Learning related interactions among neuronal systems involved in memory processes

Functional neuroimaging techniques using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have provided new insights in our understanding of brain function from the molecular to the systems level. While subtraction strategy based data analyses have revealed the involvement of distributed brain regions in memory processes, covariance analysis based data analysis strategies allow functional interactions between brain regions of a neuronal network to be assessed. The focus of this chapter is to (1) establish the functional topography of episodic and working memory processes in young and old normal volunteers, (2) to assess functional interactions between modules of networks of brain regions by means of covariance based analyses and systems level modelling and (3) to relate neuroimaging data to the underpinning neural networks. Male normal young and old volunteers without neurological or psychiatric illness participated in neuroimaging studies (PET, fMRI) on working and episodic memory. Distributed brain areas are involved in memory processes (episodic and working memory) in young volunteers and show much of an overlap with respect to the network components. Systems level modelling analyses support the hypothesis of bihemispheric, asymmetric networks subserving memory processes and revealed both similarities in general and differences in the interactions between brain regions during episodic encoding and retrieval as well as working memory. Changes in memory function with ageing are evident from studies in old volunteers activating more brain regions compared to young volunteers and revealing more and stronger influences of prefrontal regions. We finally discuss the way in which the systems level models based on PET and fMRI results have implications for the understanding of the underlying neural network functioning of the brain.     

Functional magnetic resonance imaging of semantic memory as a presymptomatic biomarker of Alzheimer's disease risk

Extensive research efforts have been directed toward strategies for predicting risk of developing Alzheimer's disease (AD) prior to the appearance of observable symptoms. Existing approaches for early detection of AD vary in terms of their efficacy, invasiveness, and ease of implementation. Several non-invasive magnetic resonance imaging strategies have been developed for predicting decline in cognitively healthy older adults. This review will survey a number of studies, beginning with the development of a famous name discrimination task used to identify neural regions that participate in semantic memory retrieval and to test predictions of several key theories of the role of the hippocampus in memory. This task has revealed medial temporal and neocortical contributions to recent and remote memory retrieval, and it has been used to demonstrate compensatory neural recruitment in older adults, apolipoprotein E ε4 carriers, and amnestic mild cognitive impairment patients. Recently, we have also found that the famous name discrimination task provides predictive value for forecasting episodic memory decline among asymptomatic older adults. Other studies investigating the predictive value of semantic memory tasks will also be presented. We suggest several advantages associated with the use of semantic processing tasks, particularly those based on person identification, in comparison to episodic memory tasks to study AD risk. Future directions for research and potential clinical uses of semantic memory paradigms are also discussed. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

Physiological variation in estradiol and brain function: a functional magnetic resonance imaging study of verbal memory across the follicular phase of the menstrual cycle

Women frequently complain of memory problems at times in their reproductive lives that are associated with changes in estrogen concentration (e.g. around menopause and childbirth). Further, behavioural studies suggest that memory performance may fluctuate across the menstrual cycle. For example, performance on verbal tasks has been reported to be greatest during phases associated with high estrogen concentrations whereas the opposite has been reported with visuo-spatial tasks. The biological basis of these reported effects remains poorly understood. However, brain imaging studies into the effects of estrogen therapy in postmenopausal women suggest that estrogen modulates the metabolism and function of brain regions sub-serving memory. Furthermore, we have recently reported that acute suppression of ovarian function in young women (with a Gonadotropin Hormone Releasing Hormone agonist) is associated with decreased activation in left prefrontal cortex, particularly the left inferior frontal gyrus (LIFG), during successful verbal memory encoding. We therefore investigated whether physiological variation in plasma estradiol concentration is associated with differences in activity of the LIFG during successful verbal encoding. We hypothesised that higher plasma concentrations of estradiol would be associated with increased brain activity at the LIFG and improved recall performance. Although we did not find a significant relationship between plasma estradiol concentration and verbal recall performance, we report a positive correlation between brain function and estradiol concentration at the LIFG.     

Development of an α-synuclein positron emission tomography tracer for imaging synucleinopathies

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Functional magnetic resonance imaging of the primary motor cortex in humans: response to increased functional demands

Functional magnetic resonance imaging (fMRI) studies have been performed on 20 right handed volunteers at 1.5 Tesla using echo planar imaging (EPI) protocol. Index finger tapping invoked localized activation in the primary motor area. Consistent and highly reproducible activation in the primary motor area was observed in six different sessions of a volunteer over a period of one month. Increased tapping rate resulted in increase in the blood oxygenation level dependent (BOLD) signal intensity as well as the volume/area of activation (pixels) in the contra-lateral primary motor area up to tapping rate of 120 taps/min (2 Hz), beyond which it saturates. Activation in supplementary motor area was also observed. The obtained results are correlated to increased functional demands.     

Cortical activation during finger tapping in thyroid dysfunction: A functional magnetic resonance imaging study

Thyroid dysfunction is associated with attention deficit and impairment of the motor system (muscle weakness and fatigue). This paper investigates possible motor function deficit in thyroid patients, compared to the controls. Functional MRI studies (fMRI) were carried out in five hypo and five hyperthyroid patients and six healthy volunteers. Whole brain imaging was performed using echo planar imaging (EPI) technique, on a 1.5T whole body MR system (Siemens Magnetom Vision). The task paradigm consisted of 8 cycles of active and reference phases of 6 measurements each, with right index finger tapping at a rate of 120 taps/min. Post-processing was performed using statistical parametric mapping on a voxel-by-voxel basis using SPM99. Clusters of activation were found in the contralateral hemisphere in primary somatomotor area (M1), supplementary motor area (SMA), somatosensory, auditory receptive and integration areas, inferior temporal lobe, thalamus and cerebellum. Increased clusters of activation were observed in M1 in thyroid subjects as compared to controls and with bilateral activation of the primary motor cortex in two hyperthyroid patients. The results are explained in terms of increased functional demands in thyroid patients compared to volunteers for the execution of the same task.     

Capillaries within compartments: microvascular interpretation of dynamic positron emission tomography data

Measurement of exchange of substances between blood and tissue has been a long-lasting challenge to physiologists, and considerable theoretical and experimental accomplishments were achieved before the development of the positron emission tomography (PET). Today, when modeling data from modern PET scanners, little use is made of earlier microvascular research in the compartmental models, which have become the standard model by which the vast majority of dynamic PET data are analysed. However, modern PET scanners provide data with a sufficient temporal resolution and good counting statistics to allow estimation of parameters in models with more physiological realism. We explore the standard compartmental model and find that incorporation of blood flow leads to paradoxes, such as kinetic rate constants being time-dependent, and tracers being cleared from a capillary faster than they can be supplied by blood flow. The inability of the standard model to incorporate blood flow consequently raises a need for models that include more physiology, and we develop microvascular models which remove the inconsistencies. The microvascular models can be regarded as a revision of the input function. Whereas the standard model uses the organ inlet concentration as the concentration throughout the vascular compartment, we consider models that make use of spatial averaging of the concentrations in the capillary volume, which is what the PET scanner actually registers. The microvascular models are developed for both single- and multi-capillary systems and include effects of non-exchanging vessels. They are suitable for analysing dynamic PET data from any capillary bed using either intravascular or diffusible tracers, in terms of physiological parameters which include regional blood flow.     

正常人长时数字记忆信息提取的神经基础的功能磁共振研究

本文旨在通过功能磁共振成像(functional magnetic resonance imaging,fMRI)技术研究正常人进行长时数字记忆信息提取的神经基础。选取22名右利手志愿者进行长时数字记忆任务实验,采用组块设计,记忆任务与对照任务交替进行,同时利用Siemens 1.5T超导型磁共振仪进行fMRI成像,采用SPM99软件进行数据分析,脑功能区定位在Talairach坐标中显示。结果显示被试者在进行长时数字记忆提取任务时,激活最显著的皮层是左侧额中回(Brodmann分区9区,BA9区),另外左额叶内侧回、左额下回、右额下回、扣带回、左顶下小叶、左顶上小叶、右顶上小叶、右颞中回、左枕舌回、左枕中回、右中脑、小脑、右尾状核尾部等结构也有激活,各大脑皮层的激活均呈现明显的左侧半球优势。根据上述结果推论,长时数字记忆由以左侧大脑半球为优势的各脑区共同参与完成,其中左侧额叶外侧面可能是信息提取的重要结构,而其它脑叶及其之间的广泛联系可能在数字信息的加工、处理和存储中起重要作用。     

18F-2-deoxy-2-fluoro-D-glucose positron emission tomography, computed tomography, and magnetic resonance imaging for the detection of experimental colorectal liver metastases

During the treatment of colorectal liver metastases, evaluation of treatment efficacy is of the utmost importance for decision making. The aim of the present study was to explore the ability of preclinical imaging modalities to detect experimental liver metastases. Nine male Wag/Rij rats underwent a laparotomy with intraportal injection of CC531 tumor cells. On days 7, 10, and 14 after tumor induction, sequential positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging (MRI) scans were acquired of each rat. At each time point, three rats were euthanized and the metastases in the liver were documented histologically. Topographically, the liver was divided into eight segments and the image findings were compared on a segment-by-segment basis with the histopathologic findings. Sixty-four liver segments were analyzed, 20 of which contained tumor deposits. The overall sensitivity of PET, CT, and MRI was 30%, 25%, and 20%, respectively. For the detection of tumors with a histologic diameter exceeding 1 mm (n = 8), the sensitivity of PET, CT, and MRI was 63%, 38%, and 38%, respectively. The overall specificity of PET, CT, and MRI was 98%, 100%, and 93%, respectively. This study showed encouraging detectability and sensitivity for preclinical imaging of small liver tumors and provides valuable information on the imaging techniques for designing future protocols.     

Functional assessment of hepatobiliary secretion by 11C-cholylsarcosine positron emission tomography

Positron emission tomography (PET) with ¹¹C-cholylsarcosine (¹¹C-CSar), a radiolabelled synthetic N-methylglycine (sarcosine) conjugate of cholic acid, is a novel molecular imaging technique that enables quantitative assessment of the individual transport steps involved in hepatic secretion of conjugated bile acids. Here, we present the method and discuss its potential clinical and scientific applications based on findings in the first human study of healthy subjects and patients with cholestasis. We also present a clinical example of a patient studied during and six months after an episode of drug-induced cholestatic liver injury.     

Concept of functional imaging of memory decline in Alzheimer’s disease

Functional imaging methods such as Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI) have contributed inestimably to the understanding of physiological cognitive processes in the brain in the recent decades. These techniques for the first time allowed the in vivo assessment of different features of brain function in the living human subject. It was therefore obvious to apply these methods to evaluate pathomechanisms of cognitive dysfunction in disorders such as Alzheimer’s disease (AD) as well. One of the most dominant symptoms of AD is the impairment of memory. In this context, the term “memory” represents a simplification and summarizes a set of complex cognitive functions associated with encoding and retrieval of different types of information. A number of imaging studies assessed the functional changes of neuronal activity in the brain at rest and also during performance of cognitive work, with regard to specific characteristics of memory decline in AD. In the current article, basic principles of common functional imaging procedures will be explained and it will be discussed how they can be reasonably applied for the assessment of memory decline in AD. Furthermore, it will be illustrated how these imaging procedures have been employed to improve early and specific diagnosis of the disease, to understand specific pathomechanisms of memory dysfunction and associated compensatory mechanisms, and to draw reverse conclusions on physiological function of memory.     

Design,synthesis, radiolabeling and in vivo evaluation of potential positron emission tomography (PET) radioligands for brain imaging of the 5-HT7 receptor

Here we describe the design, synthesis, and pharmacological evaluation of a set of compounds structurally related to the high affinity serotonin 5-HT₇ receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (6, LP-211). Specific structural modifications were performed in order to maintain affinity for the target receptor and to improve the selectivity over 5-HT_1A and adrenergic α₁ receptors. The synthesized compounds have chemical features that could enable labeling with a positron emitter radioisotope (carbon-11 or fluorine-18) and lipophilicity within the range considered optimal for brain penetration and low non-specific binding. 4-[2-(4-Methoxyphenyl)phenyl]-N-(pyridin-4-ylmethyl)piperazinehexanamide (23a) and N-pyridin-4-ylmethyl-3-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]ethoxy]propanamide (26a) were radiolabeled on the methoxy group with carbon-11. Positron emission tomography (PET) analysis revealed that [¹¹C]-23a and [¹¹C]-26a were P-glycoprotein (P-gp) substrates and rapidly metabolized, resulting in poor brain uptake. These features were not predicted by in vitro tests.     

人脑对不同频率穴位电刺激反应的功能性磁共振成像

利用功能性磁共振方法研究人脑对不同频率穴位体表电刺激（transcutaneous electric nerve stimulation,TENS)的反应。实验对11名志愿得进行了22次脑部功能性磁共振成像。成像过程中,每名志愿者分别接受了2和100HzTENS刺激,刺激部位为左腿足三里和三阴交穴,结果为不同频率TENS都激活了初级和次级躯体感觉区,频率特异性的激活信号出现在与运动相关的区域、丘脑、边缘系统和联络皮层。结果显示,在相同穴位给予不同频率的TENS要以在大脑引起不同的反应,提示2和100HzTENS可能激活了不同的神经通路,这些神经通路分别在中枢神经系统起着不同的作用。     

Identification of positron emission tomography ligands for NPY Y5 receptors in the brain

A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide derivatives were synthesized and profiled for NPY Y5 binding affinity, brain and CSF penetrability in rats, and susceptibility to human and mouse P-glycoprotein transporters in order to develop a PET ligand. Compound 12b exhibited an acceptable profile for a PET ligand, and [¹¹C]12b was successfully utilized in clinical settings as a Y5 PET ligand.     

Evaluation of 64Cu radiolabeled anti-hPD-L1 Nb6 for positron emission tomography imaging in lung cancer tumor mice model

Recently, we selected a novel anti-hPD-L1-specific HCAb named Nb6 with high affinity (EC₅₀ = 0.65 ng/mL) for potential hPD-L1 targeted non-invasive PET imaging. In this research, Nb6 was conjugated with the bifunctional chelator NCS-Bz-NOTA ((2-[(4-Isothiocyanophenyl) methyl]-1,4,7-triazacy-clononane-1,4,7-triacetic acid)) and further labeled with radio-nuclide ⁶⁴Cu. ⁶⁴Cu-NOTA-Nb6 was prepared with over 95% labeling yield, over 99% radiochemical purity and 14–16 GBq/μmol specific activity after PD-10 column purification. It shows good stability in 0.01 M PBS and 5% HSA solutions. ⁶⁴Cu-NOTA-Nb6 has a high binding affinity to 3.60 nM which was tested by human lung adenocarcinoma A549 cell lines. Tumor lesion can be clearly observed from 20 h to 38 h by Micro-PET equipment after ⁶⁴Cu-NOTA-Nb6 administration. The study revealed that ⁶⁴Cu-NOTA-Nb6 has good lesion detection ability, high ratios between tumor and non-tumor signal and can specifically target A549 xenografted tumor model. Taken together of good stability, high binding affinity, and tumor detection ability, ⁶⁴Cu labeled Nb6 is a promising radio-tracer in diagnosing of hPD-L1 overexpression tumor, supposed to monitor PD-L1overexpression tumor progression and guide targeted therapy with PET molecular imaging.     

Single-trial classification of parallel pre-attentive and serial attentive processes using functional magnetic resonance imaging

Theories of perception have proposed a basic distinction between parallel pre-attentive and serial attentive modes of processing. However, chronometric measures are often ambiguous in separating parallel and serial processes. We have used the activity of attention-related regions of the human brain, measured with functional magnetic resonance imaging, to separate parallel from serial processes at the single-trial level in a visual quantification task. In this task, some have suggested the deployment of two qualitatively different processes, a fast parallel 'subitizing' for sets of one, two or three objects and a slow serial counting for larger sets. Our results indicate that attention-related regions of the posterior parietal and frontal cortices show a sudden increase in activity only from numerosity four onwards, confirming the parallel-serial dichotomy of subitizing and counting. Moreover, using the presence or absence of attentional shifts, as inferred from the activation of posterior parietal regions, we successfully predict whether, on a given trial, subjects deployed a serial exploration of the display or a parallel apprehension. Beyond the subitizing/counting debate, this approach may prove useful to probe the attentional demands of other cognitive tasks.     

Cross-validation of a non-invasive positron detector to measure the arterial input function for pharmacokinetic modelling in dynamic positron emission tomography

Kinetic modeling of positron emission tomography (PET) data can assess index rate of uptake, metabolism and predict disease progression more accurately than conventional static PET. However, it requires knowledge of the time-course of the arterial blood radioactivity concentration, called the arterial input function (AIF). The gold standard to acquire the AIF is by invasive means. The purpose of this study was to validate a previously developed dual readout scintillating fiber-based non-invasive positron detector, hereinafter called non-invasive detector (NID), developed to determine the AIF for dynamic PET measured from the human radial artery. The NID consisted of a 3 m long plastic scintillating fiber with each end coupled to a 5 m long transmission fiber followed by a silicon photomultiplier. The scintillating fiber was enclosed inside the grooves of a plastic cylindrical shell. Two sets of experiments were performed to test the NID against a previously validated microfluidic positron detector. A closed-loop microfluidic system combined with a wrist phantom was used. During the first experiment, the three PET radioisotopes ¹⁸F, ¹¹C and ⁶⁸Ga were tested. After optimizing the detector, a second series of tests were performed using only ¹⁸F and ¹¹C. The maximum pulse amplitude to electronic noise ratio was 52 obtained with ¹¹C. Linear regressions showed a linear relation between the two detectors. These preliminary results show that the NID can accurately detect positrons from a patient’s wrist and has the potential to non-invasively measure the AIF during a dynamic PET scan. The accuracy of these measurements needs to be determined.     

In situ positron emission tomography monitoring of endothelial cells embedded in perfused fibrin gels

In tissue engineering, the continuous monitoring of cell and tissue cultures in vitro is crucial to assess their functional status over time. However, these constructs can be large, thick and non-transparent. Medical imaging techniques can allow real-time in situ monitoring of cell and tissue cultures in thick solid scaffolds. Here, human endothelial cells were embedded in fibrin gels that were continuously perfused by a culture medium. Positron emission tomography (PET) imaging was used to assess cell viability non-destructively over periods extending up to a few weeks. PET imaging protocols were adapted and validated to measure culture perfusion and cell metabolism using [¹⁸F]-fluorodeoxyglucose (¹⁸FDG). Cell densities down to 100,000 cells/mL were detectable after 12 h of culture and cell structures were localized within the fibrin gels after 1–2 weeks of culture. PET is a promising tool to investigate a wide range of cellular properties and reveal information on tissue development.     

Spontaneous brain activity observed with functional magnetic resonance imaging as a potential biomarker in neuropsychiatric disorders

As functional magnetic resonance imaging (fMRI) studies have yielded increasing amounts of information about the brain’s spontaneous activity, they have revealed fMRI’s potential to locate changes in brain hemodynamics that are associated with neuropsychiatric disorders. In this paper, we review studies that support the notion that changes in brain spontaneous activity observed by fMRI can be used as potential biomarkers for diagnosis and treatment evaluation in neuropsychiatric disorders. We first review the methods used to study spontaneous activity from the perspectives of (1) the properties of local spontaneous activity, (2) the spatial pattern of spontaneous activity, and (3) the topological properties of brain networks. We also summarize the major findings associated with major neuropsychiatric disorders obtained using these methods. Then we review the pilot studies that have used spontaneous activity to discriminate patients from normal controls. Finally, we discuss current challenges and potential research directions to further elucidate the clinical use of spontaneous brain activity in neuropsychiatric disorders.     

Synthesis of fluorinated analogues of sphingosine-1-phosphate antagonists as potential radiotracers for molecular imaging using positron emission tomography

Sphingosine-1-phosphate (S1P) receptors play major roles in cardiovascular, immunological and neurological diseases. The recent approval of the sphingolipid drug Fingolimod (Gilenya®), a sphingosine-1-phosphate agonist for relapsing multiple sclerosis, in 2010 exemplifies the potential for targeting sphingolipids for the treatment of human disorders. Moreover, non-invasive in vivo imaging of S1P receptors that are not available till now would contribute to the understanding of their role in specific pathologies and is therefore of preclinical interest. Based on fluorinated analogues of the S1P₁ receptor antagonist W146 showing practically equal in vitro potency as the lead structure, the first S1P receptor antagonist [¹⁸F]-radiotracer has been synthesized and tested for in vivo imaging of the S1P₁ receptor using positron emission tomography (PET). Though the tracer is serum stable, initial in vivo images show fast metabolism and subsequent accumulation of free [¹⁸F]fluoride in the bones.