Wireless Simultaneous Stimulation-and-Recording Device (SRD) to Train Cortical Circuits in Rat Somatosensory Cortex

The primary goal of this project is to develop a wireless system for simultaneous recording-and-stimulation (SRD) to deliver low amplitude current pulses to the primary somatosensory cortex (SI) of rats to activate and enhance an interhemispheric cortical pathway. Despite the existence of an interhemispheric connection between similar forelimb representations of SI cortices, forelimb cortical neurons respond only to input from the contralateral (opposite side) forelimb and not to input from the ipsilateral (same side) forelimb. Given the existence of this interhemispheric pathway we have been able to strengthen/enhance the pathway through chronic intracortical microstimulation (ICMS) in previous acute experiments of anesthetized rats. In these acute experiments strengthening the interhemispheric pathway also brings about functional reorganization whereby cortical neurons in forelimb cortex respond to new input from the ipsilateral forelimb. Having the ability to modify cortical circuitry will have important applications in stroke patients and could serve to rescue and/or enhance responsiveness in surviving cells around the stroke region. Also, the ability to induce functional reorganization within the deafferented cortical map, which follows limb amputation, will also provide a vehicle for modulating maladaptive cortical reorganization often associated with phantom limb pain leading to reduced pain. In order to increase our understanding of the observed functional reorganization and enhanced pathway, we need to be able to test these observations in awake and behaving animals and eventually study how these changes persist over a prolonged period of time. To accomplish this a system was needed to allow simultaneous recording and stimulation in awake rats. However, no such commercial or research system exists that meets all requirements for such an experiment. In this project we describe the (1) system design, (2) system testing, (3) system evaluation, and (4) system implementation of a wireless simultaneous stimulation-and-recording device (SRD) to be used to modulate cortical circuits in an awake rodent animal model

A power efficient time-to-current stimulator for vagal-cardiac connection after heart transplantation

This paper presents a stimulator for a cardiac neuroprosthesis aiming to restore the parasympathetic control after heart transplantation. The stimulator is based on time-to-current conversion, instead of the conventional current mode digital-to-analog converter (DAC) that drives the output current mirrors. It uses a DAC based on capacitor charging to drive a power efficient voltage-to-current converter for output. The stimulator uses 1.8 V for system operation and 10 V for stimulation. The total power consumption is Istim × 10 V +18. u μW during the biphasic current output, with a maximum Istim of 512 μA. The stimulator was designed in CMOS 0.18 μm technology and post-layout simulations are presented

Closed-loop approaches for innovative neuroprostheses

The goal of this thesis is to study new ways to interact with the nervous system in case of damage or pathology. In particular, I focused my effort towards the development of innovative, closed-loop stimulation protocols in various scenarios: in vitro, ex vivo, in vivo

Intermittent Theta Burst Stimulation: Application to Spinal Cord Injury Rehabilitation and Computational Modeling

Loss of motor function from spinal cord injuries (SCI) results in loss of independence. Rehabilitation efforts are targeted to enhance the ability to perform activities of daily living (ADLs), but outcomes from physical therapy alone are often insufficient. Neuromodulation techniques that induce neuroplasticity may push the limits on recovery. Neuromodulation by intermittent theta burst transcranial magnetic stimulation (iTBS) induces neuroplasticity by increasing corticomotor excitability, though this has most frequently been studied with motor targets and on individuals not in need of rehabilitation. Increased corticomotor excitability is associated with motor learning. The response to iTBS, however, is highly variable and unpredictable, while the mechanisms are not well understood. Studies have proposed brain anatomy and individual subject differences as a source of variability but have not quantified the effects. Existing models have not incorporated known neurotransmitter changes at the synaptic level to pair mechanisms to cell output in a neural circuit. To use iTBS in practical rehabilitative efforts, the technique must either be consistent, have a predictable responsiveness, or present with enough mechanistic understanding to improve its efficacy. To that effect, this study has two primary objectives for the improvement of rehabilitation techniques. The first is to establish how iTBS affects both a motor target and population that typically undergoes physical rehabilitation often with unsatisfactory outcomes, in this case the biceps brachii in individuals with SCI and relate the empirical effects of iTBS to individual anatomy. This will establish the consistency of the technique and predictability of its effects, relevant to rehabilitative efforts. The secondary objective is to create the foundation of a model that exhibits circuit organization, which would start the development of a motor neuroplasticity functional unit with simulation of the synaptic long-term potentiation (LTP) like effects of iTBS. Summary of Methods: iTBS was performed targeting the biceps, on multiple cohorts, with changes in motor evoked potential amplitude (MEP) tracked after sham and active intervention. This was compared between nonimpaired individuals and those with SCI. Furthermore, iTBS of both biceps and first dorsal interosseus (FDI) was compared to simulation of TMS on MRI derived head models to establish the impact of individualized neuroanatomy. Finally, a motor canonical neural circuit was programmed to display fundamental physiological spiking behavior of membrane potentials. Summary of Results: iTBS did facilitate corticomotor excitability in the biceps of nonimpaired individuals and in those with SCI. iTBS had no group-wide effect on the FDI, highlighting the variability in response to the protocol. TMS response (motor thresholds) and iTBS response (change in MEPs) both were related to parameters extracted from MRI-derived head models representing variations in individual neuroanatomy. The neural circuit model represents a canonical networked unit. In the future, this can be further tuned to exhibit biological variability and generate population-based values being run in parallel, while matching the understood mechanisms of neuroplasticity: disinhibition and LTP. Conclusion: These studies provide missing information of iTBS responsivity by (1) determining group-wide responsiveness in a clinically relevant target; (2) establishing individual level influences that affect responsivity which can be measured prior to iTBS; and (3) beginning design of a tool to test a single neural circuit and its mechanistic responses

Tactile Modulation of the Sensory and Cortical Responses Elicited by Focal Cooling in Humans and Mice

Distinct sensory receptors transduce thermal and mechanical energies, but we have unified, coherent thermotactile experiences of the objects we touch. These experiences must emerge from the interaction of thermal and tactile signals within the nervous system. How do thermal and mechanical signals modify each other as they interact along the pathway from skin to conscious experience? In this thesis, we study how mechanical touch modulates cooling responses by combining psychophysics in humans and neural recordings in rodents. For this, we developed a novel stimulator to deliver focal, temperature-controlled cooling without touch. First, we used this method to study in humans the sensitivity to focal cooling with and without touch. We found that touch reduces the sensitivity to near-threshold cooling, which is perhaps analogous to the well-established ‘gating’ of pain by touch. Second, we studied the perceived intensity of cooling with and without touch. We found that tactile input enhances the perceived intensity of cooling. Third, we measured the responses of the mouse primary somatosensory cortex to cooling and mechanical stimuli using imaging and electrophysiological methods. We found multisensory stimuli elicited non-linear cortical responses at both the population and cellular level. Altogether, in this thesis, we show perceptual and cortical responses to non-tactile cooling for the first time. Based on our observations, we propose a new model to explain the interactions between cooling and mechanical signals in the nervous system. This thesis advances our understanding of how touch modulates cold sensations during thermotactile stimulation

Recent Progress of Development of Optogenetic Implantable Neural Probes

As a cell type-specific neuromodulation method, optogenetic technique holds remarkable potential for the realisation of advanced neuroprostheses. By genetically expressing light-sensitive proteins such as channelrhodopsin-2 (ChR2) in cell membranes, targeted neurons could be controlled by light. This new neuromodulation technique could then be applied into extensive brain networks and be utilised to provide effective therapies for neurological disorders. However, the development of novel optogenetic implants is still a key challenge in the field. The major requirements include small device dimensions, suitable spatial resolution, high safety, and strong controllability. In this paper, I present a concise review of the significant progress that has been made towards achieving a miniaturised, multifunctional, intelligent optogenetic implant. I identify the key limitations of current technologies and discuss the possible opportunities for future development

Advances in Scalable Implantable Systems for Neurostimulation Using Networked ASICs

Neurostimulation is a known method for restoring lost functions to neurologically impaired patients. This paper describes recent advances in scalable implantable stimulation systems using networked application specific integrated circuits (ASICs). It discusses how they can meet the ever-growing demand for high-density neural interfacing and long-term reliability. A detailed design example of an implantable (inductively linked) scalable stimulation system for restoring lower limb functions in paraplegics after spinal cord injury is presented. It comprises a central hub implanted at the costal margin and multiple Active Books which provide the interface for stimulating nerve roots in the cauda equina. A 16-channel stimulation system using four Active Books is demonstrated. Each Active Book has an embedded ASIC, which is responsible for initiating stimulus current to the electrodes. It also ensures device safety by monitoring temperature, humidity, and peak electrode voltage during stimulation. The implant hub was implemented using a microcontroller-based circuit. The ASIC in the Active Book was fabricated using XFAB’s 0.6-µm high-voltage CMOS process. The stimulation system does not require an accurate reference clock in the implant. Measured results are provided

Transcranial magnetic stimulation to the occipital place area biases gaze during scene viewing

We can understand viewed scenes and extract task-relevant information within a few hundred milliseconds. This process is generally supported by three cortical regions that show selectivity for scene images: parahippocampal place area (PPA), medial place area (MPA) and occipital place area (OPA). Prior studies have focused on the visual information each region is responsive to, usually within the context of recognition or navigation. Here, we move beyond these tasks to investigate gaze allocation during scene viewing. Eye movements rely on a scene’s visual representation to direct saccades, and thus foveal vision. In particular, we focus on the contribution of OPA, which is i) located in occipito-parietal cortex, likely feeding information into parts of the dorsal pathway critical for eye movements, and ii) contains strong retinotopic representations of the contralateral visual field. Participants viewed scene images for 1034 ms while their eye movements were recorded. On half of the trials, a 500 ms train of five transcranial magnetic stimulation (TMS) pulses was applied to the participant’s cortex, starting at scene onset. TMS was applied to the right hemisphere over either OPA or the occipital face area (OFA), which also exhibits a contralateral visual field bias but shows selectivity for face stimuli. Participants generally made an overall left-to-right, top-to-bottom pattern of eye movements across all conditions. When TMS was applied to OPA, there was an increased saccade latency for eye movements toward the contralateral relative to the ipsilateral visual field after the final TMS pulse (400ms). Additionally, TMS to the OPA biased fixation positions away from the contralateral side of the scene compared to the control condition, while the OFA group showed no such effect. There was no effect on horizontal saccade amplitudes. These combined results suggest that OPA might serve to represent local scene information that can then be utilized by visuomotor control networks to guide gaze allocation in natural scenes

Biointegrated and wirelessly powered implantable brain devices: a review

Implantable neural interfacing devices have added significantly to neural engineering by introducing the low-frequency oscillations of small populations of neurons known as local field potential as well as high-frequency action potentials of individual neurons. Regardless of the astounding progression as of late, conventional neural modulating system is still incapable to achieve the desired chronic in vivo implantation. The real constraint emerges from mechanical and physical diffierences between implants and brain tissue that initiates an inflammatory reaction and glial scar formation that reduces the recording and stimulation quality. Furthermore, traditional strategies consisting of rigid and tethered neural devices cause substantial tissue damage and impede the natural behaviour of an animal, thus hindering chronic in vivo measurements. Therefore, enabling fully implantable neural devices, requires biocompatibility, wireless power/data capability, biointegration using thin and flexible electronics, and chronic recording properties. This paper reviews biocompatibility and design approaches for developing biointegrated and wirelessly powered implantable neural devices in animals aimed at long-term neural interfacing and outlines current challenges toward developing the next generation of implantable neural devices