The Role of Bioinformatics and Imaging Models in Tumorigenesis and Treatment Response of Brain and Spinal Cord Neoplasm.

This chapter focuses on the division and location of brain deformities such as tumors in magnetic resonance imaging (MRI) through Chan-Vese active contour segmentation. Brain tumor division and identification is a major test in the area of biomedical picture processing. To detect the size and location of the tumor, various techniques are available, but active contour gives accurate knowledge of the region for segmentation. Chan-Vese Active contour method provides independent, robust and more flexible segmentation. In this chapter, firstly we used preprocessing technique in which noise and unused parts of the brain and skull are removed, for this we proposed the skull stripping method. Then, we applied feature extraction to enhance the image intensity and quality, and lastly, used Chan-Vese active contour with a level set image segmentation technique to detect the tumor. The tumor area was calculated after tumor detection.

Convergence Analysis of Adaptive Exponential Functional Link Network.

The adaptive exponential functional link network (AEFLN) is a recently introduced novel linear-in-the-parameters nonlinear filter and is used in numerous nonlinear applications, including system identification, active noise control, and echo cancellation. The improved modeling accuracy offered by AEFLN for different nonlinear applications can be attributed to the exponentially varying sinusoidal basis functions used for nonlinear expansion. Even though AEFLN has been widely used for the identification of nonlinear systems, no theoretical analysis of AEFLN is available in the literature. Hence, in this article, a theoretical performance analysis of AEFLN trained using an adaptive exponential least mean square (AELMS) algorithm under the Gaussian input assumption is discussed. Expressions describing the mean as well as mean square behavior of the weight vector and adaptive exponential parameter are derived. Computer simulations are carried out, and the derived theoretical expressions show a close correspondence with simulation results.

The application of a multi-reference control strategy to noise cancelling headphones.

Active noise cancelling (ANC) headphones have seen significant commercial success and a number of control strategies have been proposed, including feedforward, feedback, and hybrid configurations, using both analogue and digital implementations. Irrespective of the configuration or implementation approach, the strategies proposed in the open-literature have focused on implementations where the control system for each ear of the headphones operates independently. In this paper, a multi-reference ANC strategy is proposed and investigated for noise cancelling headphones. As with standard feedforward ANC headphones, the system utilises a single error microphone and single reference microphone on each cup; however, in the proposed configuration, the left and right reference microphones are used to achieve control at both the left and right ear cups. The performance of this controller design is compared to a standard single reference feedforward controller implementation under a variety of different sound field conditions. Although the proposed strategy requires an increased computational demand, it is shown that there is a significant control advantage for noise sources originating from the side of the user, whilst the performance for front and rear sources is maintained.

KELM-CPPpred: Kernel Extreme Learning Machine Based Prediction Model for Cell-Penetrating Peptides.

Cell-penetrating peptides (CPPs) facilitate the transport of pharmacologically active molecules, such as plasmid DNA, short interfering RNA, nanoparticles, and small peptides. The accurate identification of new and unique CPPs is the initial step to gain insight into CPP activity. Experiments can provide detailed insight into the cell-penetration property of CPPs. However, the synthesis and identification of CPPs through wet-lab experiments is both resource- and time-expensive. Therefore, the development of an efficient prediction tool is essential for the identification of unique CPP prior to experiments. To this end, we developed a kernel extreme learning machine (KELM) based CPP prediction model called KELM-CPPpred. The main data set used in this study consists of 408 CPPs and an equal number of non-CPPs. The input features, used to train the proposed prediction model, include amino acid composition, dipeptide amino acid composition, pseudo amino acid composition, and the motif-based hybrid features. We further used an independent data set to validate the proposed model. In addition, we have also tested the prediction accuracy of KELM-CPPpred models with the existing artificial neural network (ANN), random forest (RF), and support vector machine (SVM) approaches on respective benchmark data sets used in the previous studies. Empirical tests showed that KELM-CPPpred outperformed existing prediction approaches based on SVM, RF, and ANN. We developed a web interface named KELM-CPPpred, which is freely available at http://sairam.people.iitgn.ac.in/KELM-CPPpred.html.

Metabolic changes in the rodent brain after acute administration of salvinorin A.

PURPOSE: Salvinorin A (SA) is a potent and highly selective kappa-opioid receptor (KOR) agonist with rapid kinetics and commensurate behavioral effects; however, brain regions associated with these effects have not been determined. PROCEDURES: Freely moving adult male rats were given SA intraperitoneally during uptake and trapping of the brain metabolic radiotracer, 2-deoxy-2-[F-18]fluoro-D: -glucose (FDG), followed by image acquisition in a dedicated animal positron emission tomography (PET) system. Age-matched control animals received vehicle treatment. Animal behavior during FDG uptake was recorded digitally and later analyzed for locomotion. Group differences in regional FDG uptake normalized to whole brain were determined using Statistical Parametric Mapping (SPM) and verified by region of interest (ROI) analysis. RESULTS: SA-treated animals demonstrated significant increases in FDG uptake compared to controls in several brain regions associated with the distribution of KOR such as the periaqueductal grey, bed nucleus of the stria terminalis and the cerebellar vermis, as well as in the hypothalamus. Significant bilateral activations were also observed in the auditory, sensory, and frontal cortices. Regional decreases in metabolic demand were observed bilaterally in the dorsolateral striatum and hippocampus. Locomotor activity did not differ between SA and vehicle during FDG uptake. CONCLUSIONS: We have provided the first extensive maps of cerebral metabolic activation due to the potent kappa-opioid agonist, salvinorin A. A major finding from our small animal PET studies using FDG was that neural circuits affected by SA may not be limited to direct activation or inhibition of kappa-receptor-expressing cells. Instead, salvinorin A may trigger brain circuits that mediate the effects of the drug on cognition, mood, fear and anxiety, and motor output.

Racemic gamma vinyl-GABA (R,S-GVG) blocks methamphetamine-triggered reinstatement of conditioned place preference.

Preventing relapse poses a significant challenge to the successful management of methamphetamine (METH) dependence. Although no effective medication currently exists for its treatment, racemic gamma vinyl-GABA (R,S-GVG, vigabatrin) shows enormous potential as it blocks both the neurochemical and behavioral effects of a variety of drugs, including METH, heroin, morphine, ethanol, nicotine, and cocaine. Using the reinstatement of a conditioned place preference (CPP) as an animal model of relapse, the present study specifically investigated the ability of an acute dose of R,S-GVG to block METH-triggered reinstatement of a METH-induced CPP. Animals acquired a METH CPP following a 20-day-period of conditioning, in which they received 10 pairings of alternating METH and saline injections. During conditioning, rats were assigned to one of four METH dosage groups: 1.0, 2.5, 5.0, or 10.0 mg/kg (i.p., n = 8/group). Animals in all dosage groups demonstrated a robust and consistent CPP. This CPP was subsequently extinguished in each dosage group with repeated saline administration. Upon extinction, all groups reinstated following an acute METH challenge. On the following day, an acute dose of R,S-GVG (300 mg/kg, i.p.) was administered 2.5 h prior to an identical METH challenge. R,S-GVG blocked METH-triggered reinstatement in all four groups. Given that drug re-exposure may potentiate relapse to drug-seeking behavior, the ability of R,S-GVG to block METH-triggered reinstatement offers further support for its use in the successful management of METH dependence.

Subchronic racemic gamma vinyl-GABA produces weight loss in Sprague Dawley and Zucker fatty rats.

Given the growing obesity epidemic, pressure to develop an effective pharmacologic treatment is mounting. Following the completion of a randomized, double-blind, placebo controlled trial as well as two small open label trials, gamma vinyl-GABA (GVG) has been shown to be safe and effective for treating cocaine and/or methamphetamine dependence. In an extension of these findings, the present study examined whether GVG could produce weight loss in adolescent as well as genetically obese animals. Specifically, adolescent Sprague Dawley and adolescent and adult Zucker fatty rats received GVG at various doses (75-300 mg/kg, i.p., racemic) for treatment periods lasting no longer than 14 consecutive days. GVG produced significant weight loss in a dose dependent fashion in all groups. These effects were marked, as average decreases of 12-20% of original body weight were observed. These findings suggest that GVG may be useful as a treatment for obesity. Further, that these results occurred in genetically obese animals offers the possibility that GVG may even help manage severe obesity resulting from binge-eating, a disorder involving food consumption in a pattern similar to the compulsive drug-seeking behavior observed in cocaine and methamphetamine dependent subjects.

Imaging dopamine release with Positron Emission Tomography (PET) and (11)C-raclopride in freely moving animals.

We investigated an imaging strategy that provides simultaneous measurements of radiotracer binding and behavior in awake, freely moving animals. In this strategy, animals are injected intravenously (i.v.) through a catheterized line and permitted to move freely for 30 min during uptake of the imaging agent, in this case 11C-raclopride. After this Awake Uptake period, animals are anesthetized and scanned for 25 min. We tested the utility of this strategy for measuring changes in striatal 11C-raclopride binding under control conditions (awake and freely moving in the home cage) and with several drug challenges: a loading dose of unlabeled raclopride, pretreatment with methamphetamine (METH) or pretreatment with gamma-vinyl-GABA [S+-GVG] followed by METH. An additional group of animals underwent a stress paradigm that we have previously shown increases brain dopamine. For drug challenge experiments, the change in 11C-raclopride binding was compared to data from animals that were anesthetized for the uptake period ("Anesthetized Uptake") and full time activity curves were used to calculate 11C-raclopride binding. Regardless of the drug treatment protocol, there was no difference in 11C-raclopride striatum to cerebellum ratio between the Awake versus the Anesthetized Uptake conditions. Awake and Anesthetized groups demonstrated over 90% occupancy of dopamine receptors with a loading dose of cold raclopride, both groups demonstrated approximately 30% reduction in 11C-raclopride binding from METH pretreatment and this effect was modulated to the same degree by GVG under both uptake conditions. Restraint during Awake Uptake decreased 11C-raclopride binding by 29%. These studies support a unique molecular imaging strategy in which radiotracer uptake occurs in freely moving animals, after which they are anesthetized and scanned. This imaging strategy extends the applicability of small animal PET to include functional neurotransmitter imaging and the neurochemical correlates of behavioral tasks.

Targeting the treatment of drug abuse with molecular imaging.

Although imaging studies in and of themselves have significant contributions to the study of human behavior, imaging in drug abuse has a much broader agenda. Drugs of abuse bind to molecules in specific parts of the brain in order to produce their effects. Positron emission tomography (PET) provides a unique opportunity to track this process, capturing the kinetics with which an abused compound is transported to its site of action. The specific examples discussed here were chosen to illustrate how PET can be used to map the regional distribution and kinetics of compounds that may or may not have abuse liability. We also discussed some morphological and functional changes associated with drug abuse and different stages of recovery following abstinence. PET measurements of functional changes in the brain have also led to the development of several treatment strategies, one of which is discussed in detail here. Information such as this becomes more than a matter of academic interest. Such knowledge can provide the bases for anticipating which compounds may be abused and which may not. It can also be used to identify biological markers or changes in brain function that are associated with progression from drug use to drug abuse and also to stage the recovery process. This new knowledge can guide legislative initiatives on the optimal duration of mandatory treatment stays, promoting long-lasting abstinence and greatly reducing the societal burden of drug abuse. Imaging can also give some insights into potential pharmacotherapeutic targets to manage the reinforcing effects of addictive compounds, as well as into protective strategies to minimize their toxic consequences.

Brain metabolic changes following 4-week citalopram infusion: increased 18FDG uptake and gamma-amino butyric acid levels.

We used 2-week and 4-week citalopram infusion (10 mg/kg/day) to determine how this selective serotonin reuptake inhibitor (SSRI) would alter 2-deoxy-2-[18F]-fluoro-D-glucose (18FDG) uptake and neurotransmitter tissue levels in male Sprague-Dawley rodents. A weekly time course of 18FDG uptake altered by chronic citalopram treatment was determined in vivo with small animal positron emission tomography (microPET). Additionally, end of study monoamine levels were measured ex vivo using high pressure liquid chromatography (HPLC) and amino acid levels were determined ex vivo with proton nuclear magnetic resonance spectroscopy (1H-NMRS). We found increased striatal 18FDG uptake, reduced tissue levels of noradrenaline and serotonin in the striatum and prefrontal cortex, and increased striatal gamma-amino-butyric acid following 4-week citalopram infusion.

Synthesis and positron emission tomography studies of C-11-labeled isotopomers and metabolites of GTS-21, a partial alpha7 nicotinic cholinergic agonist drug.

INTRODUCTION: (3E)-3-[(2,4-dimethoxyphenyl)methylene]-3,4,5,6-tetrahydro-2,3'-bipyridine (GTS-21), a partial alpha7 nicotinic acetylcholine receptor agonist drug, has recently been shown to improve cognition in schizophrenia and Alzheimer's disease. One of its two major demethylated metabolites, 4-OH-GTS-21, has been suggested to contribute to its therapeutic effects. METHODS: We labeled GTS-21 in two different positions with carbon-11 ([2-methoxy-(11)C]GTS-21 and [4-(11)C]GTS-21) along with two corresponding demethylated metabolites ([2-methoxy-(11)C]4-OH-GTS-21 and [4-methoxy-(11)C]2-OH-GTS-21) for pharmacokinetic studies in baboons and mice with positron emission tomography (PET). RESULTS: Both [2-(11)C]GTS-21 and [4-methoxy-(11)C]GTS-21 showed similar initial high rapid uptake in baboon brain, peaking from 1 to 3.5 min (0.027-0.038%ID/cc) followed by rapid clearance (t(1/2)<15 min), resulting in low brain retention by 30 min. However, after 30 min, [2-methoxy-(11)C]GTS-21 continued to clear while [4-methoxy-(11)C]GTS-21 plateaued, suggesting the entry of a labeled metabolite into the brain. Comparison of the pharmacokinetics of the two labeled metabolites confirmed expected higher brain uptake and retention of [4-methoxy-(11)C]2-OH-GTS-21 (the labeled metabolite of [4-methoxy-(11)C]GTS-21) relative to [2-methoxy-(11)C]4-OH-GTS-21 (the labeled metabolite of [2-methoxy-(11)C]GTS-21), which had negligible brain uptake. Ex vivo studies in mice showed that GTS-21 is the major chemical form in the mouse brain. Whole-body dynamic PET imaging in baboon and mouse showed that the major route of excretion of C-11 is through the gallbladder. CONCLUSIONS: The major findings are as follows: (a) extremely rapid uptake and clearance of [2-methoxy-(11)C]GTS-21 from the brain, which may need to be considered in developing optimal dosing of GTS-21 for patients, and (b) significant brain uptake of 2-OH-GTS-21, suggesting that it might contribute to the therapeutic effects of GTS-21. This study illustrates the value of comparing different label positions and labeled metabolites to gain insight on the behavior of a central nervous system drug and its metabolites in the brain, providing an important perspective on drug pharmacokinetics.

Serial microPET measures of the metabolic reaction to a microdialysis probe implant.

Despite the widespread use of chronic brain implants in experimental and clinical settings, the effects of these long-term procedures on brain metabolism and receptor expression remain largely unknown. Under the hypothesis that intracerebral microdialysis transiently alters tissue metabolism, we performed a series of 18FDG microPET scans prior to and following surgical implantation of microdialysis cannulae. Parallel microPET measures using the competitive dopamine (DA) D2 receptor antagonist, 11C-raclopride, provided an assay of DA stability in these same animals. 18FDG scans were performed prior to microdialysis cannulation and again at 2, 12, 24, 48, 120, 168, 360 and 500 h (0.2, 0.5, 1, 2, 5, 7, 15 and 25 days). Separate animals received a sham surgery and the control group had no surgical intervention. For the first 24 h (scans at 2, 12 and 24 h post-surgery) uptake was reduced in both hemispheres. However, by 48 h, contralateral uptake had returned to pre-surgical levels. The striking finding was that from 48 to 500 h, the microdialysis cannulation produced widespread ipsilateral reductions in 18FDG uptake that encompassed the entire hemisphere. Despite the extent and persistence of these reductions, 11C-raclopride binding and ECF DA concentrations remained stable.