Current Medical Imaging - Volume 7, Issue 2, 2011

Dynamic molecular imaging methods now allow detection of acute changes in neurotransmission in the live human brain (neurotransmitter imaging) during task performance. These methods have extended the scope of neuroimaging by allowing study of neurochemical changes associated with cognitive and behavior processing. The neurotransmitter imaging methods however are at the initial stages of development. There is a need to develop novel receptor kinetic models and novel ligands so of development that multiple neurochemicals can be simultaneously detected. Even at the current stage, the technique allows better understanding of human cognition and cognitive disorders. This special issue introduces different aspects of neurotransmitter imaging and provides a flavor of the challenges ahead. Neurochemical control of human cognition has not been adequately studied because of the lack of a reliable method that can detect task induced changes in chemical concentration of the live human brain [1]. Neuroimaging studies are therefore focused the brain mostly on understanding of spatial and temporal aspects of processing. Since neurochemicals, particularly neurotransmitters are important for regulation of brain functions, investigators have explored the possibility of using dynamic molecular imaging to develop methods for detection of neurotransmitters released in the brain in response to pharmacological [2, 3] and cognitive [4-8] challenges. Most of the techniques developed for detection of neurotransmission are based on the principles of molecular imaging which has been traditionally used to study chronic changes in neurotransmission [9]. In recent years these techniques have been increasingly used to study acute changes. This was possible because of development of simplified reference tissue model [10], which allows detection and measurement of time dependent changes in receptor kinetic parameters. This model however, has a significant limitation. It requires maintenance of steady physiological state during the entire scan session. This requirement limits the scope of cognitive studies that can be performed using neurotransmitter imaging because most cognitive paradigms require volunteers to perform control and test task in the same scan session. Since a change of task violates the assumption region of steady state, we developed another model - the linear extension of simplified reference model [11] to eliminate the assumption of steady state. This model allows detection and measurement of dopamine released during transition from the control to test condition in a cognitive experiment. Development of this model allowed cognitive studies in the live human brain but there are a number of other issues that need to be addressed before full potential of neurotransmitter imaging can be exploited to study neurochemical control of the human brain. Issues that need immediate attention include improved sensitivity and specificity of detection; development of methods that allow simultaneous detection of multiple neurochemicals; development of algorithms to allow estimation of temporal sequence of activation. These developments would require efforts at multiple levels and involve formulation of better receptor kinetic models, development of newer ligands and innovative experimental designs. We hope this special issue will stimulate cross talk between experts involved in these areas. The introductory paper by Badgaiyan provides an overview of neurotransmitter imaging method. It highlights some of the basic concepts and problems associated with neurotransmitter imaging. The paper primarily focuses on imaging of dopamine neurotransmission and underscores the importance of receptor-ligand interaction at local and global levels. Dopamine imaging is further discussed by Yodar and colleagues. This paper underscores modeling and design challenges associated with dopamine imaging. It provides a good review of different approaches investigators have used to extract relevant information in neurotransmitter imaging experiments. Imaging of cholinergic receptors is reviewed by Lotfipour and colleagues. The review focuses on detection, mapping and quantification of nicotinic receptors in the context of smoking. It provides an insight into the current state of cholinergic imaging. This insight may be useful in designing studies aimed at understanding neurocognitive conditions in which the cholinergic system is dysregulated. Issues associated with receptor kinetic modeling are discussed by Wack and Badgaiyan. This paper demonstrates that in neurotransmitter imaging experiments noise can be significantly reduced by using complex singular value decomposition approach. This approach could become an integral part of image processing routine in these experiments. Finally, Liu and colleagues discuss how neurotransmitter imaging could be used to evaluate pathophysiological bases of traditional Chinese therapeutic techniques. This approach can be applied to other traditional systems of medicine. Since this is the first special issue on neurotransmitter imaging published in any journal, we hope it will allow development of novel ideas and help advance neurotransmitter imaging technique to a higher level of sensitivity and reliability....

Neurochemistry of human cognition remains uninvestigated because neuroimaging techniques have limited ability to detect neurochemical changes associated with cognitive processing. In recent years investigators have used molecular imaging to develop methods for detection, mapping and measurement of neurotransmitters released acutely during cognitive processing in the live human brain. Most of these methods exploit the competition between endogenous neurotransmitter and a radiolabeled receptor ligand. Because of the competition, the ligand concentration decreasesin the brain areas where neurotransmitter is released endogenously during a task performance. The decreased concentration is detected by measuring the activity of intravenously injected radioligand using a PET camera. The PET data acquired dynamically isapplied to a receptor kinetic model, which estimates kinetic parameter values at multiple time point. Based on these values dopamine released during performance of a task is detected, mapped and measured. By using different ligands, dopamine released inside or outside the striatum can be detected using this technique. The neurotransmitter imaging technique at present can detect acute changes only in dopamine neurotransmission. Since it significantly limits the scope, there is a need to develop methods and ligands for detection of acute changes in the levels of other neurochemicals.

This review depicts characteristics of nuclear neuroimaging investigations of dopamine release in response to non-pharmacological stimuli. Investigations of dopamine release in response to pharmacological challenges have focused mainly on the striatum, a region with a relatively high density of dopamine D2/D3 receptors. Non-pharmacological stimuli likely elicit dopamine release in extrastriatal regions with a relatively low density of dopamine D2/D3 receptors. Several strategies will facilitate the optimal design of investigations of dopamine release in response to non-pharmacological stimuli. (1) Employ radioligands with relatively high affinities for dopamine D2/D3 receptors in extrastriatal regions, including [11C] FLB457 and [11C] fallypride. (2) Correct images for head movement during the scanning procedure. (3) Develop protocols to incorporate the influences of regional blood flow on scans of dopamine D2/D3 receptors in the striatum and in extrastriatal regions. (4) Recruit healthy adults aged 18 to 35 years to avoid the effects of ageing. (5) Identify the phase of the menstrual cycle for women to account for the normal alterations in dopamine release in the various hormonal stages. Utilization of novel techniques to quantitate the dopamine release in the appropriate extrastriatal regions will likely result in fruitful advances in knowledge about non-pharmacological alternative interventions including acupuncture, the external Qi of Yan Xin Qigong, and other therapies of traditional Chinese medicine. Neuroimaging investigations of dopamine release following these alternative treatments will likely facilitate the appropriate application of alternative treatments to a vast spectrum of nervous and mental diseases. Since the effects of dopamine release on drug and non-drug interventions are powerful tools to assess the pathophysiology and the treatment of neuropsychiatric disorders, we provide this review of the literature to guide future research.

Neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated in a spectrum of cognitive functions as well as psychiatric and neurodegenerative disorders, including tobacco addiction and Alzheimer's Disease. The examination of neuronal nAChRs in living humans is a relatively new field. Researchers have developed brain-imaging radiotracers for nAChRs, with radiolabeled A-85380 compounds having the most widespread use. We provide a brief background on nAChRs, followed by a discussion of the development and application of A-85380 radiotracers in human imaging studies. We describe potential future studies using nicotinic receptor radioligands for the study of tobacco addiction, including the mechanism of action of the smoking-cessation therapy varenicline. Throughout this review, we focus on the significant potential that resides in the identification and quantification of nAChRs in the living human brain.

Individual images in dynamic molecular imaging studies are noisy because of short duration of frames. To reduce noise in these studies we used a method that employed the Hilbert transform and Singular Value Decomposition (SVD) processing. Use of this method, which we call the Complex Singular Value Decomposition (CSVD), significantly reduces noise while preserving signal intensity of dynamic images. Further, we used simulations to examine the effect of CSVD processing on estimates of receptor kinetic parameters. We found a significant reduction in variance when CSVD processing was applied to images that had Gaussian noise added to the signal. The signals were preserved even after adding noise, thus the simulations revealed that noise reduction was not at the cost of relevant signal. It therefore appears that CSVD processing can be used in dynamic molecular imaging and other similar studies to reduce noise and improve signal quality.

Over the last two decades, using PET imaging to assess changes in endogenous dopamine has become a standard neurochemical research technique. Initially, investigators focused on the in vivo study of direct pharmacological manipulation of the dopamine system (e.g., amphetamine, cocaine, methylphenidate). More recently, there has been a shift toward studying the role that dopamine plays in cognitive processes and in response to commonly used drugs with subtler effects on the dopamine system. Here, we outline the conceptual foundations of using PET to assess alterations in brain dopamine, and provide the reader with important theoretical constructs that must be addressed when designing such studies. Data from recent work with dopaminergic PET ligands are used to provide concrete examples of relevant design considerations.

In three dimensional (3D) imaging, the field of view (FOV) is a significant factor that defines the ability of the system. Due to the small flat detector, the size of the FOV is limited. It is known that the FOV can be enlarged by using a horizontally shifted detector and x-ray source, but the projection data are horizontally truncated at each view angle. We have developed a dual-helical cone-beam computed tomography (CT), in which the x-ray source and planar detector are shifted a given distance before two helical scans. This work presents another reconstruction algorithm for dual-helical cone-beam CT. The method utilizes the property that PI-line segment within the imaged object can be reconstructed if the data, on the PI-line segment, can be available. The method presented in this paper is an extension of backprojection filtration (BPF) algorithm for single helical cone-beam CT, and consists of a weight during the backprojection step. Computer simulation shows that the BPF-type algorithm for dual-helical scanning can obtain better quality images than other reconstruction method, despite the large pitch.

A variety of medications can produce severe abdominal pain simulating an acute abdomen and, in some cases, a surgical abdomen. Nonsteroidal anti-inflammatory drugs are a well-established cause of peptic ulcer. Hemorrhage is the most serious complication of antithrombotic therapy. Pseudomembraneous colitis after use of antibiotics or chemotherapeutic agents can result in acute abdominal pain. Neutropenic enterocolitis or cytomegalovirus enterocolitis often occurs in immunocompromised patients after chemotherapy. Some other medications are associated with acute pancreatitis, biliary sludge, angioedema, pneumatosis intestinalis, renal stones, and hemorrhagic cystitis. The diagnosis of medicationinduced diseases can be suggested by combinations of clinical information including acute onset of abdominal pain, medication history, laboratory data and characteristic imaging findings. Therefore, recognizing CT findings of the medicationinduced acute abdomen and knowledge of the clinical significance of each entity are important for establishing a correct diagnosis and for guiding appropriate management.

To better understand the temporal pattern of hsp70 transcription, three tumor cell lines (M21, SCCVII, NIH3T3) were transfected with a Hsp70A.1 promoter to express luciferase (luc). The cells were exposed to a range of temperatures (38-52°C) for 20 minutes and luciferase activity was measured using a CCD camera. Luciferase activity was assessed every 2 h for 12 h, then every 6 h for another 12 h, and finally every 12 h for an additional 84 h post stress. Each cell line had its own distinct temporal pattern of luciferase activity. The NIH3T3 cells had the highest luciferase activity at 46°C 12 h post-stress. The SCCVII line was the least heat resistant cell line. The human M21 line was the most heat resistant cell line, maximum luciferase activity occurred at 48°C and 48 h post-stress. At the highest level of luciferase activity, the SCCVII and the NIH3T3 line had 54% and 58% viable cells whereas the M21 line had 94%. The combination of assessing the luciferase activity and the viability of cells may be useful for gene therapy applications and for evaluating collateral thermal damage generated during treatment of biological tissue with heat.

Radiotherapy aims to deliver the prescribed radiation dose to the entire volume of moving tumor while avoiding high radiation to the adjacent healthy tissues. Due to the physiological factors, (e.g. respiratory and, to a lesser extent, cardiac motion) the tumor and its surrounding tissue inside the thorax or abdomen move dynamically. Thus the subsequent targeting uncertainty existing in intra-fractional tumor motion and deformation became the main obstacle of intensity- modulated radiation therapy (IMRT), which also gives large challenges to image-guided radiotherapy (IGRT). This article gave an overview of real-time image-guided technologies for radiotherapy, and consisted of four parts of contents, i.e. the article (1) expressly clarified the primary characteristics and the problems in dynamic radiotherapy; (2) introduced the current application level of radiotherapy on imaging, tumor detection, dealing with tumor motion and dynamic treatment; (3) compared solving methods in dealing with the intra-fractional tissue motion; (4) summarized the main aspects and the development direction of the dynamic radiotherapy.