Conformable neural interfaces : from engineering stretchability at the micro-scale to translational applications

Recently, flexible and soft bioelectronic interfaces have been proposed as a solution to improve existing neural interfaces that currently present mechanical mismatch with the soft tissue. These are devices fabricated with thin polymeric or elastomeric backbones to enable an optimal contact to the target tissue as well as reduced mechanical mismatch. For this the electrical interconnects that carry the electrical information from the tissue or deliver the stimulation charges need to be elastic to accommodate the stresses and remain conductive. Several strategies for creating stretchable tracks have been proposed in the past but are not compatible with high-density low-profile electrode arrays for chronic implantation in vivo.A method of patterning thin material stacks of flexible polymers and platinum layers embedded in silicone membranes was proposed in the Laboratory for Soft Bioelectronic Interfaces at EPFL. By creating specific microscopic cuts in the materials permits the out-of-plane deformation of the film and enables stretchability above 50% strain while remaining conductive. However, the previous fabrication method was not optimal, was not hermetically encapsulated and not reliable. In this thesis, novel soft electrode arrays were designed and fabricated using an improved manufacturing process named core-shell micropatterning. This enables fully encapsulated electrical tracks that can be micropatterned with superior electromechanical performances and notable increase in hermetic barrier lifetimes. Additionally, this method was applied to other material systems enabling new functions such as completely transparent devices to enable concurrent optical stimulation and microscopy through the implanted electrodes.These fabricated devices were applied to several device concepts in multiple animal models. First, microelectrode arrays for electrocorticography (ECoG) recordings were designed to be implanted over the auditory cortex of rat and non-human primate (NHP) models to capture evoked potentials from acoustic stimulation. This enabled the precise tonotopic mapping and the spatial representation of the auditory cortex. Next, auditory brainstem implants (ABI), targeting the cochlear nucleus (CN) after the auditory nerve were designed. This implant needs to conform to the curved surface of the CN and stimulate the auditory pathway. In non-human primates, the placement of this device is challenging and new tools were developed for the insertion of the device. Finally, the combination of soft ABI and ECoG was implanted in chronic settings in a NHP to evoke auditory percepts from brainstem stimulation that could be monitored using the cortical evoked potentials. This will enable the fine-tuning of stimulation protocols for hearing restoration and verify the stability of the implants over time.Overall, this work represents a framework to design and fabricate soft electrode arrays that can be applied for recording and stimulation in small to large animal models in a reliable way. The careful design of the system around the implant such as fine-tuning of microfabrication parameters, the characterization in vitro, device geometry, connection scheme, experimental setup and tracking of the device properties in vivo enables reliable long-term implantations in new experimental paradigms.

Fabrication and validation of an intraneural interface tailored for optic nerve stimulation

Eleonora Borda

Technological progress in materials science and microengineering along with new discoveries in neuroscience have contributed to restore lost or impaired sensory functions by closely interfacing with the nervous system. Electronic devices have begun to be integrated within the body to artificially reproduce or record the electrical encoding of neural signals, the language of the nervous system. This has allowed us to restore the impaired communication between the missing or defective organ and the brain. As evidence of this, cochlear implants have returned hearing to millions of people world wide. On the other hand, there is no suitable solution yet for the 43 millions people who are currently blind. Nevertheless, several research groups and companies are trying to tackle this issue. So far, different devices have demonstrated the capability of restoring a certain degree of artificial vision, however, with limited success in delivering meaningful improvements in daily life activities. This is because, unlike hearing, vision is an extremely complex sense and requires higher stimulation resolution. Limitations of retinal prostheses have pushed further the investigation of other targets along the visual pathway, such as the optic nerve, the thalamus and the visual cortex. Among these, our group has started to explore the possibility of stimulating the optic nerve. The main advantages are the direct stimulation of the axon fibers and the access to the entire visual field with only one device. It is also interesting because it could work for those patients who are not eligible for retinal prostheses, due to severe eye trauma or retinal detachment, and it does not require optical transparency.In this thesis, we investigate stimulation strategies and materials to improve the outcome of optic nerve prostheses and make them one step closer to a viable option for blind patients. We first propose the use of machine learning algorithms to classify cortical activity upon electrical stimulation of the optic nerve. Secondly, we investigate a strategy to achieve higher spatial selectivity of the optic nerve stimulation. We design a three-dimensional (3D) multilayer concentric bipolar (CB) configuration and fabricate a modified version of the OpticSELINE. We validate the efficacy of the novel design during in-vivo experiments on rabbits and find that cortical activation is reduced when using the 3D multilayer CB electrodes compared to the classic monopolar configuration. In parallel, we explore the use of novel polymers, namely Off-Stoichiometry Thiol- Ene Epoxy (OSTE+), to design conformable neural interfaces. Their chemistry makes them a suitable candidate for easy integration in cleanroom processes and they show superior adhesion properties with respect to standard thin films currently in use. Hence, we characterise their usability as substrate and encapsulation for neural interfaces in-vitro and in-vivo. Lastly, we propose an alternative fabrication technique, ink-jet printing of platinum on flexible substrates, for neurophysiology applications. Altogether, the findings highlighted in this thesis will hopefully lead to a more in-depth investigation of the optic nerve prosthesis and can also be relevant for other applications in the field of neuroprosthetics.

EPFL2022

Analysis of Anticipation Related Potentials for Brain Computer Interaction

Gangadhar Garipelli

Anticipation is a mental process during which a person actively engages in a phase required for the sensory perception and execution of the optimal actions at the arrival of the relevant future events. Since this process occurs before the execution of an intended action, it may be used as a control signal for Brain Computer Interface (BCI) applications. Recognition of neural correlates of this process can enhance the performance of a BCI and in turn reduce mental workload of its users. To this end, it is vital to understand the neural correlates involved in this process and to design robust methods for its recognition in single trials. The analysis of these correlates may also contribute to the basic knowledge of the mechanisms underlying this behavior. The thesis provides three major contributions: (i) it reports methods for the robust recognition of anticipation related Electroencephalogram (EEG) potentials (ii) it provides insights into the selection of appropriate preprocessing steps required for enhancing the Signal-to-Noise Ratio (SNR) of anticipatory slow cortical potentials (SCPs) and (iii) it identifies scalp area specific oscillatory activity related to different aspects of anticipatory behavior. First, we focus on methods for the single trial recognition of anticipatory SCPs using the widely known classical contingent negative variation (CNV) paradigm. Using this paradigm, we demonstrate the feasibility of recognizing the anticipatory SCPs (CNV potentials) using features thatmodel its temporal pattern. We propose a Bayesian approach that exploits temporal evolution and redundancy to quickly classify (e.g., within half of the anticipatory period), without compromising classification accuracy. We then improve upon these recognition rates by using a source localization technique based on the biophysical model of the human head. We further validate the feasibility of recognizing CNV potentials in an online experiment, and report for the first time that, under controlled conditions, these potentials can be reproduced and recognized in realistic interaction scenarios (assistive technology web-browsing) with high accuracies. Second, the thesis provides insights into the selection of appropriate preprocessing stages required for improving the SNR of SCPs. The CNV potentials are characterized by low frequencies that are usually recorded with full-DC, and hence suffer from task-irrelevant high amplitude fluctuations and spatial noise. To account for this, we identified appropriate spectral and spatial filters to improve the SNR. We demonstrate the potential of these preprocessing stages by using fusing multiple electrode specific linear classifiers, which achieve recognition performances of 90±2% (area under curve of receiver operating characteristic), where the classifiers are trained using recordings from one day and tested on the recordings from several days apart. Finally, the thesis identifies different facets of anticipatory behavior. Apart from the widely known CNV potentials, it is not clear which other spectral bands could be related to anticipatory behavior. Using recordings from an experiment (i.e., the assistive technology web browser) where multiple warning stimuli predicted an imperative stimulus, we explored the phase and amplitude response of various oscillatory sub-bands for the identification of markers that could be associated with different aspects of anticipation. From this study we report that: (i) there are duration (4-10 seconds) specific changes in Electroencephalography (EEG) activity in the range 0-1 Hz in the central electrodes correlate with reaction time, (ii) there exist slow oscillations (0.1-1 Hz) in the central electrodes that exhibit phase tuning up to 4 seconds before the onset of a target cue, (iii) there are delta oscillations (1.5-3 Hz), which are entrained to predictive rhythmic warning cues, (iv) there is a selective modulation (increase or decrease) in the amplitude of occipital alpha band (8-12 Hz) based on the relevance of forthcoming visual cue, and (v) there exist a reduction in the beta band (14-30 Hz) amplitude in the sensory motor and association areas lasting up to 10 seconds. The phase tuning and entrainment resulted in a low variance of phase values at the arrival of the imperative stimulus, which may be required for its optimal processing. The amplitude modulation of alpha band activity is likely to be a resultant of sensory suppression and attention. The reduction of beta-band activity over long periods of time suggests holding of sensory-motor association areas until the execution of a planned action. We believe that these observations are the consequence of the endogenous drive on the ongoing oscillations to enhance the processing of the forthcoming stimuli and preparation for an intended action. In summary, the thesis provides methods for the recognition of anticipatory SCPs by exploiting spectral and spatio-temporal characteristics with high performances. By exploring various other oscillatory sub-bands, the spectral characteristics of different aspects of anticipatory behavior are also identified. Further, methods modeling these characteristics can bring forth more robust and faster techniques for BCI systems.

EPFL2011

Development of a Transient Neural Interface for Minimally Invasive Recording and Stimulation

Adele Fanelli

Transient electronics enabling devices to safely disappear in the environment can be applied not only in green electronics, but also in bioelectronic medicine. Neural implants able to degrade harmlessly inside the body eliminate the need for removal surgery, allow for safe tissue remodelling, and potentially reduce inflammation responses and the chronic adverse reactions hindering device functionality and putting patients' health at risk. Sadly, current transient neurotechnology can be used only for very short-term applications. Fast degrading metals generally used to build these interfaces allow in fact for operations rarely longer than a few days, strongly limiting the available time window for collecting information or for a therapy to be finished.To solve this problem, we propose a transient, all-polymeric neural interface able to work for longer time scales. This would enable new applications of transient neurotechnology, such as recording of brain activity for a prolonged and more useful period of time before resection of epilepsy foci or tumours. The device consists of a polycaprolactone (PCL) scaffold with patterned poly 3,4-ethylene dioxythiophene : polystyrene sulfonate (PEDOT:PSS) traces and electrodes. In vivo neural recording demonstrated low noise levels for twelve weeks and histological analysis highlighted the cellular infiltration inside the PCL scaffold over time, hinting to potential tissue remodelling processes, which would not occur with a non-degradable device. To increase the device potential for a clinical translation, a minimally invasive procedure for its implantation has been proposed. The blood vasculature supplying the brain and nerves can be used as an access route to the neural tissue, offering a close enough location without direct damage to the tissue. By re-shaping the all-polymeric transient neural probe using a stent-inspired design, the new interface can be navigated through a 5Fr catheter and deployed inside 2 mm-diameter channels. Characterization showed promising electrodes endurance to pulsatile flow and prolonged stimulation, together with a good safety profile. This device can be used for neural recording or stimulation from within a blood vessel, for either central or peripheral nervous system. By simplifying the implantation procedure of the neural interface and maintaining its transiency, physicians and patients could feel more confident in applying innovative neurotechnology-based treatments, widening for example the access to deep brain stimulation therapy. To enable crossing of complex vasculature without wall ruptures caused by current manual push of guidewires, a new navigation paradigm for endovascular devices has been designed and tested on thin polyimide strips. A physiological pulsatile flow can propel these probes, even at curvatures as high as 0.25 mm-1, and low amplitude magnetic fields can steer their direction. Electrodes and sensors for temperature and flow can be embedded onto these micro-probes, for unprecedented local interrogation of deep vasculature regions. In conclusion, this thesis introduces new neural interfaces in the field of minimally invasive neurotechnology, reducing adverse effects and complications of non-degradable implants and open surgery. These devices and their concepts have the potential one day to be new tools of the bioelectronic medicine toolbox, contributing to the advancement of innovative treatments for neurodegenerative disorders.

EPFL2022

Development of a Transient Neural Interface for Minimally Invasive Recording and Stimulation

Adele Fanelli

EPFL2022

Fabrication and validation of an intraneural interface tailored for optic nerve stimulation

Eleonora Borda

EPFL2022

Analysis of Anticipation Related Potentials for Brain Computer Interaction

Gangadhar Garipelli

EPFL2011