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Radiotracers labeled with carbon-11 (t1/2 = 20.4 min) are widely used with positron emission tomography for biomedical research. Radiotracers must be produced for positron emission tomography studies in humans according to prescribed time schedules while also meeting current good manufacturing practice. Translation of an experimental radiosynthesis to a current good manufacturing practice environment is challenging. Here we exemplify such translation with a protocol for the production of an emerging radiotracer for imaging brain translocator protein 18 kDa, namely [11C]ER176. This radiotracer is produced by rapid conversion of cyclotron-produced [11C]carbon dioxide into [11C]iodomethane, which is then used to treat N-desmethyl-ER176 in the presence of base (tBuOK) at room temperature for 5 min. [11C]ER176 is separated in high purity by reversed-phase HPLC and formulated for intravenous injection in sterile ethanol-saline. The radiosynthesis is reliable and takes 50 min. Quality control takes another 20 min. All aspects of the protocol, including quality control, are discussed.

Transient disruption of the blood-brain barrier (BBB) with focused ultrasound (FUS) is an emerging clinical method to facilitate targeted drug delivery to the brain. The focal noninvasive disruption of the BBB can be applied to promote the local delivery of hyperpolarized substrates. In this study, we investigated the effects of FUS on imaging brain metabolism using two hyperpolarized 13C-labeled substrates in rodents: [1-13C]pyruvate and [1-13C]glycerate. The BBB is a rate-limiting factor for pyruvate delivery to the brain, and glycerate minimally passes through the BBB. First, cerebral imaging with hyperpolarized [1-13C]pyruvate resulted in an increase in total 13C signals (p = 0.05) after disrupting the BBB with FUS. Significantly higher levels of both [1-13C]lactate (lactate/total 13C signals, p = 0.01) and [13C]bicarbonate (p = 0.008) were detected in the FUS-applied brain region as compared to the contralateral FUS-unaffected normal-appearing brain region. The application of FUS without opening the BBB in a separate group of rodents resulted in comparable lactate and bicarbonate productions between the FUS-applied and the contralateral brain regions. Second, 13C imaging with hyperpolarized [1-13C]glycerate after opening the BBB showed increased [1-13C]glycerate delivery to the FUS-applied region (p = 0.04) relative to the contralateral side, and [1-13C]lactate production was consistently detected from the FUS-applied region. Our findings suggest that FUS accelerates the delivery of hyperpolarized molecules across the BBB and provides enhanced sensitivity to detect metabolic products in the brain; therefore, hyperpolarized 13C imaging with FUS may provide new opportunities to study cerebral metabolic pathways as well as various neurological pathologies.

Objective The aim of this study is to measure the average corpus callosum (CC) volume of healthy Turkish humans and to analyze the effects of gender and age on volumes, including the genu, truncus, and splenium parts of the CC. Patients and Methods Magnetic resonance imaging brain scans were obtained from 301 healthy male and female subjects, aged 11 to 84 years. The median age was 42 years (min–max: 11–82) in females and 49 years (min–max: 12–84) in males. Corpus callosum and its parts were calculated by using MRICloud. CC volumes of each subject were compared with those of the age and gender groups. Results All volumes of the CC were significantly higher in males than females. All left volumes except BCC were significantly higher than the right volumes in both males and females. The oldest two age groups (50–69 and 70–84 years) were found to have higher bilateral CC volumes, and bilateral BCC volumes were also higher than in the other two age groups (11–29 and 30–49 years). Conclusion The results suggest that compared with females/males, females have a faster decline in the volume of all volumes of the CC. We think that quantitative structural magnetic resonance data of the brain is vital in understanding human brain function and development.

Magnetic resonance spectroscopy (MRS) is a valuable tool for imaging brain tumors, primarily as an adjunct to conventional imaging and clinical presentation. MRS is useful in initial diagnosis of brain tumors, helping differentiate tumors from possible mimics such as metastatic disease, lymphoma, demyelination, and infection, as well as in the subsequent follow-up of patients after resection and chemoradiation. Unfortunately, the spectroscopic appearance of many pathologies can overlap, and ultimately follow-up or biopsy may be required to make a definitive diagnosis. Future developments may continue to increase the value of MRS for initial diagnosis, treatment planning, and early detection of recurrence.

The broad area of neuroscience has witnessed an increasing exploitation of a variety of synthetic biomaterials with controlled nanosized features. Different bionanomaterials offer very peculiar physicochemical and biochemcial properties contributing to the development of novel imaging devices toward imaging the brain, or as smartly functionalized scaffolds, or diverse tools contributing toward a better understanding of nervous tissue and its functions. DNA nanotechnology-based devices and scaffolds have emerged as ideal materials for cellular and tissue engineering due to their very biocompatible properties, robust adaptation with diverse biological systems, and biosafety in terms of reduced immune response triggering. Here we present technologies with respect to DNA nanodevices that are designed to better interact with nervous systems like neural cells, advanced molecular imaging technologies for imaging brain, biomaterials in neural regeneration, neuroprotection, and targeted delivery of drugs and small molecules across the blood-brain barrier. Along with comments regarding the progress of DNA nanotechnology in neuroscience, we also present a perspective on challenges and opportunities for applying DNA nanotechnology in applications pertaining to neurosciences.

BACKGROUND AND PURPOSE: Efficient detection of metastases is important for patient’ treatment. This prospective study was to explore the clinical value of contrast-enhanced T2 FLAIR in imaging brain metastases using half-dose gadobenate dimeglumine. MATERIALS AND METHODS: In vitro signal intensity of various gadolinium concentrations was explored by spin-echo T1-weighted imaging and T2 FLAIR. Then, 46 patients with lung cancer underwent nonenhanced T2 FLAIR before administration of half-dose gadobenate dimeglumine and 3 consecutive contrast-enhanced T2 FLAIR sequences followed by 1 spin-echo T1WI after administration of half-dose gadobenate dimeglumine. After an additional dose of 0.05 mmol/kg, 3D brain volume imaging was performed. All brain metastases were classified as follows: solid-enhancing, ≥ 5 mm (group A); ring-enhancing, ≥ 5 mm (group B); and lesion diameter of

Since its development in the late 1970s, 18F-FDG has been a major driver of basic science and translational discoveries, which have revolutionized the day-to-day clinical practice of nuclear imaging ([1][1]). Initially launched as a tracer for imaging brain metabolism, 18F-FDG rapidly found its

An ultimate goal of neuroscience is to decipher the principles underlying neuronal information processing at the molecular, cellular, circuit, and system levels. The advent of miniature fluorescence microscopy has furthered the quest by visualizing brain activities and structural dynamics in animals engaged in self-determined behaviors. In this brief review, we summarize recent advances in miniature fluorescence microscopy for neuroscience, focusing mostly on two mainstream solutions - miniature single-photon microscopy, and miniature two-photon microscopy. We discuss their technical advantages and limitations as well as unmet challenges for future improvement. Examples of preliminary applications are also presented to reflect on a new trend of brain imaging in experimental paradigms involving body movements, long and complex protocols, and even disease progression and aging.

Aberrant metabolism is a key factor in many neurological disorders. The ability to measure such metabolic impairment could lead to improved detection of disease progression, and development and monitoring of new therapeutic approaches. Hyperpolarized 13C magnetic resonance spectroscopy (MRS) is a developing imaging technique that enables non-invasive measurement of enzymatic activity in real time in living organisms. Primarily applied in the fields of cancer and cardiac disease so far, this metabolic imaging method has recently been used to investigate neurological disorders. In this review, we summarize the preclinical research developments in this emerging field, and discuss future prospects for this exciting technology, which has the potential to change the clinical paradigm for patients with neurological disorders.

Purpose Beta-secretase 1 (BACE1) enzyme is implicated in the pathophysiology of Alzheimer’s disease. [18F]PF-06684511 is a positron emission tomography (PET) radioligand for imaging BACE1. Despite favorable brain kinetic properties, the effective dose (ED) of [18F]PF-06684511 estimated in non-human primates was relatively high. This study was therefore designed to evaluate the whole-body distribution, dosimetry, quantification, and test-retest reliability of imaging brain BACE1 with [18F]PF-06684511 in healthy volunteers. Methods Five subjects were studied for the dosimetry study. Whole-body PET was performed for 366 min with 4 PET-CT sessions. Estimates of the absorbed radiation dose were calculated using the male adult model. Eight subjects participated in the test-retest study. Brain PET measurements were conducted for 123 min with an interval of 5 to 19 days between test and retest conditions. The total distribution volume (VT) was estimated with one-tissue (1T), two-tissue (2T), compartment model (CM), and graphical analysis. Test-retest variability (TRV) and intraclass correlation coefficient (ICC) of VT were calculated as reliability measures. Results In the dosimetry study, the highest uptake was found in the liver (25.2 ± 2.3 %ID at 0.5 h) and the largest dose was observed in the pancreas (92.9 ± 52.2 μSv/MBq). The calculated ED was 24.7 ± 0.8 μSv/MBq. In the test-retest study, 2TCM described the time-activity curves well. VT (2TCM) was the highest in the anterior cingulate cortex (6.28 ± 1.09 and 6.85 ± 0.81) and the lowest in the cerebellum (4.23 ± 0.88 and 4.20 ± 0.75). Mean TRV and ICC of VT (2TCM) were 16.5% (12.4–20.5%) and 0.496 (0.291–0.644). Conclusion The ED of [18F]PF-06684511 was similar to other 18F radioligands, allowing repeated PET measurements. 2TCM was the most appropriate quantification method. TRV of VT was similar to other radioligands without a reference region, albeit with lower ICC. These data indicated that [18F]PF-06684511 is a suitable radioligand to measure BACE1 level in the human brain. Trial registration EudraCT 2016-001110-19 (registered 2016-08-08)

Iodide homeostasis and thyroid hormone metabolism in the brain are potentially related to changes in the activity of the sodium iodide symporter (NIS). No radiotracers are currently available for imaging brain NIS activity. Here, we synthesized 6-[124I]iodo-9-pentylpurine that can noninvasively measure iodide efflux from the brain and showed that the efflux rate of [124I]I- in NIS knockout mice was 84% lower than that of wild-type mice. Thus, 6-[124I]iodo-9-pentylpurine would be useful for imaging brain NIS activity.

Genetically encoded fluorescent indicators, combined with optical imaging, enable the detection of physiologically or behaviorally relevant neural activity with high spatiotemporal resolution. Recent developments in protein engineering and screening strategies have improved the dynamic range, kinetics, and spectral properties of genetically encoded fluorescence indicators of brain chemistry. Such indicators have detected neurotransmitter and calcium dynamics with high signal-to-noise ratio at multiple temporal and spatial scales in vitro and in vivo. This review summarizes the current trends in these genetically encoded fluorescent indicators of neurotransmitters and calcium, focusing on their key metrics and in vivo applications.

The brain is an enormously complex organ that consumes a substantial amount of body energy. Understanding how brain function requires the ability to not only map out the cellular structure but also probe functional processes. Multiphoton fluorescence microscopy has played a crucial role in current investigations due to the wide variety of synthetic dyes and proteins available for imaging brain cells and neuronal activities at high spatial and temporal resolution. However, it has limited capability to resolve multiple features simultaneously. We combine multiphoton fluorescence with label-free nonlinear imaging techniques including transient absorption microscopy and stimulated Raman scattering microscopy to expand the structural and functional features that can be imaged simultaneously. With this platform, we demonstrate the reconstruction of axonal features and microvascular networks together with the mapping of cellular organization.

The neonatal brain is a vulnerable organ, and lesions due to hemorrhage and/or ischemia occur frequently in preterm neonates. Even though neuroprotective therapies exist, there is no tool available to detect the ischemic lesions. To address this problem, we have recently designed and built the new time-domain near-infrared optical tomography (TD NIROT) system – Pioneer. Here we present the results of a phantom study of the system performance. We used silicone phantoms to mimic risky situations for brain lesions: hemorrhage and hypoxia. Employing Pioneer, we were able to reconstruct accurately both position and optical properties of these inhomogeneities.

A variety of radiolabeled amino acids have been used for imaging brain tumors. FET and MET have been the most widely used amino acid tracers. Amino acid tracers can be used for detection, tumor grading, targeting biopsy, and evaluation of response. Fluorothymidine (FLT) is a nucleoside thymidine analog. Assessment of treatment response in gliomas is very challenging. Amino acid tracers have been proven to be more appropriate. FET PET/CT offers high diagnostic power in this scenario. FET PET with additional dynamic data analysis was significantly superior to conventional MRI in discriminating tumor recurrence from post-therapeutic changes. The present literature in neuroimaging using PET highlights the ability of amino acid PET to quantify biological responses to treatment and allows its application to monitor patients to identify early disease relapse and response to treatment. However, the diagnostic impact of amino acid PET needs to be compared with a variety of advanced MR imaging techniques to develop the most accurate and useful multi-modal biomarkers possible.

We report herein the discovery of a positron emission tomography (PET) tracer for the (NOD)-like receptor protein 3 (NLRP3). Our recent medicinal chemistry campaign on developing sulfonamide-based NLRP3 inhibitors led to an analog, 1, with a methoxy substituent amenable to labeling with carbon-11. PET/CT imaging studies indicated that [(11)C]1 exhibited rapid blood-brain barrier (BBB) penetration and moderate brain uptake, as well as blockable uptake in the brain. [(11)C]1, thus suggesting the potential to serve as a useful tool for imaging NLRP3 inflammasome in living brains.

Imaging is an indispensable tool for brain tumour diagnosis, surgical planning, and follow-up. Definite diagnosis, however, often demands histopathological analysis of microscopic features of tissue samples, which have to be obtained by invasive means. A non-invasive alternative may be to probe corresponding microscopic tissue characteristics by MRI, or so called 'microstructure imaging'. The promise of microstructure imaging is one of 'virtual biopsy' with the goal to offset the need for invasive procedures in favour of imaging that can guide pre-surgical planning and can be repeated longitudinally to monitor and predict treatment response. The exploration of such methods is motivated by the striking link between parameters from MRI and tumour histology, for example the correlation between the apparent diffusion coefficient and cellularity. Recent microstructure imaging techniques probe even more subtle and specific features, providing parameters associated to cell shape, size, permeability, and volume distributions. However, the range of scenarios in which these techniques provide reliable imaging biomarkers that can be used to test medical hypotheses or support clinical decisions is yet unknown. Accurate microstructure imaging may moreover require acquisitions that go beyond conventional data acquisition strategies. This review covers a wide range of candidate microstructure imaging methods based on diffusion MRI and relaxometry, and explores advantages, challenges, and potential pitfalls in brain tumour microstructure imaging.

Electroencephalogram (EEG) has evolved to be a well-established tool for imaging brain activity. This progress is mainly due to the development of high-resolution (HR) EEG methods. One class of HR-EEG is the cortical potential imaging (CPI), which aims to estimate the potential distribution on the cortical surface, which is much more informative than EEG. Even though these methods exhibit good performance, most of them have inherent inaccuracies that originate from their operating principles that constrain the solution or require a complex calculation process. The back-projection CPI (BP-CPI) method is relatively new and has the advantage of being constraint-free and computation inexpensive. The method has shown relatively good accuracy, which is necessary to become a clinical tool. However, better performance must be achieved. In the present study, two improvements are proposed. Both are embedded as adjacent stages to the BP-CPI and are based on the multi-resolution optimization approach (MR-CPI). A series of Monte-Carlo simulations were performed to examine the characteristics of the proposed improvements. Additional tests were done, including different EEG noise levels and variation in electrode-numbers. The results showed highly accurate cortical potential estimations, with a reduction in estimation error by a factor of 3.75 relative to the simple BP-CPI estimation error. We also validated these results with true EEG data. Analyzing these EEGs, we have demonstrated the MR-CPI competence to correctly localize cortical activations in a real environment. The MR-CPI methods were shown to be reliable for estimating cortical potentials, enabling researchers to obtain fast and robust high-resolution EEGs.

In our preceding paper (Part 1), we identified three 1,5-bis-diaryl-1,2,4-triazole-based compounds that merited evaluation as potential positron emission tomography (PET) radioligands for selectively imaging cyclooxygenase-1 (COX-1) in monkey and human brain, namely, 1,5-bis(4-methoxyphenyl)-3-(alkoxy)-1 H-1,2,4-triazoles bearing a 3-methoxy (PS1), a 3-(2,2,2-trifluoroethoxy) (PS13), or a 3-fluoromethoxy substituent (PS2). PS1 and PS13 were labeled from phenol precursors by O-11C-methylation with [11C]iodomethane and PS2 by O-18F-fluoroalkylation with [2H2,18F]fluorobromomethane. Here, we evaluated these PET radioligands in monkey. All three radioligands gave moderately high uptake in brain, although [2H2,18F]PS2 also showed undesirable radioactivity uptake in skull. [11C]PS13 was selected for further evaluation, mainly based on more favorable brain kinetics than [11C]PS1. Pharmacological preblock experiments showed that about 55% of the radioactivity uptake in brain was specifically bound to COX-1. An index of enzyme density, VT, was well identified from serial brain scans and from the concentrations of parent radioligand in arterial plasma. In addition, VT values were stable within 80 min, suggesting that brain uptake was not contaminated by radiometabolites. [11C]PS13 successfully images and quantifies COX-1 in monkey brain, and merits further investigation for imaging COX-1 in monkey models of neuroinflammation and in healthy human subjects.

Objectives: Idiopathic Parkinson’s disease (iPD) is a common neurodegenerative disorder where misdiagnosis occurs in up to 30% of patients after initial assessment and in 10-15% even after long-term follow-up. Vesicular monoamine transporter type II (VMAT2) imaging with Positron Emission Tomography (PET) allows assessment of the integrity of the presynaptic dopaminergic pathway. We investigated the management impact of VMAT2 imaging in patients with Clinically Uncertain Parkinsonian Syndromes (CUPS). Methods: Forty-seven patients with CUPS (56.9 +/-14.9 years, range 21-80) were referred from movement disorder specialists. All participants underwent a 20-minute PET acquisition 2 hours post injection of 250 MBq of 18F-AV-133, and the resulting images were quantitatively assessed. Clinical impact was recorded as high, moderate or low based on diagnosis and management questionnaires completed by the referring specialists pre and post release of the PET results. Management impact was high if there was a change in diagnostic category; moderate if there was a change in medication and low if there was no change. Results: VMAT2 PET changed the diagnosis in 11 (23%) and medication in 25 (53%) participants. Management impact was high in 23%, moderate in 38% and low in 39% of the participants. High diagnostic confidence increased from 11% of patients to 80% after the release of the scan results. Conclusion:18F-AV-133 had substantial management impact in patients with Clinically Uncertain Parkinsonian Syndromes. This suggests that VMAT2 imaging with 18F-AV133 might improve diagnosis, prognosis and appropriate use of medication, translating into better patient outcomes.

In the current issue of ACS Chemical Neuroscience, Kim et al. report on the early characterization of 4-(3-[18F] fluorophenethoxy)pyrimidine (18F-FPP) as a new positron emission tomography radiotracer for imaging brain 5-HT2C receptors (Kim, J., et al. (2017) A potential PET radiotracer for the 5-HT2c receptor: Synthesis and in vivo evaluation of 4-(3-[18F]Fluorophenethoxy)pyrimidine. ACS Chem. Neurosci., DOI: 10.1021/acschemneuro.6b00445). At the present time, the tracer properties of 18F-FPP have only been reported in rats. If 18F-FPP is indeed shown to be suitable as a 5-HT2C receptor PET tracer in humans, it will very likely have an important impact both in the development of any new chemical entities (NCEs) targeted to 5-HT2C receptors, as well as a tool to advance understanding of 5-HT2C receptor function both in normal and abnormal brain states.

The World Health Organization reported that the brain tumor is one of the serious diseases because it affects a large number of people including children around the world. Developing a system to detect brain tumors at an early stage would help save the lives of many people. Much research has been made in this area to develop a system for detecting brain tumors, but this system needs to be improved, its accuracy enhanced and the time taken for the classification of brain tumors reduced. Thus, feature selection methods are required to enhance the system. The feature selection method is more significant in the data mining algorithm to remove redundant features from the data set. In this paper, I proposed a hybrid Principal Component Analysis and Rough Set theory (PCA + RST) approach to reduce the dimension of the data set. The approach is evaluated using ADNT and OASIS standard databases. Two segmentation methods were applied to find out the region of interest from the MRI image. To obtain several features from an MRI image, the Discrete Wavelet Transform (DWT) methods are employed. The novelty of the proposed new hybrid PCA+RST approach is to obtain the most significant features for enhancing the classification algorithms. Four classification algorithms namely J48, Support Vector Machine (SVM), K-nearest neighbor (KNN) and Naive Bayes have been implemented. Evaluation and comparison of the proposed approach with alternative approaches like DWT+SVM, DWT+PCA+ANN, DWT+PCA+KNN, STRSPOS-QR+J48, and STRSPOS-QR+Naive Bayes are presented. The proposed approach outperforms both these approaches.

Tracing the entirety of ultrastructures in large three-dimensional electron microscopy (3D-EM) images of the brain tissue requires automated segmentation techniques. Current segmentation techniques use deep convolutional neural networks (DCNNs) and rely on high-contrast cellular membranes and high-resolution EM volumes. On the other hand, segmenting low-resolution, large EM volumes requires methods to account for severe membrane discontinuities inescapable. Therefore, we developed DeepACSON, which performs DCNN-based semantic segmentation and shape-decomposition-based instance segmentation. DeepACSON instance segmentation uses the tubularity of myelinated axons and decomposes under-segmented myelinated axons into their constituent axons. We applied DeepACSON to ten EM volumes of rats after sham-operation or traumatic brain injury, segmenting hundreds of thousands of long-span myelinated axons, thousands of cell nuclei, and millions of mitochondria with excellent evaluation scores. DeepACSON quantified the morphology and spatial aspects of white matter ultrastructures, capturing nanoscopic morphological alterations five months after the injury., With DeepACSON, Abdollahzadeh et al. combines existing deep learning-based methods for semantic segmentation and a novel shape decomposition technique for the instance segmentation. The pipeline is used to segment low-resolution 3D-EM datasets allowing quantification of white matter morphology in large fields-of-view.

We will discuss the developments in TSPO PET imaging and the contribution this technique has had to understanding neuroinflammation in vivo, as well as the limitations inherent to the currently available radioligands and the potential future direction. Positron emission tomography (PET) imaging targeting the translocator protein 18 kDa (TSPO) has led to major advances in understanding the pathological role played by microglia activation and neuroinflammation in a diverse range of neurodegenerative conditions. The first-generation radioligand 11[C](R)-PK11195 has been the most widely studied and has led to considerable advancements in defining the role of neuroinflammation in neuronal degeneration and dysfunction. However, limitations including low signal-to-noise ratio and high nonspecific binding have led to the development of new TSPO-specific radioligands in an attempt to improve the quality of TSPO imaging. Unfortunately, these new radioligands have not been without their own problems, and the expected improvement in image quality has not been achieved.

As the most pivotal organ of the human body, brain is susceptible to various disorder and trauma. Generally, brain diseases can be diagnosed only in the advanced stage where there is no treatment to fully cure these diseases. Although enormous efforts have been involved in the treatment of brain diseases over the years, it still acts as one of the most frequent causes of death and disability worldwide and is recognized as the largest and fastest growing field of unmet medical need. Hence early diagnosis is highly essential and crucial for prevention and treatment of brain diseases. Owing to their non-invasiveness and trackable signals, luminescent probes are particularly promising tools for brain disease diagnosis. Activatable luminescent probes can respond to specific pathologic stimuli and improve signal-to-background ratio of detection, permitting real-time semi-quantification of biomarkers and investigating pathological mechanism at the molecular level. Thus, activatable luminescent probes are of great importance to management of brain diseases and restoration of lost brain functions. In this review, we present the recent developments in this area, including blood-brain barrier (BBB)-crossing strategies and activation approaches of both molecular probes and nanoprobes for brain disease imaging.

Objective: Transcranial focused ultrasound (tFUS) has been introduced as a noninvasive neuromodulation technique with good spatial selectivity. We report an experimental investigation to detect noninvasive electrophysiological response induced by low-intensity tFUS in an in vivo animal model and perform electrophysiological source imaging (ESI) of tFUS-induced brain activity from noninvasive scalp EEG recordings. Methods: A single-element ultrasound transducer was used to generate low-intensity tFUS ( $\rm{I}_{\rm{spta}} ) and induce brain activation at multiple selected sites in an in vivo rat model. Up to 16 scalp electrodes were used to record tFUS-induced EEG. Event-related potentials were analyzed in time, frequency, and spatial domains. Current source distributions were estimated by ESI to reconstruct spatiotemporal distributions of brain activation induced by tFUS. Results: Neuronal activation was observed following low-intensity tFUS, as correlated to tFUS intensity and sonication duration. ESI revealed initial focal activation in cortical area corresponding to tFUS stimulation site and the activation propagating to surrounding areas over time. Conclusion: The present results demonstrate the feasibility of noninvasively recording brain electrophysiological response in vivo following low-intensity tFUS stimulation, and the feasibility of imaging spatiotemporal distributions of brain activation as induced by tFUS in vivo . Significance: The present approach may lead to a new means of imaging brain activity using tFUS perturbation and a closed-loop ESI-guided tFUS neuromodulation modality.

The development of reversibly binding radioligands for imaging brain proteins in vivo, such as enzymes, neurotransmitter transporters, receptors and ion channels, with positron emission tomography (PET) is keenly sought for biomedical studies of neuropsychiatric disorders and for drug discovery and development, but is recognized as being highly challenging at the medicinal chemistry level. This article aims to compile and discuss the main considerations to be taken into account by chemists embarking on programs of radioligand development for PET imaging of brain protein targets.

Brain imaging is one of the valuable applications of the hybrid PET/MRI given the anatomical and physiological complexity of the brain and the subtlety of the neurological changes that accompany many of the neurodegenerative, epileptic, and oncological diseases. The limited resolution of CT in imaging brain makes the MRI the ideal modality for neuroimaging. This resulted in growing interest in the medical, physics, and pharmaceutical communities to develop novel radiopharmaceuticals and apply new MRI sequences for early diagnosis, predicting the behavior and having a better insight of the neurological disorders. This chapter provides a concise overview of the combined PET/MRI clinical uses in neuroimaging of patients with neurodegenerative, epileptic and brain neoplastic diseases. It also compares its advantages and disadvantages to those of other available imaging modalities.

A comprehensive understanding of how the brain responds to a changing environment requires techniques capable of recording functional outputs at the whole-brain level in response to external stimuli. Positron emission tomography (PET) is an exquisitely sensitive technique for imaging brain function but the need for anaesthesia to avoid motion artefacts precludes concurrent behavioural response studies. Here, we report a technique that combines motion-compensated PET with a robotically-controlled animal enclosure to enable simultaneous brain imaging and behavioural recordings in unrestrained small animals. The technique was used to measure in vivo displacement of [11C]raclopride from dopamine D2 receptors (D2R) concurrently with changes in the behaviour of awake, freely moving rats following administration of unlabelled raclopride or amphetamine. The timing and magnitude of [11C]raclopride displacement from D2R were reliably estimated and, in the case of amphetamine, these changes coincided with a marked increase in stereotyped behaviours and hyper-locomotion. The technique, therefore, allows simultaneous measurement of changes in brain function and behavioural responses to external stimuli in conscious unrestrained animals, giving rise to important applications in behavioural neuroscience.

When imaging brain vasculature with optical coherence tomography angiography (OCTA), volumetric analysis of cortical vascular networks in OCTA datasets is frequently challenging due to the presence of artifacts, which appear as multiple-scattering tails beneath superficial large vessels in OCTA images. These tails shadow underlying small vessels, making the assessment of vascular morphology in the deep cortex difficult. In this work, we introduce an image processing technique based on mean subtraction of the depth profile that can effectively reduce these tails to better reveal small hidden vessels compared to the current tail removal approach. With the improved vascular image quality, we demonstrate that this simple method can provide better visualization of three-dimensional vascular network topology for quantitative cerebrovascular studies.

The purpose of this study is to test the feasibility of using acoustoelectric brain imaging (ABI) to map physiological activity in the rat hippocampus using depth and surface recording electrodes on a new mobile system. A new method in imaging brain activity using the acoustoelectric (AE) allows for the combination of high temporal and spatial resolution imaging beyond existing techniques. AE imaging takes advantage of mechanoelectrical properties of ultrasound (US) pressure waves which modulate the tissue's electrical resistivity. Using surface and depth electrodes we record these modulated signals to electrically map local brain activity. In recent experiments we have been able to image evoked responses in the hippocampus of an anesthetized rat showing high temporal correlations between low frequency recordings and ABI. Further optimization of ABI can allow for better detection of evoked potentials in the brain to allow for faster real-time scanning possibilities with capabilities of miniaturizing a system for hand held imaging.

PURPOSE There is a need for an alternative PET probe, which does not show normal brain tissue uptake in the evaluation of metastasis to the brain. Therefore, we investigate the feasibility of F-labeled glutamine analog, F-(2S,4R)-4-fluoroglutamine (F-FGln), as a new metabolic probe to detect brain metastasis. METHODS Patients (7 men and 7 women; age, 25-67 years) with suspected brain metastasis were enrolled for this study. All patients were imaged first with F-FGln PET (3 patients for 1-hour dynamic whole-body PET/CT scans, and 11 patients for static whole-body scans at 30 ± 10 minutes after injection), followed by a whole-body F-FDG PET performed in the same week. The characteristics of F-FGln PET imaging in brain metastasis patients were compared with that of F-FDG PET and/or contrast-enhanced MRI patient-by-patient. A composite of all functional and anatomic imaging studies served as the imaging comparator. RESULTS Initial study in 3 patients using 1-hour dynamic scan showed that 30 ± 10 minutes after injection is optimal for identifying brain metastasis with a high-contrast ratio. All patients were positive for brain metastasis on this studies that demonstrated 38 lesions in 6 anatomic regions on the imaging comparator. The per-lesion detection rates for F-FGln PET and F-FDG PET were 81.6% and 36.8%, respectively. The average tumor-to-normal brain ratio of F-FGln PET was significantly better than that of F-FDG PET in all patients (4.97 ± 2.23 vs 1.22 ± 0.69, P < 0.05). Furthermore, our results suggest that F-FGln uptake in brain metastasis appeared to be independent of tumor size and peripheral edema. In addition, in 14 brain metastatic lesions visualized by both F-FDG PET and F-FGln PET imaging, a positive correlation of SUVmax was observed (r = 0.780, P < 0.01). As to the extracranial metastasis, both tracers showed a concordant increased radioactive uptake except in liver and bone. CONCLUSIONS The initial imaging of F-FGln presenting a promising new PET radiotracer for patients with brain metastasis and its utility in the liver and bone metastatic lesions may require more caution due to uptake in normal structures.

In this review, we discuss molecular brain imaging studies using positron emission tomography (PET) with 2-deoxy-2(18F)fluoro-d-glucose (FDG) in human newborns and infants, and illustrate how this technology can be applied to probe the neuropathophysiology of neonatal neurologic disorders. PET studies have been difficult to perform in sick babies because of patient transportation issues and suboptimal spatial resolution. With approval from the FDA and the institutional review board, we modified and installed the Focus 220 animal microPET scanner (Concorde Microsystems, Knoxville, TN) directly in our neonatal intensive care unit in Children’s Hospital of Michigan and verified the high spatial resolution (Areceptors (using11C-flumazenil) in newborns also show a pattern very different from adults, with high binding in amygdala-hippocampus, sensory-motor cortex, thalamus, brain stem, and basal ganglia, in that order. We speculate that the early development of amygdala/hippocampus prepares the baby for bonding, attachment, and memory, and the deprivation of such experiences during a sensitive period results in malfunction of these networks and psychopathology, as has been shown in studies on severely socioemotionally deprived children. Recently developed hybrid PET/magnetic resonance (MR) scanners allow the simultaneous acquisition of PET and MR data sets with advanced applications. These devices are particularly advantageous for scanning babies and infants because of the high spatial resolution, automated coregistration of anatomical and functional images and, in the case of need for sedation, maximal data acquired in 1 session.

Although FASD is characterized by physical, behavioral and cognitive deficits that provide compelling evidence of brain damage, routine clinical brain imaging (e.g. magnetic resonance imaging; MRI) often yields non-significant findings that add little insight into the diagnostic process. Nonetheless, research studies using advanced methods have identified numerous abnormalities of brain structure when comparing groups of individuals with FASD to groups of typically developing individuals, including brain volume reductions and abnormalities of cortical thickness and white matter microstructure. In addition, several studies have identified group-level associations between abnormal brain structure and cognitive performance, degree of prenatal alcohol exposure, or other key clinical metrics. This chapter summarizes some of these key findings, highlighting how MRI has advanced our understanding of FASD while also discussing its current limitations as a biomarker of prenatal alcohol exposure.

We present three approaches for using optical coherence tomography (OCT) to visualize neuritic plaques in Alzheimer’s disease based on intrinsic optical properties, namely their birefringence, spectroscopic characteristics and scattering profile.

In recent decades a significant effort has been directed towards experimental and theoretical approaches aiming at the establishment of neural correlates of higher cognitive functions and awareness. These efforts produce massive amounts of data on imaging brain structure and functions, and efficient methods are in high demand to make these data easily accessible and understandable to human experts. Here we describe the development of qualitative tools and methodologies where large quantities of brain imaging data are processed and displayed for the purpose of visually discriminating the various stages of the cognitive processes. In this work we report and describe in detail a methodology inspired by the art of encephalography, whereby brain dynamics movies are created based on experimental data. The results are presented to identify large-scale synchronizations and de- synchronizations across broad frequency bands as a potential manifestation of the cycle of creation of knowledge and meaning. This visual process is also useful for the description of learning and adaptation processes in brains.

Functional Magnetic Resonance Imaging (fMRI) is a common technique for imaging brain activity in humans. However, the fMRI signal stems from local changes in oxygen level rather than from neuronal ...

Background Carbon-11 labeled L-methionine (11C–MET) is a popular tracer used in the clinic for imaging brain tumors with positron emission tomography. However, the stability of 11C–MET in its final formulation is not well documented in literature. Recently, we observed fast degradation of HPLC-purified 11C–MET over time, and systematic investigation was conducted to identify the cause. Results In this study, we verified the degraded product as 11C–labeled methionine sulfoxide (11C–METSO). To minimize oxidation, ascorbate (100 ppm) was added to the HPLC eluant, and the resulting HPLC-purified 11C–MET was stable in the final formulation solution without noticeable degradation for up to 1 h after the end of synthesis. Conclusions Our data suggest that to minimize degradation, ascorbate can be added to the 11C–MET formulation solution especially if it is not administered into patients soon after the end of synthesis. Electronic supplementary material The online version of this article (10.1186/s41181-017-0032-x) contains supplementary material, which is available to authorized users.

In vivo brain activity imaging is a key to understanding the mechanisms of complex neural behavior. Functional MRI records brain-wide mechanisms, but at the cost of subject sedation which excludes behavioral experiments. Functional Ultrasound (fUS) Imaging, based on Doppler Imaging, is a powerful new tool for imaging brain activation with high spatiotemporal sampling (80μm, 1ms). It has been successively applied in anesthesized and awake rodents and in humans in preoperative settings. However, the brain mechanisms and functional connectivity are inherently three-dimensional, it is thus crucial to work toward imaging of the full brain in 3D. In this study, we present the first full 3D fUS Imaging of a mouse using a matrix array.

Sensors for imaging brain activity have been under development for almost 50 years. The development of some of these tools is relatively mature, whereas qualitative improvements of others are needed and are actively pursued. In particular, genetically encoded voltage indicators are just now starting to be used to answer neurobiological questions and, at the same time, more than 10 laboratories are working to improve them. In this Biophysical Perspective, we attempt to discuss the present state of the art and indicate areas of active development.

Imaging brain tissues is an essential part of neuroscience because understanding brain structure provides relevant information about brain functions and alterations associated with diseases. Magnetic resonance imaging and positron emission tomography exemplify conventional brain imaging tools, but these techniques suffer from low spatial resolution around 100 μm. As a complementary method, histopathology has been utilized with the development of optical microscopy. The traditional method provides the structural information about biological tissues to cellular scales, but relies on labor-intensive staining procedures. With the advances of illumination sources, label-free imaging techniques based on nonlinear interactions, such as multiphoton excitations and Raman scattering, have been applied to molecule-specific histopathology. Nevertheless, these techniques provide limited qualitative information and require a pulsed laser, which is difficult to use for pathologists with no laser training. Here, we present a label-free optical imaging of mouse brain tissues for addressing structural alteration in Alzheimer’s disease. To achieve the mesoscopic, unlabeled tissue images with high contrast and sub-micrometer lateral resolution, we employed holographic microscopy and an automated scanning platform. From the acquired hologram of the brain tissues, we could retrieve scattering coefficients and anisotropies according to the modified scattering-phase theorem. This label-free imaging technique enabled direct access to structural information throughout the tissues with a sub-micrometer lateral resolution and presented a unique means to investigate the structural changes in the optical properties of biological tissues.

Purpose To perform quantitative susceptibility mapping (QSM) in negligible acquisition time and apply it to measuring iron-rich subcortical gray matter. Methods Whole brain QSM was performed using single-shot gradient echo-planar imaging (EPI) in under 7 seconds on a standard 1.5 T system for imaging brain iron in subcortical gray matter. The method was compared to a standard 6-minute gradient recalled echo (GRE) QSM acquisition in healthy subjects. Region-of-interest QSM measurements were compared between methods in six subcortical gray-matter nuclei and two white matter territories. Results EPI-QSM provided similar mean susceptibility values to standard GRE-QSM in iron-rich subcortical gray matter regions, while providing greater than 50-fold scan time reduction. Blurring from the low spatial resolution and transverse relaxation decay of EPI affected edges but had negligible effect on whole subcortical nuclei measurements, which had a high correlation (R2 = 0.96) to estimated iron content. Conclusion EPI-QSM can be performed in several seconds, which enables expansion of brain iron studies of subcortical gray matter to cases where time is limited and to existing MRI studies that already uses gradient echo EPI. Magn Reson Med 73:1932–1938, 2015. © 2014 Wiley Periodicals, Inc.

We report herein the discovery of a fatty acid amide hydrolase (FAAH) positron emission tomography (PET) tracer. Starting from a pyrazole lead, medicinal chemistry efforts directed toward reducing lipophilicity led to the synthesis of a series of imidazole analogues. Compound 6 was chosen for further profiling due to its appropriate physical chemical properties and excellent FAAH inhibition potency across species. [(11)C]-6 (MK-3168) exhibited good brain uptake and FAAH-specific signal in rhesus monkeys and is a suitable PET tracer for imaging FAAH in the brain.

Imaging acetylcholinesterase (AChE) is valuable not only for diagnosing and understanding dementia but also for monitoring the effects of cholinesterase inhibitors used as antidementia drugs and for determining the appropriate clinical dosage of newly developed cholinesterase inhibitors. The distribution of AChE in the living brain can be imaged with two different types of radioprobes, including substrate-type and ligand-type probes. The substrate-type positron emission tomography (PET) probes, N-[(11) C]methylpiperidin-4-yl acetate ([(11) C]MP4A), and its propionate, [(11) C]MP4P, have been widely used in clinical studies of dementia, including Alzheimer's disease. [(11) C]MP4A and [(11) C]MP4P have been used to demonstrate a reduction in AChE activity in the brains of dementia patients, as well as the bioavailability of AChE inhibitors, leading to the subsequent development of the widely available (18) F-labeled derivatives of MP4A. In addition, several radiolabeled cholinesterase inhibitors have been developed as PET probes for AChE mapping in the brain. Herein, we have reviewed the development of PET probes for the imaging of AChE in the brain and described the principles of measuring AChE activity in the brain using PET with substrate-type radioprobes. A discussion of the reagents developed from substrate-type PET probes for the specific measurement of AChE activity in vitro has also been provided.

Optical topography guided diffuse optical tomography is developed to regularize the ill-posed inverse problems involved in brain imaging. Simulation experiments demonstrate that stronger robustness and higher quantitativeness are obtained without adding any other modality measurements.

Neurophotonics involves optical techniques for brain imaging - in health and disease. This review will present two technologies, laser speckle imaging and photoacoustic imaging. Laser speckle contrast can be correlated with blood flow and therefore can be used for imaging brain blood flow and microcirculation in applications such as stroke. Further, speckle imaging can be combined with electrophysiological monitoring. Photoacoustic imaging is a more recent technique suitable for imaging deeper into brain tissue, and for studying cortical structures and function in applications such as angiogenesis accompanying tumors. Further improvements in contrast and specificity may come from using nanoparticles. These technologies are advancing rapidty towards clinical applications.

BACKGROUND: DPD scintigraphy has been advocated for imaging cardiac amyloid in ATTR amyloidosis. PET utilizing (11)C-Pittsburgh compound B (PIB) is the gold standard for imaging brain amyloid in Alzheimer's disease. PIB was recently shown to identify cardiac amyloidosis in both AL and ATTR amyloidosis. In the ATTR population, two types of amyloid fibrils exist, one containing fragmented and full-length TTR (type A) and the other only full-length TTR (type B). The aim of this study was to further evaluate PIB-PET in patients with hereditary ATTR amyloidosis. METHODS: Ten patients with biopsy-proven V30M ATTR amyloidosis and discrete or no signs of cardiac involvement were included. Patients were grouped according to TTR-fragmentation. All underwent DPD scintigraphy, echocardiography, and PIB-PET. A left ventricular PIB-retention index (PIB-RI) was established and compared to five normal volunteers. RESULTS: PIB-RI was increased in all patients (P

SUMMARY The progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS) are atypical parkinsonian disorders that are both associated with characteristic patterns of atrophy that can be detected on MRI and can be diagnostically useful for the clinician. Much recent work has focused on developing imaging biomarkers, particularly utilizing measurements of the brainstem, which can differentiate PSPS from CBS and other parkinsonian disorders. The utility of longitudinal measures of atrophy as biomarkers of disease progression has also been assessed with a view to how these measures could be utilized in clinical treatment trials. Here, these studies are reviewed and the potential value of imaging biomarkers to aid diagnosis and monitor disease progression in PSPS and CBS will be discussed.