Focal, remote-controlled, chronic chemical modulation of brain microstructures

Direct delivery of fluid to brain parenchyma is critical in both research and clinical settings. This is usually accomplished through acutely inserted cannulas. This technique, however, results in backflow and significant dispersion away from the infusion site, offering little spatial or temporal control in delivering fluid. We present an implantable, MRI-compatible, remotely controlled drug delivery system for minimally invasive interfacing with brain microstructures in freely moving animals. We show that infusions through acutely inserted needles target a region more than twofold larger than that of identical infusions through chronically implanted probes due to reflux and backflow. We characterize the dynamics of in vivo infusions using positron emission tomography techniques. Volumes as small as 167 nL of copper-64 and fludeoxyglucose labeled agents are quantified. We further demonstrate the importance of precise drug volume dosing to neural structures to elicit behavioral effects reliably. Selective modulation of the substantia nigra, a critical node in basal ganglia circuitry, via muscimol infusion induces behavioral changes in a volume-dependent manner, even when the total dose remains constant. Chronic device viability is confirmed up to 1-y implantation in rats. This technology could potentially enable precise investigation of neurological disease pathology in preclinical models, and more efficacious treatment in human patients. Keywords: brain; drug delivery; substantia nigra; neural implant; PETNational Institutes of Health (U.S.) (Grant R01 EB016101)National Institute of Biomedical Imaging and Bioengineering (U.S.) (Grant R01 EB016101)National Cancer Institute (U.S.) (Grant P30-CA14051

Robust penetrating microelectrodes for neural interfaces realized by titanium micromachining

Neural prosthetic interfaces based upon penetrating microelectrode devices have broadened our understanding of the brain and have shown promise for restoring neurological functions lost to disease, stroke, or injury. However, the eventual viability of such devices for use in the treatment of neurological dysfunction may be ultimately constrained by the intrinsic brittleness of silicon, the material most commonly used for manufacture of penetrating microelectrodes. This brittleness creates predisposition for catastrophic fracture, which may adversely affect the reliability and safety of such devices, due to potential for fragmentation within the brain. Herein, we report the development of titanium-based penetrating microelectrodes that seek to address this potential future limitation. Titanium provides advantage relative to silicon due to its superior fracture toughness, which affords potential for creation of robust devices that are resistant to catastrophic failure. Realization of these devices is enabled by recently developed techniques which provide opportunity for fabrication of high-aspect-ratio micromechanical structures in bulk titanium substrates. Details are presented regarding the design, fabrication, mechanical testing, in vitro functional characterization, and preliminary in vivo testing of devices intended for acute recording in rat auditory cortex and thalamus, both independently and simultaneously

Penetration force measurements in the central nervous system with silicon electrodes

One of the major challenges in neural engineering is the tissue damage that occurs during insertion of microelectrodes into the central nervous system. The damage occurs as a result of the dimpling effect that is due to the insertion force. A method which can reduce the penetration force can also reduce dimpling and the resulting tissue damage. There are two objectives in this thesis. One is to measure the penetration force with Michigan electrodes, which are silicon based electrodes. The second is to reduce the penetration force by using mechanical vibrations. First, the penetration force was measured in the rat brain. To measure the penetration force, the microelectrode was connected to a load transducer. Because dura is a tough membrane to penetrate, it is usually removed during surgery in experimental animals. The dura mater was not removed in these experiments in order to keep the intactness of the cortex. The microelectrode was pulsed at a rate of 5 Hz using a piezoelectric crystal and a pulse generator. The results show that the vibration technique is successful in reducing the penetration force by 25%. In this study, we have concentrated only on reducing the penetration force in order to reduce dimpling. To our best knowledge no work has been yet reported on the use of vibrations for reducing electrode penetration force. Chronic experiments will have to be conducted to investigate if the vibrations alone cause any tissue damage

Hand-Tool-Tissue Interaction Forces in Neurosurgery for Haptic Rendering

Haptics provides sensory stimuli that represent the interaction with a virtual or telemanipulated object, and it is considered a valuable navigation and manipulation tool during tele-operated surgical procedures. Haptic feedback can be provided to the user via cutaneous information and kinesthetic feedback. Sensory subtraction removes the kinesthetic component of the haptic feedback, having only the cutaneous component provided to the user. Such a technique guarantees a stable haptic feedback loop, while it keeps the transparency of the tele-operation system high, which means that the system faithfully replicates and render back the user's directives. This work focuses on checking whether the interaction forces during a bench model neurosurgery operation can lie in the solely cutaneous perception of the human finger pads. If this assumption is found true, it would be possible to exploit sensory subtraction techniques for providing surgeons with feedback from neurosurgery. We measured the forces exerted to surgical tools by three neurosurgeons performing typical actions on a brain phantom, using contact force sensors, whilst the forces exerted by the tools to the phantom tissue were recorded using a load cell placed under the brain phantom box. The measured surgeon-tool contact forces were 0.01 - 3.49 N for the thumb and 0.01 - 6.6 N for index and middle finger, whereas the measured tool- tissue interaction forces were from six to eleven times smaller than the contact forces, i.e., 0.01 - 0.59 N. The measurements for the contact forces fit the range of the cutaneous sensitivity for the human finger pad, thus, we can say that, in a tele-operated robotic neurosurgery scenario, it would possible to render forces at the fingertip level by conveying haptic cues solely through the cutaneous channel of the surgeon's finger pads. This approach would allow high transparenc

Parylene Based Flexible Multifunctional Biomedical Probes And Their Applications

MEMS (Micro Electro Mechanical System) based flexible devices have been studied for decades, and they are rapidly being incorporated into modern society in various forms such as flexible electronics and wearable devices. Especially in neuroscience, flexible interfaces provide tremendous possibilities and opportunities to produce reliable, scalable and biocompatible instruments for better exploring neurotransmission and neurological disorders. Of all the types of biomedical instruments such as electroencephalography (EEG) and electrocorticography (ECoG), MEMS-based needle-shape probes have been actively studied in recent years due to their better spatial resolution, selectivity, and sensitivity in chronical invasive physiology monitoring. In order to address the inherent issue of invasiveness that causes tissue damage, research has been made on biocompatible materials, implanting methods and probe structural design. In this dissertation, different types of microfabricated probes for various applications are reviewed. General methods for some key fabrication steps include photolithography patterning, chemical vapor deposition, metal deposition and dry etching are covered in detail. Likewise, three major achievements, which aim to the tagets of flexibility, functionality and mechanical property are introduced and described in detail from chapter 3 to 5. The essential fabrication processes based on XeF2 isotropic silicon etching and parylene conformal deposition are covered in detail, and a set of characterization is summarized

Parylene Based Flexible Multifunctional Biomedical Probes And Their Applications

MEMS (Micro Electro Mechanical System) based flexible devices have been studied for decades, and they are rapidly being incorporated into modern society in various forms such as flexible electronics and wearable devices. Especially in neuroscience, flexible interfaces provide tremendous possibilities and opportunities to produce reliable, scalable and biocompatible instruments for better exploring neurotransmission and neurological disorders. Of all the types of biomedical instruments such as electroencephalography (EEG) and electrocorticography (ECoG), MEMS-based needle-shape probes have been actively studied in recent years due to their better spatial resolution, selectivity, and sensitivity in chronical invasive physiology monitoring. In order to address the inherent issue of invasiveness that causes tissue damage, research has been made on biocompatible materials, implanting methods and probe structural design. In this dissertation, different types of microfabricated probes for various applications are reviewed. General methods for some key fabrication steps include photolithography patterning, chemical vapor deposition, metal deposition and dry etching are covered in detail. Likewise, three major achievements, which aim to the tagets of flexibility, functionality and mechanical property are introduced and described in detail from chapter 3 to 5. The essential fabrication processes based on XeF2 isotropic silicon etching and parylene conformal deposition are covered in detail, and a set of characterization is summarized