Integrated In Vivo Neural Imaging and Interface CMOS Devices: Design, Packaging, and Implementation

We have developed two CMOS devices to demonstrate the use of CMOS technology for neural imaging and interfacing with the aim of studying the functions of the brain at the molecular level. In this work, we discuss the design, packaging, and implementation of a compact, single device imaging system for imaging inside the mouse brain. We show that the device is capable of imaging and measuring fluorophore concentrations down to 1 mum . The packaged device was tested for in vivo fluorescence imaging by imaging the activity of serine protease in the mouse hippocampus. The result shows imaging of neural activity with spatial resolution close to the pixel size of 7.5 mum and less than 300 ms temporal resolution. A second device was developed to image neuronal network activity and to provide a means for electrical interfacing with neurons. Characterization tests show that the device has comparable performance to current tools used in electrophysiological experiments of the brain. This work paves the way for simultaneous imaging and electrophysiological experiments using a single compact and minimally invasive device in the future.     

An ultrahigh resolution SPECT system for I-125 mouse brain imaging studies

This paper presents some initial experimental results obtained with a dual-head prototype single photon emission microscope system (SPEM) that is dedicated to mouse brain studies using I-125 labeled radiotracers. In particular, this system will be used for in vivo tacking of radiolabeled T cells in mouse brain. This system is based on the use of the intensified electron multiplying charge-coupled device (I-EMCCD) camera that offers the combination of an excellent intrinsic spatial resolution, a good signal-to-noise ratio, a large active area and a reasonable detection efficiency over an energy range between 27–140 keV. In this study, the dual-head SPEM system was evaluated using both resolution phantoms and a mouse with locally injected T cells labeled with I-125. It was demonstrated that for a relatively concentrated source object, the current dual-head SPEM system is capable of visualizing the tiny amount of radioactivity (～12 nCi) carried by a very small number (<1000) of T cells. The current SPEM system design allows four or six camera heads to be installed in a stationary system configuration that offers a doubled or tripled sensitivity at a spatial resolution similar to that obtained with the dual-head system. This development would provide a powerful tool for in vivo and non-invasive tracking of radiolabeled T cells in mouse brain and potentially for other rodent brain imaging studies.     

A hybrid PET‐MRI: An integrated molecular‐genetic imaging system with HRRT‐PET and 7.0‐T MRI

A PET‐MRI fusion system is developed for molecular‐genetic imaging. The purpose of the system is to obtain images of the in‐vivo human brain using two high‐end imaging devices, an advanced PET and an ultrahigh‐field MRI. These are the HRRT‐PET, a high‐resolution research tomograph dedicated to brain imaging on the molecular level, and the 7.0‐T MRI, an ultrahigh field version used for morphological imaging. HRRT‐PET delivers high‐resolution molecular imaging with a resolution down to 2.5 mm FWHM, which is currently the highest spatial resolution available for the observation of the human brain's molecular activities, including enzymes and receptors, which are manipulated genetically, such as reporter genes and probes. The 7.0‐T MRI began to reveal submillimeter resolution images of the cortical as well as deep brain areas, down to 250 μm, which allows us to visualize the fine details of the cortical and brainstem areas, including the line of Gennari in the visual cortex and the corticospinal tracts in the pontine area. The current PET‐MRI fusion imaging system produces the highest quality images of molecular and genetic activities of the human brain in vivo. It is starting to provide many answers to the key questions about the neurological diseases. Some of these start providing answers to many cognitive neuroscience problems with clear molecular and genetic bases. There is great potential in the PET‐MRI for early diagnosis of cancers as well as other neurological diseases, which we were previously unable to diagnose, such as microscopic molecular changes that occur in Parkinson's and Alzheimer's diseases. © 2007 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 17, 252–265, 2007     

Atomic‐Precision Gold Clusters for NIR‐II Imaging

Near‐infrared II (NIR‐II) imaging at 1100–1700 nm shows great promise for medical diagnosis related to blood vessels because it possesses deep penetration and high resolution in biological tissue. Unfortunately, currently available NIR‐II fluorophores exhibit slow excretion and low brightness, which prevents their potential medical applications. An atomic‐precision gold (Au) cluster with 25 gold atoms and 18 peptide ligands is presented. The Au₂₅ clusters show emission at 1100–1350 nm and the fluorescence quantum yield is significantly increased by metal‐atom doping. Bright gold clusters can penetrate deep tissue and can be applied in in vivo brain vessel imaging and tumor metastasis. Time‐resolved brain blood‐flow imaging shows significant differences between healthy and injured mice with different brain diseases in vivo. High‐resolution imaging of cancer metastasis allows for the identification of the primary tumor, blood vessel, and lymphatic metastasis. In addition, gold clusters with NIR‐II fluorescence are used to monitor high‐resolution imaging of kidney at a depth of 0.61 cm, and the quantitative measurement shows 86% of the gold clusters are cleared from body without any acute or long‐term toxicity at a dose of 100 mg kg^?1.     

局部高空间分辨率的应用适应性PET系统设计初探

研制成本可负担的高空间分辨率正电子发射断层成像(positron emission tomography,PET)系统在PET成像应用中具有决定性的意义,也是PET成像面临的关键性挑战之一。设想一种PET系统,能够根据应用的需求对不同性能的探测器进行布局,在一个具体时刻,对部分成像区域获得很高的性能,而在其他的区域获得普通性能。提出了一种应用适应性PET系统原型,由大部分普通固有空间分辨率的探测模块和少量更高甚至极端高固有空间分辨率的探测模块组成。研究了在含有连续放置的一段高固有空间分辨率探测模块的PET系统中,高性能模块的布局位置和数量对视场内不同位置点的空间分辨率的影响。初步研究结果表明,所提出的系统能够为局部区域带来高空间分辨率,其空间分辨率提升程度与高性能模块布局位置有关,在同一高性能模块布局位置下,视场中不同位置点的提升程度不同。该研究结果也显示,根据应用需求规划探测模块的构成和布局以在感兴趣区域获得局部高空间分辨率是可能的。     

Diffuse optical tomography system to image brain activation with improved spatial resolution and validation with functional magnetic resonance imaging

Although most current diffuse optical brain imaging systems use only nearest- neighbor measurement geometry, the spatial resolution and quantitative accuracy of the imaging can be improved through the collection of overlapping sets of measurements. A continuous-wave diffuse optical imaging system that combines frequency encoding with time-division multiplexing to facilitate overlapping measurements of brain activation is described. Phantom measurements to confirm the expected improvement in spatial resolution and quantitative accuracy are presented. Experimental results showing the application of this instrument for imaging human brain activation are also presented. The observed improvement in spatial resolution is confirmed by functional magnetic resonance imaging.     

New Developments in Transmission Electron Microscopy for Nanotechnology

High‐resolution transmission electron microscopy (HRTEM) is one of the most powerful tools used for characterizing nanomaterials, and it is indispensable for nanotechnology. This paper reviews some of the most recent developments in electron microscopy techniques for characterizing nanomaterials. The review covers the following areas: in‐situ microscopy for studying dynamic shape transformation of nanocrystals; in‐situ nanoscale property measurements on the mechanical, electrical and field emission properties of nanotubes/nanowires; environmental microscopy for direct observation of surface reactions; aberration‐free angstrom‐resolution imaging of light elements (such as oxygen and lithium); high‐angle annular‐dark‐field scanning transmission electron microscopy (STEM); imaging of atom clusters with atomic resolution chemical information; electron holography of magnetic materials; and high‐spatial resolution electron energy‐loss spectroscopy (EELS) for nanoscale electronic and chemical analysis. It is demonstrated that the picometer‐scale science provided by HRTEM is the foundation of nanometer‐scale technology.     

Real‐Time and High‐Resolution Bioimaging with Bright Aggregation‐Induced Emission Dots in Short‐Wave Infrared Region

Fluorescence imaging in the spectral region beyond the conventional near‐infrared biological window (700–900 nm) can theoretically afford high resolution and deep tissue penetration. Although some efforts have been devoted to developing a short‐wave infrared (SWIR; 900–1700 nm) imaging modality in the past decade, long‐wavelength biomedical imaging is still suboptimal owing to the unsatisfactory materials properties of SWIR fluorophores. Taking advantage of organic dots based on an aggregation‐induced emission luminogen (AIEgen), herein microscopic vasculature imaging of brain and tumor is reported in living mice in the SWIR spectral region. The long‐wavelength emission of AIE dots with certain brightness facilitates resolving brain capillaries with high spatial resolution (≈3 µm) and deep penetration (800 µm). Owning to the deep penetration depth and real‐time imaging capability, in vivo SWIR microscopic angiography exhibits superior resolution in monitoring blood–brain barrier damage in mouse brain, and visualizing enhanced permeability and retention effect in tumor sites. Furthermore, the AIE dots show good biocompatibility, and no noticeable abnormalities, inflammations or lesions are observed in the main organs of the mice. This work will inspire new insights on development of advanced SWIR techniques for biomedical imaging.     

Liquid-crystal tunable filter spectral imaging for brain tumor demarcation

Past studies have demonstrated that combined fluorescence and diffuse reflectance spectroscopy can successfully discriminate between normal, tumor core, and tumor margin tissues in the brain. To achieve efficient, real-time surgical resection guidance with optical biopsy, probe-based spectroscopy must be extended to spectral imaging to spatially demarcate the tumor margins. We describe the design and characterization of a combined fluorescence and diffuse reflectance imaging system that uses liquid-crystal tunable filter technology. Experiments were conducted to quantitatively determine the linearity, field of view, spatial and spectral resolution, and wavelength sensitivity of the imaging system. Spectral images were acquired from tissue phantoms, mouse brain in vitro, and human cortex in vivo for functional testing of the system. The spectral imaging system produces measured intensities that are linear with sample emission intensity and integration time and possesses a 1 in. (2.54 cm) field of view for a 7 in. (18 cm) object distance. The spectral resolution is linear with wavelength, and the spatial resolution is pixel-limited. The sensitivity spectra for the imaging system provide a guide for the distribution of total image integration time between wavelengths. Functional tests in vitro demonstrate the capability to spectrally discriminate between brain tissues based on exogenous fluorescence contrast or endogenous tissue composition. In vivo imaging captures adequate fluorescence and diffuse reflectance intensities within a clinically viable 2 min imaging time frame and demonstrates the importance of hemostasis to acquired signal strengths and imaging speed.     

Dual‐Modal NIR‐Fluorophore Conjugated Magnetic Nanoparticle for Imaging Amyloid‐β Species In Vivo

Senile plaques, the extracellular deposit of amyloid‐β (Aβ) peptides, are one of the neuropathological hallmarks found in Alzheimer's disease (AD) brain. The current method of brain imaging of amyloid plaques based on positron emission tomography (PET) is expensive and invasive with low spatial resolution. Thus, the development of sensitive and nonradiative amyloid‐β (Aβ)‐specific contrast agents is highly important and beneficial to achieve early AD detection, monitor the disease progression, and evaluate the effectiveness of potential AD drugs. Here a neuroprotective dual‐modal nanoprobe developed by integrating highly Aβ‐specific and turn‐on fluorescence cyanine sensors with superparamagnetic iron oxide nanoparticles as an effective near‐infrared imaging (NIRI)/magnetic resonance imaging (MRI) contrast agent for imaging of Aβ species in vivo is reported. This Aβ‐specific probe is found not only nontoxic and noninvasive, but also highly blood brain barrier permeable. It also shows a potent neuroprotective effect against Aβ‐induced toxicities. This nanoprobe is successfully applied for in vivo fluorescence imaging with high sensitivity and selectivity to Aβ species, and MRI with high spatial resolution in an APP/PS1 transgenic mice model. Its potential as a powerful in vivo dual‐modal imaging tool for early detection and diagnosis of AD in humans is affirmed.     

High-resolution tomographic imaging of a human cerebellum: comparison of absorption and grating-based phase contrast

Human brain tissue belongs to the most impressive and delicate three-dimensional structures in nature. Its outstanding functional importance in the organism implies a strong need for brain imaging modalities. Although magnetic resonance imaging provides deep insights, its spatial resolution is insufficient to study the structure on the level of individual cells. Therefore, our knowledge of brain microstructure currently relies on two-dimensional techniques, optical and electron microscopy, which generally require severe preparation procedures including sectioning and staining. X-ray absorption microtomography yields the necessary spatial resolution, but since the composition of the different types of brain tissue is similar, the images show only marginal contrast. An alternative to absorption could be X-ray phase contrast, which is known for much better discrimination of soft tissues but requires more intricate machinery. In the present communication, we report an evaluation of the recently developed X-ray grating interferometry technique, applied to obtain phase-contrast as well as absorption-contrast synchrotron radiation-based microtomography of human cerebellum. The results are quantitatively compared with synchrotron radiation-based microtomography in optimized absorption-contrast mode. It is demonstrated that grating interferometry allows identifying besides the blood vessels, the stratum moleculare, the stratum granulosum and the white matter. Along the periphery of the stratum granulosum, we have detected microstructures about 40 µm in diameter, which we associate with the Purkinje cells because of their location, size, shape and density. The detection of individual Purkinje cells without the application of any stain or contrast agent is unique in the field of computed tomography and sets new standards in non-destructive three-dimensional imaging.     

扩展目标高分辨力斑点成象的模拟

介绍了扩展目标高分辨力斑点成象过程的计算机模拟,内容包括大气湍波的模拟、目标短曝光象的形成、目标功率谱的估计、目标傅里叶相位的恢复以及克服大气湍流影响后目标高分瘁力图象的重建。模拟结果显示,斑点成象技术可以克服大气湍流的影响,获得了望远镜口径决定的衍射极限的成象分辨力。模拟所建立的系统,也为进一步深入研究扩展目标的高分辨力斑点成象技术打下了基础。     

Recent trends in surface characterization and chemistry with high-resolution scanning force methods

The current status and future prospects of non-contact atomic force microscopy (nc-AFM) and Kelvin probe force microscopy (KPFM) for studying insulating surfaces and thin insulating films in high resolution are discussed. The rapid development of these techniques and their use in combination with other scanning probe microscopy methods over the last few years has made them increasingly relevant for studying, controlling, and functionalizing the surfaces of many key materials. After introducing the instruments and the basic terminology associated with them, state-of-the-art experimental and theoretical studies of insulating surfaces and thin films are discussed, with specific focus on defects, atomic and molecular adsorbates, doping, and metallic nanoclusters. The latest achievements in atomic site-specific force spectroscopy and the identification of defects by crystal doping, work function, and surface charge imaging are reviewed and recent progress being made in high-resolution imaging in air and liquids is detailed. Finally, some of the key challenges for the future development of the considered fields are identified.     

The quantum magnetism of individual manganese-12-acetate molecular magnets anchored at surfaces

The high intrinsic spin and long spin relaxation time of manganese-12-acetate (Mn(12)) makes it an archetypical single molecular magnet. While these characteristics have been measured on bulk samples, questions remain whether the magnetic properties replicate themselves in surface supported isolated molecules, a prerequisite for any application. Here we demonstrate that electrospray ion beam deposition facilitates grafting of intact Mn(12) molecules on metal as well as ultrathin insulating surfaces enabling submolecular resolution imaging by scanning tunneling microscopy. Using scanning tunneling spectroscopy we detect spin excitations from the magnetic ground state of the molecule at an ultrathin boron nitride decoupling layer. Our results are supported by density functional theory based calculations and establish that individual Mn(12) molecules retain their intrinsic spin on a well chosen solid support.     

Simulation study of magnetic resonance imaging-guided cortically constrained diffuse optical tomography of human brain function

Diffuse optical imaging can measure brain activity noninvasively in humans through the scalp and skull by measuring the light intensity modulation arising from localized-activity-induced absorption changes within the cortex. Spatial resolution and localization accuracy are currently limited by measurement geometry to approximately 3 cm in the plane parallel to the scalp. Depth resolution is a more significant challenge owing to the limited angle tomography permitted by reflectance-only measurements. We combine previously established concepts for improving image quality and demonstrate, through simulation studies, their application for improving the image quality of adult human brain function. We show in a three-dimensional human head model that localization accuracy is significantly improved by the addition of measurements that provide overlapping samples of brain tissue. However, the reconstructed absorption contrast is significantly underestimated because its depth is underestimated. We show that the absorption contrast amplitude accuracy can be significantly improved by providing a cortical spatial constraint in the image reconstruction to obtain a better depth localization. The cortical constraint makes physiological sense since the brain-activity-induced absorption changes are occurring in the cortex and not in the scalp, skull, and cerebral spinal fluid. This spatial constraint is provided by segmentation of coregistered structural magnetic resonance imaging (MRI). However, the absorption contrast deep within the cortex is reconstructed superficially, resulting in an underestimation of the absorption contrast. The synthesis of techniques described here indicates that multimodality imaging of brain function with diffuse optical imaging and MRI has the potential to provide more quantitative estimates of the total and deoxyhemoglobin response to brain activation, which is currently not provided by either method independently. However, issues of depth resolution within the cortex remain to be resolved.     

Disentangling dynamic changes of multiple cellular components during the yeast cell cycle by in vivo multivariate Raman imaging

Cellular processes are intrinsically complex and dynamic, in which a myriad of cellular components including nucleic acids, proteins, membranes, and organelles are involved and undergo spatiotemporal changes. Label-free Raman imaging has proven powerful for studying such dynamic behaviors in vivo and at the molecular level. To construct Raman images, univariate data analysis has been commonly employed, but it cannot be free from uncertainties due to severely overlapped spectral information. Here, we demonstrate multivariate curve resolution analysis for time-lapse Raman imaging of a single dividing yeast cell. A four-dimensional (spectral variable, spatial positions in the two-dimensional image plane, and time sequence) Raman data "hypercube" is unfolded to a two-way array and then analyzed globally using multivariate curve resolution. The multivariate Raman imaging thus accomplished successfully disentangles dynamic changes of both concentrations and distributions of major cellular components (lipids, proteins, and polysaccharides) during the cell cycle of the yeast cell. The results show a drastic decrease in the amount of lipids by ~50% after cell division and uncover a protein-associated component that has not been detected with previous univariate approaches.     

Tiny Signals from the Human Brain: Acquisition and Processing of Biomagnetic Fields in Magnetoencephalography

Low-temperature superconductivity plays an important role in some specific biomedical applications, and, in particular, in non-invasive imaging methods of human brain activity. Superconducting magnets are indispensable for functional magnetic resonance imaging (fMRI) which allows functional imaging of the brain with high spatial but poor temporal resolution. Superconducting quantum interference devices (SQUIDs) are the most sensitive magnetic field detectors. Up to a few hundreds of SQUIDs are nowdays used in modern whole-head magnetoencephalography (MEG) systems. They allow tracking brain activation with a superior temporal resolution of milliseconds, which is a quintessential condition for the monitoring of brain dynamics and the understanding of information processing in the human brain. We introduce the prerequisites of MEG data acquisition and briefly review two established methods of biomagnetic signal processing: The concept of signal averaging, and the subsequent source identification as a solution of the biomagnetic inverse problem. Beside these standard techniques, we discuss advanced methods for signal processing in MEG, which take into account the frequency content of the recorded signal. We briefly refer to the prospects of Fourier analysis and wavelet transform in MEG data analysis, and suggest matching pursuit as a promising tool for signal decomposition and reconstruction with high resolution in time-frequency plane.     

超分辨近场光学成像技术及其产业开发

超分辨近场光学成像技术是当前国内外一个重要的高新技术前沿课题,也将是我国21世纪初应该发展的一项高新技术产业。文中介绍了我国自1991年以来开拓研究的进展,探讨了国际学术界及产业开发中当前存在的主要问题,提出了各类超分辨扫描模式成像公式的乘法表达式,并作了分析比较。为解决消除假像和从有形貌等混合图像中分离纯光学图像两大难题,作者曾于1993年和1996年提出两项发明专利,为发展我国的该产业解决了两大技术关键。     

Radial mask for imaging systems that exhibit high resolution and extended depths of field

A novel algorithm for the design of an imaging system that exhibits high resolution as well as extended depth of field is presented. This novel approach searches for an optimal pupil mask that minimizes the value of the mean-square error when performed over the intensity rather than in the field distribution of the acquired image. The captured images in such system do not require any postprocessing, and thus utilization of such a system is simplified. Simulations as well as experimental results are provided.     

Second Near-Infrared (NIR-II) Window for Imaging-Navigated Modulation of Brain Structure and Function

For a long time, optical imaging of the deep brain with high resolution has been a challenge. Recently, with the advance in second near-infrared (NIR-II) bioimaging techniques and imaging contrast agents, NIR-II window bioimaging has attracted great attention to monitoring deeper biological or pathophysiological processes with high signal-to-noise ratio (SNR) and spatiotemporal resolution. Assisted with NIR-II bioimaging, the modulation of structure and function of brain is promising to be noninvasive and more precise. Herein, in this review, first the advantage of NIR-II light in brain imaging from the interaction between NIR-II and tissue is elaborated. Then, several specific NIR-II bioimaging technologies are introduced, including NIR-II fluorescence imaging, multiphoton fluorescence imaging, and photoacoustic imaging. Furthermore, the corresponding contrast agents are summarized. Next, the application of various NIR-II bioimaging technologies in visualizing the characteristics of cerebrovascular network and monitoring the changes of the pathology signals will be presented. After that, the modulation of brain structure and function based on NIR-II bioimaging will be discussed, including treatment of glioblastoma, guidance of cell transplantation, and neuromodulation. In the end, future perspectives that would help improve the clinical translation of NIR-II light are proposed.