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- Creators: Arizona State University
- Creators: Santello, Marco
Description
Neurostimulation methods currently include deep brain stimulation (DBS), optogenetic, transcranial direct-current stimulation (tDCS), and transcranial magnetic stimulation (TMS). TMS and tDCS are noninvasive techniques whereas DBS and optogenetic require surgical implantation of electrodes or light emitting devices. All approaches, except for optogenetic, have been implemented in clinical settings because they have demonstrated therapeutic utility and clinical efficacy for neurological and psychiatric disorders. When applied for therapeutic applications, these techniques suffer from limitations that hinder the progression of its intended use to treat compromised brain function. DBS requires an invasive surgical procedure that surfaces complications from infection, longevity of electrical components, and immune responses to foreign materials. Both TMS and tDCS circumvent the problems seen with DBS as they are noninvasive procedures, but they fail to produce the spatial resolution required to target specific brain structures. Realizing these restrictions, we sought out to use ultrasound as a neurostimulation modality. Ultrasound is capable of achieving greater resolution than TMS and tDCS, as we have demonstrated a ~2mm lateral resolution, which can be delivered noninvasively. These characteristics place ultrasound superior to current neurostimulation methods. For these reasons, this dissertation provides a developed protocol to use transcranial pulsed ultrasound (TPU) as a neurostimulation technique. These investigations implement electrophysiological, optophysiological, immunohistological, and behavioral methods to elucidate the effects of ultrasound on the central nervous system and raise questions about the functional consequences. Intriguingly, we showed that TPU was also capable of stimulating intact sub-cortical circuits in the anesthetized mouse. These data reveal that TPU can evoke synchronous oscillations in the hippocampus in addition to increasing expression of brain-derived neurotrophic factor (BDNF). Considering these observations, and the ability to noninvasively stimulate neuronal activity on a mesoscale resolution, reveals a potential avenue to be effective in clinical settings where current brain stimulation techniques have shown to be beneficial. Thus, the results explained by this dissertation help to pronounce the significance for these protocols to gain translational recognition.
ContributorsTufail, Yusuf Zahid (Author) / Tyler, William J (Thesis advisor) / Duch, Carsten (Committee member) / Muthuswamy, Jitendran (Committee member) / Santello, Marco (Committee member) / Tillery, Stephen H (Committee member) / Arizona State University (Publisher)
Created2011
Description
The object of this study is to charac terize the effect of focused ultrasound stimulation (FUS) on the rat ce rvix which has been observed to speed its ripening during pregnancy. Ce rvical ripening is required for successful fetal delivery. Timed-pregnant Sprague-Dawley rats (n=36) were used. On day 14 of gestation, the FUS system was placed on the body surface of the rat over the cervix and ultrasound energy was applied to cervix for variable times up to 1 hour in the control group, the FUS system was placed on rats but no energy was applied. Daily measurement of cervix light-induced florescence (LIF, photon counts of collagen x-bridge fluorescence) were made on days 16 of gestation and daily until spont-aneous delivery (day22) to estimate changes in cervical ripening. We found that pulses of 680 KHz ultrasound at 25 Hertz, 1 millisecond pulse duration at 1W/cm^2 applied for as little as 30 minutes would immediately afterwards show the cervix to hav e ripened to the degree seen just before delivery on day 22. Delivery times, fetal weights and viability were unaffected in the FUS-treated animals.
ContributorsLuo, Daishen (Author) / Towe, Bruce C (Thesis advisor) / Wang, Xiao (Committee member) / Caplan, Michael (Committee member) / Arizona State University (Publisher)
Created2012
Description
Neural tissue is a delicate system comprised of neurons and their synapses, glial cells for support, and vasculature for oxygen and nutrient delivery. This complexity ultimately gives rise to the human brain, a system researchers have become increasingly interested in replicating for artificial intelligence purposes. Some have even gone so far as to use neuronal cultures as computing hardware, but utilizing an environment closer to a living brain means having to grapple with the same issues faced by clinicians and researchers trying to treat brain disorders. Most outstanding among these are the problems that arise with invasive interfaces. Optical techniques that use fluorescent dyes and proteins have emerged as a solution for noninvasive imaging with single-cell resolution in vitro and in vivo, but feeding in information in the form of neuromodulation still requires implanted electrodes. The implantation process of these electrodes damages nearby neurons and their connections, causes hemorrhaging, and leads to scarring and gliosis that diminish efficacy. Here, a new approach for noninvasive neuromodulation with high spatial precision is described. It makes use of a combination of ultrasound, high frequency acoustic energy that can be focused to submillimeter regions at significant depths, and electric fields, an effective tool for neuromodulation that lacks spatial precision when used in a noninvasive manner. The hypothesis is that, when combined in a specific manner, these will lead to nonlinear effects at neuronal membranes that cause cells only in the region of overlap to be stimulated. Computational modeling confirmed this combination to be uniquely stimulating, contingent on certain physical effects of ultrasound on cell membranes. Subsequent in vitro experiments led to inconclusive results, however, leaving the door open for future experimentation with modified configurations and approaches. The specific combination explored here is also not the only untested technique that may achieve a similar goal.
ContributorsNester, Elliot (Author) / Wang, Yalin (Thesis advisor) / Muthuswamy, Jitendran (Committee member) / Towe, Bruce (Committee member) / Arizona State University (Publisher)
Created2022
Description
The blood-brain-barrier (BBB) is a significant obstacle for treating many neurological disorders. Bubble-assisted focused ultrasound (BAFUS) medicated BBB disruption is a promising technology that enables the delivery of large drug doses at targeted locations across the BBB. However, the current lack of an in vitro model of this process hinders the full understanding of BAFUS BBB disruption for better translation into clinics. In this work, a US-transparent organ-on-chip device has been fabricated that can be critical for the in vitro modeling of the BAFUS BBB disruption. The transparency of the device window to focused ultrasound (FUS) was calculated theoretically and demonstrated by experiments. Nanobubbles were fabricated, characterized by cryogenic transmission electron microscopy (cryo-TEM), and showed bubble cavitation under FUS. Human colorectal adenocarcinoma (Caco-2) cells were used to form a good cellular barrier for BAFUS barrier disruption, as suggested by the measured permeability and transepithelial electrical resistance (TEER). Finally, barrier disruption and recovery were observed in BAFUS disrupted US-transparent organ-on-chips with Caco-2 barriers, showing great promise of the platform for future modeling BAFUS BBB disruption in vitro.
ContributorsAkkad, Adam Rifat (Author) / Gu, Jian (Thesis advisor) / Nikkhah, Mehdi (Thesis advisor) / Belohlavek, Marek (Committee member) / Wang, Xiao (Committee member) / Arizona State University (Publisher)
Created2022
Description
The field of non-invasive neurostimulation techniques offer promising avenues for the treatment of various neurological and psychiatric disorders such as Parkinson's disease, migraines, chronic pain, and epilepsy. The proposed work is a novel technique for the production of high-end ultrasonic forces by interaction of gigahertz electromagnetic radiations for the purpose of neural modulation. These ultrasonic forces are created in dielectric materials such as cell membranes by the electrostrive effect, providing a potential new neurotherapeutic technique. The ability for this technique to provide neurostimulatory effects was investigated using in vitro studies of neuronal cultures and in vivo studies on sciatic nerves. Direct exposure of E18 rat cortical neurons to these EM radiations demonstrated changes in cellular membrane potential, suggesting effects could be potentially similar to direct electrical stimulation. An exploration of neuromodulatory effects to rat sciatic nerves indicates exposure produces changes to peak-to-peak muscular response. These findings suggest promising results for this new potential neuromodulation modality.
ContributorsDagher, Michael Jonathan (Author) / Muthuswamy, Jitendran (Thesis advisor) / Towe, Bruce (Committee member) / Sridharan, Arati (Committee member) / Aberle, James (Committee member) / Arizona State University (Publisher)
Created2023
Description
Bioimpedance measurements have been long used for monitoring tissue ischemia and blood flow. This research employs implantable microelectronic devices to measure impedance chronically as a potential way to monitor the progress of peripheral vascular disease (PVD). Ultrasonically powered implantable microdevices previously developed for the purposes of neuroelectric vasodilation for therapeutic treatment of PVD were found to also allow a secondary function of tissue bioimpedance monitoring. Having no structural differences between devices used for neurostimulation and impedance measurements, there is a potential for double functionality and closed loop control of the neurostimulation performed by these types of microimplants. The proposed technique involves actuation of the implantable microdevices using a frequency-swept amplitude modulated continuous waveform ultrasound and remote monitoring of induced tissue current. The design has been investigated using simulations, ex vivo testing, and preliminary animal experiments. Obtained results have demonstrated the ability of ultrasonically powered neurostimulators to be sensitive to the impedance changes of tissue surrounding the device and wirelessly report impedance spectra. Present work suggests the potential feasibility of wireless tissue impedance measurements for PVD applications as a complement to neurostimulation.
ContributorsCelinskis, Dmitrijs (Author) / Towe, Bruce (Thesis advisor) / Greger, Bradley (Committee member) / Sadleir, Rosalind (Committee member) / Arizona State University (Publisher)
Created2015
Description
There is a strong medical need and important therapeutic applications for improved wireless bioelectric interfaces to the nervous system. Multichannel devices are desired for neural control of robotic prosthetics that interface to remaining nerves in limb stumps of amputees and as alternatives to traditional wired arrays used in for some types of brain stimulation. This present work investigates a new approach to ultrasound-powering of implantable microelectronic devices within the tissue that may better support such applications. These devices are of ultra-miniature size that is enabled by a wireless technique. This study investigates two types of ultrasound-powered neural interfaces for multichannel sensory feedback in neurostimulation. The piezoceramics lead zirconate titanate (PZT) ceramic and polyvinylidene fluoride (PVDF) polymer were the primary materials used to build the devices. They convert ultrasound to electricity that when rectified by a diode produce a current output that is neuro stimulatory to peripheral nerve or the neurons in the brain. Multichannel devices employ a form of spatial multiplexing that directs focused ultrasound towards localized and segmented regions of PVDF or PZT that allows independent channels of nerve actuation. Different frequencies of ultrasound were evaluated for best results. Firstly, a 2.25 MHz frequency signal that is reasonably penetrating through body tissue to an implant several centimeters deep and also a 5 MHz frequency more suited to application for actuation of devices within a less than a centimeter of nerve. Results show multichannel device performance to have a complex inter-relationship with frequency, size and thickness, angular incidence, channel separations, and number of folds (layers connected in series and parallel). The output electrical port impedances of PVDF devices were examined in relationship to that of stimulating electrodes and tissue interfaces. Miniature multichannel devices were constructed using an unreported method of employing state of the art laser cutting systems. The results show that PVDF based devices have advantages over PZT, because of better acoustic coupling with tissue, known better biocompatibility, and better separation between multiple channels. However, the PZT devices proved to be better overall in terms of compactness and higher outputs for a given ultrasound power level.
ContributorsNanda Kumar, Yashwanth (Author) / Towe, Bruce (Thesis advisor) / Muthuswamy, Jitendran (Committee member) / Nikkhah, Mehdi (Committee member) / Arizona State University (Publisher)
Created2015
Description
Noninvasive neuromodulation could help treat many neurological disorders, but existing techniques have low resolution and weak penetration. Ultrasound (US) shows promise for stimulation of smaller areas and subcortical structures. However, the mechanism and parameter design are not understood. US can stimulate tail and hindlimb movements in rats, but not forelimb, for unknown reasons. Potentially, US could also stimulate peripheral or enteric neurons for control of blood glucose.
To better understand the inconsistent effects across rat motor cortex, US modulation of electrically-evoked movements was tested. A stimulation array was implanted on the cortical surface and US (200 kHz, 30-60 W/cm2 peak) was applied while measuring changes in the evoked forelimb and hindlimb movements. Direct US stimulation of the hindlimb was also studied. To test peripheral effects, rat blood glucose levels were measured while applying US near the liver.
No short-term motor modulation was visible (95% confidence interval: -3.5% to +5.1% forelimb, -3.8% to +5.5% hindlimb). There was significant long-term (minutes-order) suppression (95% confidence interval: -3.7% to -10.8% forelimb, -3.8% to -11.9% hindlimb). This suppression may be due to the considerable heating (+1.8°C between US
on-US conditions); effects of heat and US were not separable in this experiment. US directly evoked hindlimb and scrotum movements in some sessions. This required a long interval, at least 3 seconds between US bursts. Movement could be evoked with much shorter pulses than used in literature (3 ms). The EMG latency (10 ms) was compatible with activation of corticospinal neurons. The glucose modulation test showed a strong increase in a few trials, but across all trials found no significant effect.
The single motor response and the long refractory period together suggest that only the beginning of the US burst had a stimulatory effect. This would explain the lack of short-term modulation, and suggests future work with shorter pulses could better explore the missing forelimb response. During the refractory period there was no change in the electrically-evoked response, which suggests the US stimulation mechanism is independent of normal brain activity. These results challenge the literature-standard protocols and provide new insights on the unknown mechanism.
To better understand the inconsistent effects across rat motor cortex, US modulation of electrically-evoked movements was tested. A stimulation array was implanted on the cortical surface and US (200 kHz, 30-60 W/cm2 peak) was applied while measuring changes in the evoked forelimb and hindlimb movements. Direct US stimulation of the hindlimb was also studied. To test peripheral effects, rat blood glucose levels were measured while applying US near the liver.
No short-term motor modulation was visible (95% confidence interval: -3.5% to +5.1% forelimb, -3.8% to +5.5% hindlimb). There was significant long-term (minutes-order) suppression (95% confidence interval: -3.7% to -10.8% forelimb, -3.8% to -11.9% hindlimb). This suppression may be due to the considerable heating (+1.8°C between US
on-US conditions); effects of heat and US were not separable in this experiment. US directly evoked hindlimb and scrotum movements in some sessions. This required a long interval, at least 3 seconds between US bursts. Movement could be evoked with much shorter pulses than used in literature (3 ms). The EMG latency (10 ms) was compatible with activation of corticospinal neurons. The glucose modulation test showed a strong increase in a few trials, but across all trials found no significant effect.
The single motor response and the long refractory period together suggest that only the beginning of the US burst had a stimulatory effect. This would explain the lack of short-term modulation, and suggests future work with shorter pulses could better explore the missing forelimb response. During the refractory period there was no change in the electrically-evoked response, which suggests the US stimulation mechanism is independent of normal brain activity. These results challenge the literature-standard protocols and provide new insights on the unknown mechanism.
ContributorsGulick, Daniel Withers (Author) / Kleim, Jeffrey (Thesis advisor) / Towe, Bruce (Thesis advisor) / Muthuswamy, Jitendran (Committee member) / Herman, Richard (Committee member) / Helms Tillery, Steven (Committee member) / Arizona State University (Publisher)
Created2015
Description
Peripheral Vascular Disease (PVD) is a debilitating chronic disease of the lower extremities particularly affecting older adults and diabetics. It results in reduction of the blood flow to peripheral tissue and sometimes causing tissue damage such that PVD patients suffer from pain in the lower legs, thigh and buttocks after activities. Electrical neurostimulation based on the "Gate Theory of Pain" is a known to way to reduce pain but current devices to do this are bulky and not well suited to implantation in peripheral tissues. There is also an increased risk associated with surgery which limits the use of these devices. This research has designed and constructed wireless ultrasound powered microstimulators that are much smaller and injectable and so involve less implantation trauma. These devices are small enough to fit through an 18 gauge syringe needle increasing their potential for clinical use. These piezoelectric microdevices convert mechanical energy into electrical energy that then is used to block pain. The design and performance of these miniaturized devices was modeled by computer while constructed devices were evaluated in animal experiments. The devices are capable of producing 500ms pulses with an intensity of 2 mA into a 2 kilo-ohms load. Using the rat as an animal model, a series of experiments were conducted to evaluate the in-vivo performance of the devices.
ContributorsZong, Xi (Author) / Towe, Bruce (Thesis advisor) / Kleim, Jeffrey (Committee member) / Santello, Marco (Committee member) / Arizona State University (Publisher)
Created2014
Description
The application of novel visualization and modeling methods to the study of cardiovascular disease is vital to the development of innovative diagnostic techniques, including those that may aid in the early detection and prevention of cardiovascular disorders. This dissertation focuses on the application of particle image velocimetry (PIV) to the study of intracardiac hemodynamics. This is accomplished primarily though the use of ultrasound based PIV, which allows for in vivo visualization of intracardiac flow without the requirement for optical access, as is required with traditional camera-based PIV methods.
The fundamentals of ultrasound PIV are introduced, including experimental methods for its implementation as well as a discussion on estimating and mitigating measurement error. Ultrasound PIV is then compared to optical PIV; this is a highly developed technique with proven accuracy; through rigorous examination it has become the “gold standard” of two-dimensional flow visualization. Results show good agreement between the two methods.
Using a mechanical left heart model, a multi-plane ultrasound PIV technique is introduced and applied to quantify a complex, three-dimensional flow that is analogous to the left intraventricular flow. Changes in ventricular flow dynamics due to the rotational orientation of mechanical heart valves are studied; the results demonstrate the importance of multi-plane imaging techniques when trying to assess the strongly three-dimensional intraventricular flow.
The potential use of ultrasound PIV as an early diagnosis technique is demonstrated through the development of a novel elasticity estimation technique. A finite element analysis routine is couple with an ensemble Kalman filter to allow for the estimation of material elasticity using forcing and displacement data derived from PIV. Results demonstrate that it is possible to estimate elasticity using forcing data derived from a PIV vector field, provided vector density is sufficient.
The fundamentals of ultrasound PIV are introduced, including experimental methods for its implementation as well as a discussion on estimating and mitigating measurement error. Ultrasound PIV is then compared to optical PIV; this is a highly developed technique with proven accuracy; through rigorous examination it has become the “gold standard” of two-dimensional flow visualization. Results show good agreement between the two methods.
Using a mechanical left heart model, a multi-plane ultrasound PIV technique is introduced and applied to quantify a complex, three-dimensional flow that is analogous to the left intraventricular flow. Changes in ventricular flow dynamics due to the rotational orientation of mechanical heart valves are studied; the results demonstrate the importance of multi-plane imaging techniques when trying to assess the strongly three-dimensional intraventricular flow.
The potential use of ultrasound PIV as an early diagnosis technique is demonstrated through the development of a novel elasticity estimation technique. A finite element analysis routine is couple with an ensemble Kalman filter to allow for the estimation of material elasticity using forcing and displacement data derived from PIV. Results demonstrate that it is possible to estimate elasticity using forcing data derived from a PIV vector field, provided vector density is sufficient.
ContributorsWesterdale, John Curtis (Author) / Adrian, Ronald (Thesis advisor) / Belohlavek, Marek (Committee member) / Squires, Kyle (Committee member) / Trimble, Steve (Committee member) / Frakes, David (Committee member) / Arizona State University (Publisher)
Created2015