We Three: My Brain, My Homunculus, and Me

An unconscious sense of the body in all higher mammals is located in somatosensory and motor cortices, colloquially referred to as the Homunculus (H). The time has arrived to consider how H might engage in the dimensions of selfhood that go beyond embodiment. Surely, the neural network modules that process various dimensions of selfhood must at least access and interact with the H or a stored memory of it. In this review, I suggest that our traditional understanding of H is much too simplistic. This review specifies a set of experimental approaches that should enlarge our understanding of the brain mechanisms of selfhood

NMDA attenuates the neurovascular response to hypercapnia in the neonatal cerebral cortex

Cortical spreading depolarization (SD) involves activation of NMDA receptors and elicit neurovascular unit dysfunction. NMDA cannot trigger SD in newborns, thus its effect on neurovascular function is not confounded by other aspects of SD. The present study investigated if NMDA affected hypercapnia-induced microvascular and electrophysiological responses in the cerebral cortex of newborn pigs. Anesthetized piglets were fitted with cranial windows over the parietal cortex to study hemodynamic and electrophysiological responses to graded hypercapnia before/after topically applied NMDA assessed with laser-speckle contrast imaging and recording of local field potentials (LFP)/neuronal firing, respectively. NMDA increased cortical blood flow (CoBF), suppressed LFP power in most frequency bands but evoked a 2.5 Hz delta oscillation. The CoBF response to hypercapnia was abolished after NMDA and the hypercapnia-induced biphasic changes in delta and theta LFP power were also altered. MK-801 prevented NMDA-induced increases in CoBF and the attenuation of microvascular reactivity to hypercapnia. The neuronal nitric oxide synthase (nNOS) inhibitor (N-(4 S)-4-amino-5-[aminoethyl] aminopentyl-N'-nitroguanidin) also significantly preserved the CoBF response to hypercapnia after NMDA, although it didn't reduce NMDA-induced increases in CoBF. In conclusion, excess activation of NMDA receptors alone can elicit SD-like neurovascular unit dysfunction involving nNOS activity

Building And Validating Next-Generation Neurodevices Using Novel Materials, Fabrication, And Analytic Strategies

Technologies that enable scientists to record and modulate neural activity across spatial scales are advancing the way that neurological disorders are diagnosed and treated, and fueling breakthroughs in our fundamental understanding of brain function. Despite the rapid pace of technology development, significant challenges remain in realizing safe, stable, and functional interfaces between manmade electronics and soft biological tissues. Additionally, technologies that employ multimodal methods to interrogate brain function across temporal and spatial scales, from single cells to large networks, offer insights beyond what is possible with electrical monitoring alone. However, the tools and methodologies to enable these studies are still in their infancy. Recently, carbon nanomaterials have shown great promise to improve performance and multimodal capabilities of bioelectronic interfaces through their unique optical and electronic properties, flexibility, biocompatibility, and nanoscale topology. Unfortunately, their translation beyond the lab has lagged due to a lack of scalable assembly methods for incorporating such nanomaterials into functional devices. In this thesis, I leverage carbon nanomaterials to address several key limitations in the field of bioelectronic interfaces and establish scalable fabrication methods to enable their translation beyond the lab. First, I demonstrate the value of transparent, flexible electronics by analyzing simultaneous optical and electrical recordings of brain activity at the microscale using custom-fabricated graphene electronics. Second, I leverage a recently discovered 2D nanomaterial, Ti3C2 MXene, to improve the capabilities and performance of neural microelectronic devices. Third, I fabricate and validate human-scale Ti3C2 MXene epidermal electrode arrays in clinical applications. Leveraging the unique solution-processability of Ti3C2 MXene, I establish novel fabrication methods for both high-resolution microelectrode arrays and macroscale epidermal electrode arrays that are scalable and sufficiently cost-effective to allow translation of MXene bioelectronics beyond the lab and into clinical use. Thetechnologies and methodologies developed in this thesis advance bioelectronic technology for both research and clinical applications, with the goal of improving patient quality of life and illuminating complex brain dynamics across spatial scales

Carbon Fiber Electrode Arrays for Cortical and Peripheral Neural Interfaces

Neural interfaces create a connection between neural structures in the body and external electronic devices. Brain-machine interfaces and bioelectric medicine therapies rely on the seamless integration of neural interfaces with the brain, nerves, or spinal cord. However, conventional neural interfaces cannot meet the demands of high channel count, signal fidelity, and signal longevity that these applications require. I investigated the damage resulting from conventional Utah arrays after multiple years of implantation in the cortex of a non-human primate as a possible explanation for these limitations. The neuron density around the electrode shanks was compared to the neuron density of nearby healthy tissue, finding a 73% loss in density around the electrodes. The explanted arrays were imaged and characterized for degradation. Coating cracks, tip breakage, and parylene cracks were the most common degradation type. A significantly higher number of tip breakage and coating crack occurrences were found on the edges of the arrays as compared to the middle. In this work, I made clear the need for a minimally damaging alternative to the Utah electrode array. Neural interfaces composed of carbon fiber electrodes, with a diameter of 6.8 microns, could enable a seamless integration with the body. Previous work resulted in an array of individuated carbon fiber electrodes that reliably recorded high signal-to-noise ratio neural signals from the brain for months. However, the carbon fiber arrays were limited by only 30% of the electrodes recording neural signals, despite inducing minimal inflammation. Additionally, it was relatively unknown if carbon fibers would make suitable long-term peripheral neural interfaces. Here, I illustrate the potential of carbon fiber electrodes to meet the needs of a variety of neural applications. First, I optimized state-of-the-art carbon fiber electrodes to reliably record single unit electrophysiology from the brain. By analyzing the previous manufacturing process, the cause of the low recording yield of the carbon fiber arrays was identified as the consistency of the electrode tip. A novel laser cutting technique was developed to produce a consistent carbon fiber tip geometry, resulting in a near tripling of recording yield of high amplitude chronic neural signals. The longevity of the carbon fiber arrays was also addressed. The conventional polymer coating was compared against platinum iridium coating and an oxygen plasma treatment, both of which outperformed the polymer coating. In this work, I customized carbon fiber electrodes for reliable, long-term neural recording. Secondly, I translated the carbon fiber technology from the brain to the periphery in an architecture appropriate for chronic implantation. The insertion of carbon fibers into the stiffer structures in the periphery is enabled by sharpening the carbon fibers. The sharpening process combines a butane flame to sharpen the fibers with a water bath to protect the base of the array. Sharpened carbon fiber arrays recorded electrophysiology from the rat vagus nerve and feline dorsal root ganglia, both structures being important targets for bioelectric medicine therapies. The durability of carbon fibers was also displayed when partially embedded carbon fibers in medical-grade silicone withstood thousands of repeated bends without fracture. This work showed that carbon fibers have the electrical and structural properties necessary for chronic application. Overall, this work highlights the vast potential of carbon fiber electrodes. Through this thesis, future brain-machine interfaces and bioelectric medicine therapies may utilize arrays of sub-cellular electrodes such as carbon fibers in medical applications.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/169982/1/elissajw_1.pd

Variability of head tissues’ conductivities and their impact in electrical brain activity research

The presented thesis endeavoured to establish the impact that the variability in electrical conductivity of human head tissues has on electrical brain imaging research, particularly transcranial direct current stimulation (tDCS) and electroencephalography (EEG). A systematic meta-analysis was firstly conducted to determine the consistency of reported measurements, revealing significant deviations in electrical conductivity measurements predominantly for the scalp, skull, GM, and WM. Found to be of particular importance was the variability of skull conductivity, which consists of multiple layers and bone compositions, each with differing conductivity. Moreover, the conductivity of the skull was suggested to decline with participant age and hypothesised to correspondingly impact tDCS induced fields. As expected, the propositioned decline in the equivalent (homogeneous) skull conductivity as a function of age resulted in reduced tDCS fields. A further EEG analysis also revealed, neglecting the presence of adult sutures and deviation in proportion of spongiform and compact bone distribution throughout the skull, ensued significant errors in EEG forward and inverse solutions. Thus, incorporating geometrically accurate and precise volume conductors of the skull was considered as essential for EEG forward analysis and source localisation and tDCS application. This was an overarching conclusion of the presented thesis. Individualised head models, particularly of the skull, accounting for participant age, the presence of sutures and deviation in bone composition distribution are imperative for electrical brain imaging. Additionally, it was shown that in vivo, individualised measurements of skull conductivity are further required to fully understand the relationship between conductivity and participant demographics, suture closure, bone compositions, skull thickness and additional factors