Optogenetic Brain Interfaces

The brain is a large network of interconnected neurons where each cell functions as a nonlinear processing element. Unraveling the mysteries of information processing in the complex networks of the brain requires versatile neurostimulation and imaging techniques. Optogenetics is a new stimulation method which allows the activity of neurons to be modulated by light. For this purpose, the cell-types of interest are genetically targeted to produce light-sensitive proteins. Once these proteins are expressed, neural activity can be controlled by exposing the cells to light of appropriate wavelengths. Optogenetics provides a unique combination of features, including multimodal control over neural function and genetic targeting of specific cell-types. Together, these versatile features combine to a powerful experimental approach, suitable for the study of the circuitry of psychiatric and neurological disorders. The advent of optogenetics was followed by extensive research aimed to produce new lines of light-sensitive proteins and to develop new technologies: for example, to control the distribution of light inside the brain tissue or to combine optogenetics with other modalities including electrophysiology, electrocorticography, nonlinear microscopy, and functional magnetic resonance imaging. In this paper, the authors review some of the recent advances in the field of optogenetics and related technologies and provide their vision for the future of the field.United States. Defense Advanced Research Projects Agency (Space and Naval Warfare Systems Center, Pacific Grant/Contract No. N66001-12-C-4025)University of Wisconsin--Madison (Research growth initiative; grant 101X254)University of Wisconsin--Madison (Research growth initiative; grant 101X172)University of Wisconsin--Madison (Research growth initiative; grant 101X213)National Science Foundation (U.S.) (MRSEC DMR-0819762)National Science Foundation (U.S.) (NSF CAREER CBET-1253890)National Institutes of Health (U.S.) (NIH/NIBIB R00 Award (4R00EB008738)National Institutes of Health (U.S.) (NIH Director’s New Innovator award (1-DP2-OD002989))Okawa Foundation (Research Grant Award)National Institutes of Health (U.S.) (NIH Director’s New Innovator Award (1DP2OD007265))National Science Foundation (U.S.) (NSF CAREER Award (1056008)Alfred P. Sloan Foundation (Fellowship)Human Frontier Science Program (Strasbourg, France) (Grant No. 1351/12)Israeli Centers of Research Excellence (I-CORE grant, program 51/11)MINERVA Foundation (Germany

Central nervous system microstimulation: Towards selective micro-neuromodulation

Electrical stimulation technologies capable of modulating neural activity are well established for neuroscientific research and neurotherapeutics. Recent micro-neuromodulation experimental results continue to explain neural processing complexity and suggest the potential for assistive technologies capable of restoring or repairing of basic function. Nonetheless, performance is dependent upon the specificity of the stimulation. Increasingly specific stimulation is hypothesized to be achieved by progressively smaller interfaces. Miniaturization is a current focus of neural implants due to improvements in mitigation of the body's foreign body response. It is likely that these exciting technologies will offer the promise to provide large-scale micro-neuromodulation in the future. Here, we highlight recent successes of assistive technologies through bidirectional neuroprostheses currently being used to repair or restore basic brain functionality. Furthermore, we introduce recent neuromodulation technologies that might improve the effectiveness of these neuroprosthetic interfaces by increasing their chronic stability and microstimulation specificity. We suggest a vision where the natural progression of innovative technologies and scientific knowledge enables the ability to selectively micro-neuromodulate every neuron in the brain

Novel Tools to Investigate Cortical Activity in Paroxysmal Disorders

This PhD project is at the interface between academic research and industry, and is jointly sponsored by the BBSRC and the industrial partner– Scientifica UK. The goal of this research is the development of new instruments and approaches to monitor and manipulate neuronal network activity in disease states. Firstly, (I) I collaborated with Scientifica to develop and utilise the newly developed Laser Applied Stimulation and Uncaging (LASU) system. The combined usage of the LASU system, alongside novel spatially-targeted channelrhodopsin variants, has al- lowed me to test the limits of single-photon optogenetic stimulation in achieving specific activation of targeted neurons. The presented findings demonstrate that, al- though high-resolution stimulation is achievable in the rodent cortex, single-photon stimulation is insufficient to achieve single-cell resolution stimulation. Secondly, (II) I have combined the high temporal resolution of novel, transparent 16-channel epicortical graphene solution-gated field effect transistor (gSGFET) arrays with the large spatial coverage of bilateral widefield Ca2+ fluorescence imaging; to per- form investigations of the relationship between spreading depolarisation (SD) and cortical seizures in awake head-fixed mouse models of epilepsy. To analyse these complex datasets, I developed a bespoke, semi-automated analysis pipeline to pro- cess the data and probe the seizure-SD relationship. I present the advantages of this dual-modality approach by demonstrating the strengths and weaknesses of each recording method, and how a synergistic approach overcomes the limitations of each technique alone. I utilise widefield imaging to perform systematic classification of SD and seizures both temporally and spatially. Detailed electrophysiological anal- ysis of gSGFET data is then performed on extracted time periods of interest. This work demonstrates the complex interaction between seizures and SD, and proposes several mechanisms describing these interactions. The technological and analytical tools presented here lay the groundwork for insightful and flexible experimental paradigms; altogether, able to probe paroxysmal activity in profound detail

Doctor of Philosophy

dissertationRecording the neural activity of human subjects is indispensable for fundamental neuroscience research and clinical applications. Human studies range from examining the neural activity of large regions of the cortex using electroencephalography (EEG) or electrocorticography (ECoG) to single neurons or small populations of neurons using microelectrode arrays. In this dissertation, microscale recordings in the human cortex were analyzed during administration of propofol anesthesia and articulate movements such as speech, finger flexion, and arm reach. Recordings were performed on epilepsy patients who required long-term electrocorticographic monitoring and were implanted with penetrating or surface microelectrode arrays. We used penetrating microelectrode arrays to investigate the effects of propofol anesthesia on action potentials (APs) and local field potentials (LFPs). Increased propofol concentration correlated with decreased high-frequency power in LFP spectra and decreased AP firing rates, as well as the generation of large amplitude spike-like LFP activity; however, the temporal relationship between APs and LFPs remained relatively consistent at all levels of propofol anesthesia. The propofol-induced suppression of neocortical network activity allowed LFPs to be dominated by low-frequency spike-like activity, and correlated with sedation and unconsciousness. As the low-frequency spike-like activity increased, and the AP-LFP relationship became more predictable, firing rate encoding capacity was impaired. This suggests a mechanism for decreased information processing in the neocortex that accounts for propofol-induced unconsciousness. We also demonstrated that speech, finger, and arm movements can be decoded from LFPs recorded with dense grids of microelectrodes placed on the surface of human cerebral cortex for brain computer interface (BCI) applications using LFPs recorded over face-motor area, vocalized articulations of ten different words and silence were classified on a trial-by-trial basis with 82.4% accuracy. Using LFPs recorded over the hand area of motor cortex, three individual finger movements and rest were classified on a trial-by-trial basis with 62% accuracy. LFPs recorded over the arm area of motor cortex were used to continuously decode the arm trajectory with a maximum correlation coefficient of 0.82 in the x-direction and 0.76 in the y-direction. These findings demonstrate that LFPs recorded by micro-ECoG grids from the surface of the cerebral cortex contain sufficient information to provide rapid and intuitive control a BCI communication or motor prosthesis

Conformable transistors for bioelectronics

The diversity of network disruptions that occur in patients with neuropsychiatric disorders creates a strong demand for personalized medicine. Such approaches often take the form of implantable bioelectronic devices that are capable of monitoring pathophysiological activity for identifying biomarkers to allow for local and responsive delivery of intervention. They are also required to transmit this data outside of the body for evaluation of the treatment’s efficacy. However, the ability to perform these demanding electronic functions in the complex physiological environment with minimum disruption to the biological tissue remains a big challenge. An optimal fully implantable bioelectronic device would require each component from the front-end to the data transmission to be conformable and biocompatible. For this reason, organic material-based conformable electronics are ideal candidates for components of bioelectronic circuits due to their inherent flexibility, and soft nature. In this work, first an organic mixed-conducting particulate composite material (MCP) able to form functional electronic components and non-invasively acquire high–spatiotemporal resolution electrophysiological signals by directly interfacing human skin is presented. Secondly, we introduce organic electrochemical internal ion-gated transistors (IGTs) as a high-density, high-amplification sensing component as well as a low leakage, high-speed processing unit. Finally, a novel wireless, battery-free strategy for electrophysiological signal acquisition, processing, and transmission that employs IGTs and an ionic communication circuit (IC) is introduced. We show that the wirelessly-powered IGTs are able to acquire and modulate neurophysiological data in-vivo and transmit them transdermally, eliminating the need for any hard Si-based electronics in the implant

Advancing the interfacing performances of chronically implantable neural probes in the era of CMOS neuroelectronics

Tissue penetrating microelectrode neural probes can record electrophysiological brain signals at resolutions down to single neurons, making them invaluable tools for neuroscience research and Brain-Computer-Interfaces (BCIs). The known gradual decrease of their electrical interfacing performances in chronic settings, however, remains a major challenge. A key factor leading to such decay is Foreign Body Reaction (FBR), which is the cascade of biological responses that occurs in the brain in the presence of a tissue damaging artificial device. Interestingly, the recent adoption of Complementary Metal Oxide Semiconductor (CMOS) technology to realize implantable neural probes capable of monitoring hundreds to thousands of neurons simultaneously, may open new opportunities to face the FBR challenge. Indeed, this shift from passive Micro Electro-Mechanical Systems (MEMS) to active CMOS neural probe technologies creates important, yet unexplored, opportunities to tune probe features such as the mechanical properties of the probe, its layout, size, and surface physicochemical properties, to minimize tissue damage and consequently FBR. Here, we will first review relevant literature on FBR to provide a better understanding of the processes and sources underlying this tissue response. Methods to assess FBR will be described, including conventional approaches based on the imaging of biomarkers, and more recent transcriptomics technologies. Then, we will consider emerging opportunities offered by the features of CMOS probes. Finally, we will describe a prototypical neural probe that may meet the needs for advancing clinical BCIs, and we propose axial insertion force as a potential metric to assess the influence of probe features on acute tissue damage and to control the implantation procedure to minimize iatrogenic injury and subsequent FBR

Doctor of Philosophy

dissertationIntracortical microelectrode arrays create a direct interface between the brain and external devices. This “brain-machine interface” has found clinical application by allowing patients with tetraplegia to control computer cursors and robotic limbs. Unfortunately, use of intracortical microelectrode array technology is currently limited by its inconsistent ability to record neural signals over time. It is widely believed that the foreign body response (FBR) contributes to recording inconsistency. Most characterizations of the FBR to intracortical microelectrodes have been in the rat using devices with simple architecture, while the only device currently used in humans, the Utah Electrode Array (UEA), is much larger and more complex. In this work, we characterized the FBR to the UEA and found that, unlike with simpler devices, implantation of a UEA results in extensive vascular injury and loss of cortical tissue. We also sought to determine which features of the FBR correlated with recording inconsistency and found that biomarkers of astrogliosis, blood-brain barrier leakage, and tissue loss were associated with decreased recording performance. Next, since a significant portion of potential brain-machine interface recipients are aged, we applied similar methods in an aged cohort of rats in order to understand the effect of aging on the FBR and recording performance. We found that, surprisingly, recording performance was superior in the aged cohort. Astrogliosis was again associated with decreased recording performance in the aged cohort. Finally, we continued our development and validation of a finite element model of cytokine diffusion to assist in designing next-generation devices with a reduced FBR. Taken as a whole, this work provides meaningful insights into the mechanisms of inconsistent recording performance and discusses several promising avenues for overcoming them

Beta oscillations in frontal cortex and striatum represent post-processing of successful behavior

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2011.Cataloged from PDF version of thesis.Includes bibliographical references.Beta band (13-30 Hz) oscillations in sensorimotor cortex are associated with motor performance, but the nature of this relationship is not clear. Recently, excessive beta activity in cortico-basal ganglia circuits has been recognized as a hallmark of Parkinson's disease. Renewed interest in beta oscillations has since led to the suggestion that they might reflect the preservation of the current output or state of a given brain region. To investigate the potential role of beta activity in the brain, we recorded local field potentials in the frontal cortex and striatum of monkeys as they performed single and sequential arm movement tasks. To facilitate these experiments, we developed novel methods for recording simultaneously from independently moveable electrodes implanted chronically at over 100 sites in cortical and subcortical areas of the monkey brain. We found that, across tasks, beta oscillations occurred in brief, spatially localized bursts that were most prominent following task performance. Across brain regions, post-performance bursts were differentially modulated by the preceding task. In motor cortex they tracked the number of movements just performed. In contrast, striatal and prefrontal burst rates were proportional to the number of visual cues, or to a combination of the cues and movements, respectively, and were higher following correct, rewarded, trials than unrewarded errors. Pairs of striatal-prefrontal sites exhibited increased cross-covariance and coherence during post-trial beta bursts, suggesting that these bursts might be involved in communication or coordination across brain regions. Based on our results, we propose that beta oscillations may represent post-performance reinforcement of the network dynamics that led to the desired behavioral outcome obtained immediately prior.by Joseph Feingold.Ph.D

Investigating epileptiform activity associated with slow wave sleep

PhD ThesisThe characteristic EEG trait of patients with nocturnal idiopathic epilepsies during childhood is the spike and wave discharge. Cognitive dysfunction is prevalent among these patients and is thought to be linked to disturbances in memory consolidation processes that normally occur during slow wave sleep. Several genetic mutations of nicotinic receptor subunits have been linked to these disorders. However, there is little known about the underlying mechanisms or the spatiotemporal characteristics of this epileptiform activity within the neocortex. This thesis presents a rat in vitro model of the epileptiform activity synonymous with nocturnal childhood epilepsies, that allows for pharmacological manipulation of receptor subunits linked to these disorders. The application of DTC [10 M], a non-selective, competitive nicotinic acetylcholine receptor antagonist, to an in vitro model of the cortical delta rhythm induced two individual forms of paroxysm events - wave discharges and the conventional spike and wave discharges. Pharmacological manipulation of this model suggest that the epileptiform activity is mediated by excitatory currents which is consistent with the use of glutamate antagonists as anticonvulsants. A blanket blockade of inhibition by a GABAA antagonist resulted in severe discharges, hence hugely increasing excitatory response. Only partial disinhibition is suggested to be required to generate epileptiform activity as nicotinic acetylcholine receptors and 5-HT3 receptors are located on dendrite targeting interneurons. Mapping of unit activity revealed the di erence between the two paroxysm events was recruitment of super cial layers with simultaneous paroxysm events in delta frequency-generating Layer V pyramidal cells. It is proposed that the hyperexcitability responsible for the generation of the spike component of a spike and wave discharge is mediated by the lack of excitatory tone in 5-HT3 and nicotinic acetylecholine receptor expressing inhibitory interneuron subtypes. The disinhibition, spike generation and disruption of interplay between deep and super cial layers of the neocortex is thought to be associated with synaptic plastic changes

Novel Materials for Neural Interface Devices

Developments in materials science and engineering have significantly enhanced the recording and stimulation capabilities of electrophysiological neural interface devices. Enhanced biocompatibility has increased the viability and longevity of such systems, with particularly interesting advances resulting from the utilization of organic and mixed-conductive conjugated polymers. These materials tend to improve biocompatibility and signal quality by overcoming material limitations of conventional metallic electrodes. Simultaneously, advanced microfabrication methods have increased the spatiotemporal resolution and signal quality of recorded data without added invasiveness. The research work presented in this dissertation touches upon three aspects of relevance for improved neural interface use: i) improving the accuracy of histological verification procedures in research using naturally abundant organic materials; ii) introducing unconventional electrodes for neural recordings and localized drug delivery by utilizing conductive organic polymers and clinical supply items; iii) applying a high-density electrocorticography (ECoG) array to study differential neural oscillation patterns underlying memory processing in vivo. First, we showcase a chitosan (CS) based, solution-processable film for localizing neural implants by leveraging CSs intrinsic fluorescence, without impeding data quality or cell viability. Second, we develop a mixed-conductive suture by using standard silk sutures and the mixed-conductive polymer PEDOT:PSS. The resulting device (E-Suture) is shown to safely interface with live tissue and possess high-fidelity recording and stimulation capabilities as well as applicability for localized drug delivery thanks to the mixed-conductivity of PEDOT:PSS. Finally, we leverage high spatiotemporal resolution ECoG arrays to show that distinctive oscillatory memory biomarkers in the neocortex and hippocampus show significant but differential temporal coupling patterns in response to consolidation of new information and reconsolidation of that information at a later time in rats. This dissertation demonstrates the utility of different organic materials for the enhancement of neural interface functions at multiple phases of the device life cycle as well as a concrete demonstration of improved electrophysiological recording devices in answering key questions of foundational neuroscience