107 research outputs found

    Induction of a torpor-like hypothermic and hypometabolic state in rodents by ultrasound

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    Torpor is an energy-conserving state in which animals dramatically decrease their metabolic rate and body temperature to survive harsh environmental conditions. Here, we report the noninvasive, precise and safe induction of a torpor-like hypothermic and hypometabolic state in rodents by remote transcranial ultrasound stimulation at the hypothalamus preoptic area (POA). We achieve a long-lasting (\u3e24 h) torpor-like state in mice via closed-loop feedback control of ultrasound stimulation with automated detection of body temperature. Ultrasound-induced hypothermia and hypometabolism (UIH) is triggered by activation of POA neurons, involves the dorsomedial hypothalamus as a downstream brain region and subsequent inhibition of thermogenic brown adipose tissue. Single-nucleus RNA-sequencing of POA neurons reveals TRPM2 as an ultrasound-sensitive ion channel, the knockdown of which suppresses UIH. We also demonstrate that UIH is feasible in a non-torpid animal, the rat. Our findings establish UIH as a promising technology for the noninvasive and safe induction of a torpor-like state

    Ultrasound Technologies for Imaging and Modulating Neural Activity

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    Visualizing and perturbing neural activity on a brain-wide scale in model animals and humans is a major goal of neuroscience technology development. Established electrical and optical techniques typically break down at this scale due to inherent physical limitations. In contrast, ultrasound readily permeates the brain, and in some cases the skull, and interacts with tissue with a fundamental resolution on the order of 100 μm and 1 ms. This basic ability has motivated major efforts to harness ultrasound as a modality for large-scale brain imaging and modulation. These efforts have resulted in already-useful neuroscience tools, including high-resolution hemodynamic functional imaging, focused ultrasound neuromodulation, and local drug delivery. Furthermore, recent breakthroughs promise to connect ultrasound to neurons at the genetic level for biomolecular imaging and sonogenetic control. In this article, we review the state of the art and ongoing developments in ultrasonic neurotechnology, building from fundamental principles to current utility, open questions, and future potential

    Ultrasound Technologies for Imaging and Modulating Neural Activity

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    Visualizing and perturbing neural activity on a brain-wide scale in model animals and humans is a major goal of neuroscience technology development. Established electrical and optical techniques typically break down at this scale due to inherent physical limitations. In contrast, ultrasound readily permeates the brain, and in some cases the skull, and interacts with tissue with a fundamental resolution on the order of 100 μm and 1 ms. This basic ability has motivated major efforts to harness ultrasound as a modality for large-scale brain imaging and modulation. These efforts have resulted in already-useful neuroscience tools, including high-resolution hemodynamic functional imaging, focused ultrasound neuromodulation, and local drug delivery. Furthermore, recent breakthroughs promise to connect ultrasound to neurons at the genetic level for biomolecular imaging and sonogenetic control. In this article, we review the state of the art and ongoing developments in ultrasonic neurotechnology, building from fundamental principles to current utility, open questions, and future potential

    Focused ultrasound excites neurons via mechanosensitive calcium accumulation and ion channel amplification

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    Ultrasonic neuromodulation has the unique potential to provide non-invasive control of neural activity in deep brain regions with high spatial precision and without chemical or genetic modification. However, the biomolecular and cellular mechanisms by which focused ultrasound excites mammalian neurons have remained unclear, posing significant challenges for the use of this technology in research and potential clinical applications. Here, we show that focused ultrasound excites neurons through a primarily mechanical mechanism mediated by specific calcium-selective mechanosensitive ion channels. The activation of these channels results in a gradual build-up of calcium, which is amplified by calcium- and voltage-gated channels, generating a burst firing response. Cavitation, temperature changes, large-scale deformation, and synaptic transmission are not required for this excitation to occur. Pharmacological and genetic inhibition of specific ion channels leads to reduced responses to ultrasound, while over-expressing these channels results in stronger ultrasonic stimulation. These findings provide a critical missing explanation for the effect of ultrasound on neurons and facilitate the further development of ultrasonic neuromodulation and sonogenetics as unique tools for neuroscience research

    Effect of low-intensity transcranial ultrasound stimulation on theta and gamma oscillations in the mouse hippocampal CA1

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    Previous studies have demonstrated that low-intensity transcranial ultrasound stimulation (TUS) can eliminate hippocampal neural activity. However, until now, it has remained unclear how ultrasound modulates theta and gamma oscillations in the hippocampus under different behavioral states. In this study, we used ultrasound to stimulate the CA1 in mice in anesthesia, awake and running states, and we simultaneously recorded the local field potential of the stimulation location. We analyzed the power spectrum, phase-amplitude coupling (PAC) of theta and gamma oscillations, and their relationship with ultrasound intensity. The results showed that (i) TUS significantly enhanced the absolute power of theta and gamma oscillations under anesthesia and in the awake state. (ii) The PAC strength between theta and gamma oscillations is significantly enhanced under the anesthesia and awake states but is weakened under the running state with TUS. (iii) Under anesthesia, the relative power of theta decreases and that of gamma increases as ultrasound intensity increases, and the result under the awake state is opposite that under the anesthesia state. (iv) The PAC index between theta and gamma increases as ultrasound intensity increases under the anesthesia and awake states. The above results demonstrate that TUS can modulate theta and gamma oscillations in the CA1 and that the modulation effect depends on behavioral states. Our study provides guidance for the application of ultrasound in modulating hippocampal function

    Review of photoacoustic imaging plus X

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    Photoacoustic imaging (PAI) is a novel modality in biomedical imaging technology that combines the rich optical contrast with the deep penetration of ultrasound. To date, PAI technology has found applications in various biomedical fields. In this review, we present an overview of the emerging research frontiers on PAI plus other advanced technologies, named as PAI plus X, which includes but not limited to PAI plus treatment, PAI plus new circuits design, PAI plus accurate positioning system, PAI plus fast scanning systems, PAI plus novel ultrasound sensors, PAI plus advanced laser sources, PAI plus deep learning, and PAI plus other imaging modalities. We will discuss each technology's current state, technical advantages, and prospects for application, reported mostly in recent three years. Lastly, we discuss and summarize the challenges and potential future work in PAI plus X area

    Mechanism of transcranial focused ultrasound regulating the neuronal activity of the retrosplenial cortex

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    Non-invasive neuromodulation is crucial in fundamental research and clinical treatment. Among those non-invasive neuromodulations, transcranial focused ultrasound (tFUS) can penetrate the skull to focus energy on a specific brain region, temporarily affecting brain function. Compared with traditional neuromodulation methods, such as transcranial direct current stimulation and transcranial magnetic stimulation, tFUS has become a novel method for regulating neuronal activity by means of its non-invasion, reversibility, and accuracy. However, how tFUS regulates neuronal activity and cellular properties in response to tFUS remains unknown. To investigate how tFUS regulates neuronal activity, I used behavioural tests, real-time fluorescence quantitative polymerase chain reaction, immunofluorescent staining, chemical genetics, and multi-channel in vivo recording to explore whether tFUS affected neuronal activity in the pain-related brain region, retrosplenial cortex (RSC). Moreover, tFUS significantly increased paw withdrawal threshold (PWT) and prolonged thermal withdrawal latency (TWL) both in naïve and neuropathic mice. tFUS also significantly increased mRNA and protein expression levels of early growth factor response 1 (Egr1). These tFUS-activated Egr1 cells were mainly neurons. Through multi-channel in vivo recording, it was found that the spike rate of pyramidal neurons and interneurons decreased remarkably under tFUS. A greater proportion of spike rate in pyramidal neurons and interneurons showed a decrease rather than an Subsequently, Egr1 positive cells activated by tFUS were specifically inhibited by the targeted recombination in the active population system (TRAP), and then the effect of tFUS on PWT and TWL was inhibited. These results suggested that Egr1 was an essential marker of tFUS responsive neurons in RSC. Subsequently, I performed transcriptome sequencing based on Egr1-GFP cells activated by tFUS. Transient receptor potential cation channel subfamily C member 4 (Trpc4) was selected according to the transcriptome sequencing data. Combined with calcium imaging, patch-clamp recording, and short hairpin ribonucleic acid (shRNA) interference, it was found that tFUS could activate Trpc4, which could be blocked by ML204, an inhibitor of Trpc4. In vivo, with specific inhibition of Trpc4 expression in RSC, the proportion of decreased neuronal activity induced by tFUS was significantly down-regulated. At the same time, the regulation of PWT and TWL by tFUS was also inhibited. The above results showed that Trpc4 was an important factor in regulating Egr1 response to tFUS, thus regulating RSC and further regulating the somatosensory threshold of mice. To further explore the characteristics of tFUS responsive cells, I used single-cell RNA sequencing (scRNA-seq) to map the single-cell transcriptome expression of RSC. It was also identified tFUS-induced cell type-dependent transcriptome and functional changes in RSC. Subsequently, Egr1 was used as a marker to identify tFUS-activated cell types and populations. Then, it was found that Egr1 was highly expressed in neurons, endothelial cells (EC), and vascular smooth muscle cells (vSMC). These cells acted as tFUS-sensitive cells. Further analysis of cellular communication pathways between tFUS-sensitive cells and other cells revealed multiple signal pathways, which suggested that tFUS- sensitive cells received or transmitted information to other cell types, causing changes in the transcriptome. In conclusion, this study found that Trpc4 was a key factor regulating Egr1 response to tFUS. In addition, it provided transcriptome expression atlas and cellular communication pathways of tFUS-sensitive cells by scRNA-seq. These results provided a basis for the cellular and molecular mechanisms of tFUS neuromodulation, which supported ultrasonic neuromodulation in basic neuroscience research and clinical applications

    Pulsed Transcranial Ultrasound Stimulation and Its Applications in Treatment of Focal Cerebral Ischemia and Depression

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    The aims of this thesis were to investigate the therapeutic effects of pulsed transcranial ultrasound stimulation (pTUS) on focal cerebral ischemia and depression, respectively, in rodent models. Neurological and psychiatric disorders, such as Parkinson's disease, epilepsy, Alzheimer's disease, stroke (vascular disorder that results in neurological defects), depression, and etc., present an increasing challenge and a substantial social and economic burden for an aging and stressed population. However, conventional treatments, especially pharmacologic interventions, have significant limitations, such as nonspecific effects, insufficient tailoring to the individual, adverse effects such as drowsiness, weight gain and nausea, or inadequate uptake into the brain due to the blood-brain-barrier (BBB). In contrast, neuromodulation techniques have gained more attention, which are able to enhance or inhibit the neural activities in specific cortex, such as motor, somatosensory or other areas related to cognition. Neuromodulation thus could potentially restore the disrupted neural network due to neurological disorders. Capitalizing on its noninvasiveness, high precision (in the scale of mm) and penetration depth (several centimeters), low-intensity (typically <1 W/cm2 spatial-peak-pulse-average intensity-ISPTA) low-frequency (typically <1MHz), pulsed transcranial ultrasound stimulation (pTUS) has been emerging as a promising therapeutic tool for neurological and psychiatric disorders. This thesis provided the first in-vivo demonstrations that pTUS might serve as neuroprotective preconditioning of ischemic brain injury and treatment of depression. Additionally, it also proposed a novel optical imaging-based technique to characterize the neuromodulatory effect of pTUS, which facilitates the parameter optimization of therapeutic pTUS in practice. Both suppressive and excitatory pTUS are applied in this thesis. The corresponding pTUS parameters were: (a) suppressive pTUS (or pTUSS): ISPPA = 8W/cm2, frequency (f) = 0.5 MHz, pulse repetition frequency (PRF) = 100 Hz, and duty cycle (DC) =5%, and (b) excitatory pTUS (or pTUSE): ISPPA = 8W/cm2, f = 0.5MHz, PRF = 1.5 kHz, and DC = 60%, respectively. Before the therapeutic experiments, the neuromodulatory effects of both pTUSS and pTUSE were examined using laser speckle imaging(LSCI) and multispectral reflectance imaging (MSRI) in aspect of the neurovascular responses. Specifically, this thesis consists of: (1) Study on the neurovascular response to pTUS. Compared with other methods, such as pTUS-triggered motor response and visual evoked potentials (VEP), optical imaging allows to measure the neurovascular change at high spatiotemporal resolution (in the scale of μm and ms), including cortical suppression without evoked output. LSCI and MSRI were used to monitor the primary somatosensory response (Chapter 2) to hind limb electrical stimulation before, immediately, and 1 h after 5-min application of pTUSS and pTUSE, respectively. Several indicators, including Response Index, Peak Response, Latency and Response Duration, were derived from optical images to characterize the neuromodulatory effects of pTUS on primary somatosensory cortex. Our results showed that pTUSS could suppress the primary somatosensory cortex across all rats whereas pTUSE only presented excitatory effects in 5 out of 11 rats. The neuromodulatory effects of pTUS were correlated with the baseline cortical excitability. The results showed that: (i) pTUSs could serve in investigating cognitive function by silencing the neurons in the target region; (ii) pTUSE exposure should be treated with caution due to individual differences in neuromodulatory effects, which were associated with the initial brain state of rats; and (iii) optical imaging was useful in evaluating the pTUS neuromodulatory effects. (2) Neuroprotection of preconditioning pTUS. By applying suppressive pTUS, it was investigated whether the severity of stroke could be minimized or alleviated by prior exposure to ultrasound stimulation (Chapter 3). Preconditioning was supposed to increase the tolerance of brain to subsequent ischemic insult. It can potentially be used to prevent the perioperative stroke in patients undergoing cardiovascular surgeries with a series of complications. Considering the noninvasiveness and safety of ultrasound, pTUS may provide a novel preconditioning method. To test the effectiveness of preconditioning pTUS, rats were randomly assigned to control (n=12) and preconditioning pTUS (pTUS-PC) groups (n=14). The pTUS-PC animals received ultrasound stimulation before the induction of photothrombotic stroke, whereas control animals were handled identically except the ultrasound stimulation. The cerebral blood flow was monitored using LSCI in both groups during stroke induction, as well as 24 hours and 48 hours after stroke, respectively. Also, infarct volumes and edema were measured at 48 hours after euthanatizing the rats. Results showed that pTUS-PC rats had smaller ischemic volume during stroke induction, as well as 24 hours and 48 hours after the stroke than the controls. Moreover, the pTUS-PC group showed lower volume of brain edema than the control group. (3) Antidepressant-like effect by pTUS. The potential antidepressant-like effects of pTUS were further investigated in a rat model of depression with excitatory pTUS. Stimulating the left prefrontal cortex (PFC) by TMS has been clinically used for depression treatment, it was thus hypothesize that pTUSE on PFC would act similarly with TMS and result in antidepressant-like effect. To test this hypothesis, pTUS was applied for 2 weeks daily to the left PFC of depressed rats induced by 48-hour restraint. The long-term (3 weeks) efficacy of the depression model as well as the antidepressant-like effects of pTUS were investigated with a group of behavioral tests. In addition, the hippocampal BDNF was measured by western blot to study the mechanisms underlying antidepressant-like effects of pTUS. The safety of long-term (2 weeks) pTUS was assessed by histologic analysis. Results showed that 48-hour-restraint stress could stably lead to at least 3-week reduction of exploratory behavior and protracted anhedonia, whereas pTUSE treatment could successfully reverse the depression-like phenotypes and promote the BDNF expression in the left hippocampus. In addition, H& E staining of brain tissues confirmed the safety of the long-term pTUS treatment. In conclusion, the results in this work suggested that pTUS could serve as preconditioning of perioperative stroke and therapeutics for depression. Additionally, the results also demonstrated that optical neurovascular imaging could measure the neuromodulatory effect of pTUS. This study documented more evidence that pTUS is a promising tool for basic neuroscience and therapeutic applications. KEY WORDS: Neurological and psychiatric disorders, brain stimulation, pulsed ultrasound stimulation, neurovascular imaging, preconditioning, stroke, depression.Ph.D., Biomedical Engineering -- Drexel University, 201

    Time-reversed ultrasonically encoded (TRUE) focusing for deep-tissue optogenetic modulation

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    The problem of optical scattering was long thought to fundamentally limit the depth at which light could be focused through turbid media such as fog or biological tissue. However, recent work in the field of wavefront shaping has demonstrated that by properly shaping the input light field, light can be noninvasively focused to desired locations deep inside scattering media. This has led to the development of several new techniques which have the potential to enhance the capabilities of existing optical tools in biomedicine. Unfortunately, extending these methods to living tissue has a number of challenges related to the requirements for noninvasive guidestar operation, speed, and focusing fidelity. Of existing wavefront shaping methods, time-reversed ultrasonically encoded (TRUE) focusing is well suited for applications in living tissue since it uses ultrasound as a guidestar which enables noninvasive operation and provides compatibility with optical phase conjugation for high-speed operation. In this paper, we will discuss the results of our recent work to apply TRUE focusing for optogenetic modulation, which enables enhanced optogenetic stimulation deep in tissue with a 4-fold spatial resolution improvement in 800-micron thick acute brain slices compared to conventional focusing, and summarize future directions to further extend the impact of wavefront shaping technologies in biomedicine
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