoked activity common to all electrodes and the late phase of response were subtracted out, perhaps because the remaining activity is from tonotopically organized principal cells of the DCN. Responses became less tonotopic when inter-electrode distance was increased from 400 µm to 800 µm but were relatively unaffected by changing to monopolar stimulation. The results illustrate the challenges of using a surface array to present tonotopic cues and improve speech comprehension in humans who use the ABI.

Auditory Brainstem Implants: Recent Progress and Future Perspectives.

The auditory brainstem implant (ABI) was first developed nearly 40 years ago and provides auditory rehabilitation to patients who are deaf and ineligible for cochlear implant surgery due to abnormalities of the cochlea and cochlear nerve. The aims of the following review are to describe the history of the ABI and innovations leading up to the modern ABI system, as well as highlight areas of future development in implant design.

Long-term functionality of a soft electrode array for epidural spinal cord stimulation in a minipig model.

Long-term biointegration of man-made neural interfaces is influenced by the mechanical properties of the implant materials. Substantial experimental work currently aims at replacing conventional hard implant materials with soft alternatives that can favour a lower immune response. Here we assess the performance of a soft electrode array implanted in the spinal epidural space of a minipig model for a period of 6 months. The electrode array includes platinum-silicone electrode contacts and elastic thin-film gold interconnects embedded in silicone. textbfIn-vivo electrode impedance and voltage transients were monitored over time. Following implantation, epidural stimulation produced muscle-specific evoked potentials and visible muscle contractions. Over time, postoperative and stimulation induced changes in electrode impedance were observed. Such trends provide a basis for future technological improvements aiming at ensuring the stability of soft implantable electrodes for neural interfacing.

Conducting polymer electrodes for auditory brainstem implants.

The auditory brainstem implant (ABI) restores hearing in patients with damaged auditory nerves. One of the main ideas to improve the efficacy of ABIs is to increase spatial specificity of stimulation, in order to minimize extra-auditory side-effects and to maximize the tonotopy of stimulation. This study reports on the development of a microfabricated conformable electrode array with small (100 µm diameter) electrode sites. The latter are coated with a conducting polymer, PEDOT:PSS, to offer high charge injection properties and to safely stimulate the auditory system with small stimulation sites. We report on the design and fabrication of the polymer implant, and characterize the coatings in physiological conditions in vitro and under mechanical deformation. We characterize the coating electrochemically and during bending tests. We present a proof of principle experiment where the auditory system is efficiently activated by the flexible polymeric interface in a rat model. These results demonstrate the potential of using conducting polymer coatings on small electrode sites for electrochemically safe and efficient stimulation of the central auditory system.

Biomaterials. Electronic dura mater for long-term multimodal neural interfaces.

The mechanical mismatch between soft neural tissues and stiff neural implants hinders the long-term performance of implantable neuroprostheses. Here, we designed and fabricated soft neural implants with the shape and elasticity of dura mater, the protective membrane of the brain and spinal cord. The electronic dura mater, which we call e-dura, embeds interconnects, electrodes, and chemotrodes that sustain millions of mechanical stretch cycles, electrical stimulation pulses, and chemical injections. These integrated modalities enable multiple neuroprosthetic applications. The soft implants extracted cortical states in freely behaving animals for brain-machine interface and delivered electrochemical spinal neuromodulation that restored locomotion after paralyzing spinal cord injury.