H Donald Gage

Wake Forest School of Medicine, Winston-Salem, NC, United States

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Publications (48)202.77 Total impact

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    ABSTRACT: Chronic treatment with dopamine (DA) receptor agonists and antagonists can differentially affect measures of DA D2/D3 receptor number and function, but the effects of chronic treatment with a partial D2/D3 receptor agonist are not clear. We used a within-subjects design in male cynomolgus monkeys to determine the effects of repeated (17-day) treatment with the D2/D3 receptor partial agonist aripiprazole (ARI; 0.03 mg/kg and 0.1 mg/kg i.m.) on food-reinforced behavior (n = 5) and on D2/D3 receptor availability as measured with positron emission tomography (PET; n = 9). Five monkeys responded under a fixed-ratio 50 schedule of food reinforcement and D2/D3 receptor availability was measured before and 4 days after ARI treatment using PET and the D2/D3 receptor-selective radioligand [(18)F]fluoroclebopride (FCP). Four additional monkeys were studied using [(11)C]raclopride and treated sequentially with each dose of ARI for 17 days. ARI decreased food-maintained responding with minimal evidence of tolerance. Repeated ARI administration increased FCP and raclopride distribution volume ratios (DVRs) in the caudate nucleus and putamen in most monkeys, but decreases were observed in monkeys with the highest baseline DVRs. The results indicate that repeated treatment with a low-efficacy DA receptor partial agonist produces effects on brain D2/D3 receptor availability that are qualitatively different from those of both high-efficacy receptor agonists and antagonists, and suggest that the observed individual differences in response to ARI treatment may reflect its partial agonist activity.
    Psychopharmacology 09/2013; · 4.06 Impact Factor
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    ABSTRACT: PURPOSE To determine the frequency of patient-reported problems associated with the use of CDs to share outside medical imaging studies. METHOD AND MATERIALS Surveys were completed by adult patients (N = 96) in waiting rooms at a cancer clinic, radiology/MRI clinic, neurology clinic, and a general clinic serving low-income patients located in an urban area in North Carolina. This analysis restricts itself to the 53 patients who reported having had an imaging study conducted during the previous 3 years and having had to get a copy of an imaging study conducted at one hospital or outpatient center to a physician at a another location by CD. Participant responses refer to experiences during the past three years only. RESULTS Patients who had an imaging study conducted at one location and needed to have a CD copy of that imaging study provided to a physician at another location reported numerous challenges. Fifty-eight percent (29/50) reported travel of at least 5 miles to pick up an imaging study on CD or sign a form, and 38% (19/50) traveled at least 15 miles. Forty-nine percent (24/49) of patients indicated that at least 30 minutes had been spent performing tasks, such as making telephone calls and traveling to another practice or imaging center, to ensure that their physician would have the outside imaging CD. Furthermore, 25% (13/51) indicated that one or more appointments were canceled or treatment decisions delayed because their physician was waiting to receive the CD with the imaging study. Thirty-two percent (16/50) of patients reported that they had to have a duplicate scan primarily because their physician did not have a copy of an outside imaging CD. CONCLUSION Use of CDs to provide copies of imaging studies conducted at outside facilities to physicians providing patient care imposes a substantial burden on patients. Development of a successful system to share imaging studies across facilities should limit patient burden. CLINICAL RELEVANCE/APPLICATION Use of CDs to provide copies of imaging studies to physicians at outside facilities imposes substantial burdens on patients and leads to treatment delays and duplication of imaging.
    Radiological Society of North America 2012 Scientific Assembly and Annual Meeting; 11/2012
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    ABSTRACT: BACKGROUND: Current image sharing is carried out by manual transportation of CDs by patients or organization-coordinated sharing networks. The former places a significant burden on patients and providers. The latter faces challenges to patient privacy. OBJECTIVE: To allow healthcare providers efficient access to medical imaging data acquired at other unaffiliated healthcare facilities while ensuring strong protection of patient privacy and minimizing burden on patients, providers, and the information technology infrastructure. METHODS: An image sharing framework is described that involves patients as an integral part of, and with full control of, the image sharing process. Central to this framework is the Patient Controlled Access-key REgistry (PCARE) which manages the access keys issued by image source facilities. When digitally signed by patients, the access keys are used by any requesting facility to retrieve the associated imaging data from the source facility. A centralized patient portal, called a PCARE patient control portal, allows patients to manage all the access keys in PCARE. RESULTS: A prototype of the PCARE framework has been developed by extending open-source technology. The results for feasibility, performance, and user assessments are encouraging and demonstrate the benefits of patient-controlled image sharing. DISCUSSION: The PCARE framework is effective in many important clinical cases of image sharing and can be used to integrate organization-coordinated sharing networks. The same framework can also be used to realize a longitudinal virtual electronic health record. CONCLUSION: The PCARE framework allows prior imaging data to be shared among unaffiliated healthcare facilities while protecting patient privacy with minimal burden on patients, providers, and infrastructure. A prototype has been implemented to demonstrate the feasibility and benefits of this approach.
    Journal of the American Medical Informatics Association 08/2012; · 3.57 Impact Factor
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    ABSTRACT: Despite the widespread use of stimulant medications for the treatment of attention deficit hyperactivity disorder, few studies have addressed their long-term effects on the developing brain or susceptibility to drug use in adolescence. Here, we determined the effects of chronic methylphenidate (MPH) treatment on brain dopamine (DA) systems, developmental milestones, and later vulnerability to substance abuse in juvenile nonhuman primates. Male rhesus monkeys (approximately 30 months old) were treated daily with either a sustained release formulation of MPH or placebo (N=8 per group). Doses were titrated to achieve initial drug blood serum levels within the therapeutic range in children and adjusted throughout the study to maintain target levels. Growth, including measures of crown-rump length and weight, was assessed before and after 1 year of treatment and after 3-5 months washout. In addition, positron emission tomography scans were performed to quantify binding availability of D2/D3 receptors and dopamine transporters (DATs). Distribution volume ratios were calculated to quantify binding of [(18)F]fluoroclebopride (DA D2/D3) and [(18)F]-(+)-N-(4-fluorobenzyl)-2β-propanoyl-3β-(4-chlorophenyl)tropane (DAT). Chronic MPH did not differentially alter the course of weight gain or other measures of growth, nor did it influence DAT or D2/D3 receptor availability after 1 year of treatment. However, after washout, the D2/D3 receptor availability of MPH-treated animals did not continue to decline at the same rate as control animals. Acquisition of intravenous cocaine self-administration was examined by first substituting saline for food reinforcement and then cocaine doses (0.001-0.1 mg/kg per injection) in ascending order. Each dose was available for at least five consecutive sessions. The lowest dose of cocaine that maintained response rates significantly higher than saline-contingent rates was operationally defined as acquisition of cocaine reinforcement. There were no differences in rates of acquisition, overall response rates, or cocaine intake as a function of cocaine dose between groups. In an animal model that closely mimics human development; chronic treatment with therapeutic doses of sustained release MPH did not have a significant influence on the regulation of DATs or D2/D3 receptors, or on standard measures of growth. Furthermore, this treatment regimen and subsequent drug washout did not have an impact on vulnerability to cocaine abuse.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2012; 37(12):2555-65. · 8.68 Impact Factor
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    ABSTRACT: Chronic cocaine use is associated with neurobiological and cognitive deficits that persist into abstinence, hindering success of behavioral treatment strategies and perhaps increasing likelihood of relapse. The effects of current cocaine use and abstinence on neurobiology and cognition are not well characterized. Adult male rhesus monkeys with an extensive cocaine self-administration history (∼ 5 years) and age-matched control animals (n = 4/group) performed cognitive tasks in morning sessions and self-administered cocaine or food in afternoon sessions. Positron emission tomography and [(18)F]-fluorodeoxyglucose were employed to assess cerebral metabolic rates of glucose utilization during cognitive testing. Cocaine-experienced monkeys required significantly more trials and committed more errors on reversal learning and multidimensional discriminations, compared with control animals. Cocaine-naive, but not cocaine-experienced, monkeys showed greater metabolic rates of glucose utilization during a multidimensional discrimination task in the caudate nucleus, hippocampus, anterior and posterior cingulate, and regions associated with attention, error detection, memory, and reward. Using a delayed match-to-sample task, there were no differences in baseline working memory performance between groups. High-dose cocaine self-administration disrupted delayed match-to-sample performance but tolerance developed. Acute abstinence from cocaine did not affect performance, but by day 30 of abstinence, accuracy increased significantly, while performance of cocaine-naive monkeys was unchanged. These data document direct effects of cocaine self-administration on cognition and neurobiological sequelae underlying cognitive deficits. Improvements in working memory can occur in abstinence, albeit across an extended period critical for treatment seekers, suggesting pharmacotherapies designed to enhance cognition may improve success of current behavioral modification strategies.
    Biological psychiatry 06/2012; 72(10):856-63. · 8.93 Impact Factor
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    ABSTRACT: Brain imaging and behavioral studies suggest an inverse relationship between dopamine (DA) D2/D3 receptors and vulnerability to cocaine abuse, although most research has used males. For example, male monkeys that become dominant in a social group have significant elevations in D2/D3 receptor availability and are less vulnerable to cocaine reinforcement. DA D2/D3 receptor availability was assessed in female cynomolgus monkeys (n = 16) with positron emission tomography (PET) while they were individually housed, 3 months after stable social hierarchies had formed, and again when individually housed. In addition, PET was used to examine changes in dopamine transporter (DAT) availability after social hierarchy formation. After imaging studies were complete, monkeys received implantation with indwelling intravenous catheters and self-administered cocaine (.001-.1 mg/kg/injection) under a fixed-ratio 30 schedule of reinforcement. Acquisition of cocaine reinforcement occurred when response rates were significantly higher than when saline was self-administered. Neither DAT nor D2/D3 receptor availability in the caudate nucleus and putamen was predictive of social rank, but both significantly changed after formation of social hierarchies. DA D2/D3 receptor availability significantly increased in females that became dominant, whereas DAT availability decreased in subordinate females. Dominant female monkeys acquired cocaine reinforcement at significantly lower doses than subordinate monkeys. The relationship between D2/D3 receptor availability and vulnerability to cocaine reinforcement seems, on the basis of these findings, opposite in females and males. These data indicate that the social environment profoundly affects the DA system but does so in ways that have different functional consequences for females than for males.
    Biological psychiatry 04/2012; 72(5):414-21. · 8.93 Impact Factor
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    ABSTRACT: Scant knowledge exists describing health care providers' and staffs' experiences sharing imaging studies. Additional research is needed to determine the extent to which imaging studies are shared in diverse health care settings, and the extent to which provider or practice characteristics are associated with barriers to viewing external imaging studies on portable media. This analysis uses qualitative data to 1) examine how providers and their staff accessed outside medical imaging studies, 2) examine whether use or the desire to use imaging studies conducted at outside facilities varied by provider specialty or location (urban, suburban, and small town) and 3) delineate difficulties experienced by providers or staff as they attempted to view and use imaging studies available on portable media. Semi-structured interviews were conducted with 85 health care providers and medical facility staff from urban, suburban, and small town medical practices in North Carolina and Virginia. The interviews were audio recorded, transcribed, then systematically analyzed using ATLAS.ti. Physicians at family and pediatric medicine practices rely primarily on written reports for medical studies other than X-rays; and thus do not report difficulties accessing outside imaging studies. Subspecialists in urban, suburban, and small towns view imaging studies through internal communication systems, internet portals, or portable media. Many subspecialists and their staff report experiencing difficulty and time delays in accessing and using imaging studies on portable media. Subspecialists have distinct needs for viewing imaging studies that are not shared by typical primary care providers. As development and implementation of technical strategies to share medical records continue, this variation in need and use should be noted. The sharing and viewing of medical imaging studies on portable media is often inefficient and fails to meet the needs of many subspeciality physicians, and can lead to repeated imaging studies.
    Applied Clinical Informatics 01/2012; 3(4):475-87. · 0.39 Impact Factor
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    ABSTRACT: BACKGROUND PCARE is an innovative approach for personally controlled sharing of medical imaging data. It enables effective sharing among healthcare facilities without significant demands on network and storage resources and provides patients easy and explicit control of the sharing of their imaging studies with maximal protection of their privacy. At the same time, it allows healthcare facilities and providers to maintain control of their patient data with significant flexibility to protect their medico-legal and business interests. The mechanisms for personal control of health information are not present in current standards for healthcare information exchange (HIE). In this presentation we describe how standards specified in Integrating Healthcare Enterprises (IHE) can be adapted and extended to implement personally controlled sharing through the implementation of a PCARE-IHE network. EVALUATION The PCARE-IHE network is implemented with two levels of the IHE Cross Enterprise Document Sharing for Imaging (XDS-I) profile. At the core of PCARE-IHE is an extended version of XDS-I, we will call PXDS-I, that enables patient participation and control in image sharing. The PXDS-I includes a Patient-driven Master Patient Index (PMPI), a Protected Document Registry, a Protected Document Repository, and multiple Protected Imaging Document Source and Consumer Pairs (PDSC). The PMPI rely on patient participation for record linkage. The protected versions of IHE actors ensure that imaging data are shared only when patient authentication and authorization are verified. Each PDSC is coupled with a conventional XDS-I that interfaces with Imaging Document Sources and Consumers at each facility. This two level design allows the PCARE-IHE network to include HIEs as nodes. DISCUSSION By extending the IHE framework, the PCARE-IHE provides a robust and standards-based mechanism for personal control of image sharing across unaffiliated providers. The proposed PXDS-I profile will be submitted to IHE standards committee for consideration. CONCLUSION We will demonstrate how IHE XDS-I and its extended version PXDS-I can be effectively applied to implement PCARE-IHE as a personally controlled, secure and scalable image-sharing network. FIGURE (OPTIONAL)
    Radiological Society of North America 2011 Scientific Assembly and Annual Meeting; 11/2011
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    ABSTRACT: Cocaine self-administration alters brain dopaminergic and serotonergic function primarily in mesolimbic and prefrontal brain regions whereas 3,4-methylenedioxymethamphetamine (MDMA) self-administration predominately alters brain serotonergic function in a more widespread distribution across cortical regions. We previously reported that, compared to drug-naïve rhesus monkeys, self-administration of cocaine but not MDMA was associated with increased serotonin transporter (SERT) availability in two mesolimbic regions, the caudate nucleus and putamen, as measured by positron emission tomography (PET) using the SERT-specific ligand [(11)C]-3-amino-4(2-dimethylamino-methyl-phenylsulfanyl)-benzonitrile ([(11)C]DASB). The goal of the present study was to extend this comparison between cocaine and MDMA self-administration to SERT availability in cortical regions, which have been shown previously to be affected in human drug abusers and are associated with executive function. PET studies using [(11)C]DASB were conducted in adult male rhesus monkeys with a history of cocaine (mean intake = 742.6 mg/kg) or MDMA (mean intake = 121.0 mg/kg) self-administration, and drug-naïve controls (n = 4/group). Regions of interest were drawn for several cortical (prefrontal, temporal, parietal, occipital and midcingulate) and subcortical (thalamus, amygdala and hippocampus) areas. Cortical SERT availability was significantly higher in monkeys with a cocaine self-administration history compared to controls whereas MDMA self-administration resulted in lower levels of SERT availability. These data extend our previous findings indicating that cocaine and MDMA self-administration differentially alter SERT availability in subcortical and cortical regions, which may have implications for development of treatment drugs.
    Neuropharmacology 01/2011; 61(1-2):245-51. · 4.11 Impact Factor
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    ABSTRACT: Cocaine use during pregnancy is associated with alterations in the dopamine (DA) system in the fetal brain. However, little is known about the effects of prenatal cocaine exposure on the postnatal dopaminergic system. The objective of the study was to examine DA receptor function in adult monkeys that were prenatally exposed to cocaine. Male and female rhesus monkeys (approximately 13 years old) that had been prenatally exposed to cocaine (n = 10) and controls (n = 10) were used in all studies. First, DA D2-like receptor availability was assessed using positron emission tomography and the D2-like receptor radiotracer [(18)F]fluoroclebopride (FCP). Next, D(3) receptor function was assessed by measuring quinpirole-induced yawning (0.03-0.3 mg/kg). Finally, D1-like receptor function was examined by measuring eye blinking elicited by the high-efficacy D1-like receptor agonist SKF81297 (0.3-3.0 mg/kg). There were no differences between groups or sexes in D2-like receptor availability in the caudate nucleus, putamen or amygdala. However, quinpirole elicited significantly more yawns in prenatally cocaine-exposed monkeys compared with control monkeys. A significant correlation between gestational dose of cocaine and peak effects of quinpirole was observed. In all monkeys, administration of SKF81297 elicited dose-dependent increases in eye blinks that did not differ between groups. These findings suggest that prenatal cocaine exposure can have long-term effects on DA D(3) receptor function in adults.
    Psychopharmacology 07/2010; 210(4):481-8. · 4.06 Impact Factor
  • Haiyong Xu, H. Donald Gage, Pete Santago
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    ABSTRACT: Most colon CAD (computer aided detection) software products, especially commercial products, are designed for use by radiologists in a clinical environment. Therefore, those features that effectively assist radiologists in finding polyps are emphasized in those tools. However, colon CAD researchers, many of whom are engineers or computer scientists, are working with CT studies in which polyps have already been identified using CT Colonography (CTC) and/or optical colonoscopy (OC). Their goal is to utilize that data to design a computer system that will identify all true polyps with no false positive detections. Therefore, they are more concerned with how to reduce false positives and to understand the behavior of the system than how to find polyps. Thus, colon CAD researchers have different requirements for tools not found in current CAD software. We have implemented a module in 3D Slicer to assist these researchers. As with clinical colon CAD implementations, the ability to promptly locate a polyp candidate in a 2D slice image and on a 3D colon surface is essential for researchers. Our software provides this capability, and uniquely, for each polyp candidate, the prediction value from a classifier is shown next to the 3D view of the polyp candidate, as well as its CTC/OC finding. This capability makes it easier to study each false positive detection and identify its causes. We describe features in our colon CAD system that meets researchers' specific requirements. Our system uses an open source implementation of a 3D Slicer module, and the software is available to the pubic for use and for extension (http://www2.wfubmc.edu/ctc/download/).© (2010) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.
    03/2010;
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    Paul W Czoty, H Donald Gage, Michael A Nader
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    ABSTRACT: Studies in socially housed monkeys have demonstrated an influence of position in the social dominance hierarchy on brain dopamine D2 receptors and the reinforcing effects of cocaine that dissipates after long-term cocaine self-administration. The aims of the study were to examine the effects of abstinence from cocaine on D2 receptors in socially housed monkeys and to extend behavioral characterizations to measures of reactivity to a novel object. Twelve socially housed male cynomolgus monkeys with extensive cocaine self-administration experience were used (average lifetime intakes ∼270 and 215 mg/kg for dominant and subordinate monkeys, respectively). Abstinence lasted for approximately 8 months, after which D2 receptor availability was assessed using positron emission tomography and the D2 ligand [18F]fluoroclebopride. Reaction to novelty was also assessed in these subjects as well as nine individually housed monkeys. During abstinence, D2 receptor availability in the caudate nucleus was significantly higher in dominant versus subordinate monkeys. Average latency to touch a novel object was also significantly higher in dominant monkeys compared to subordinates or individually housed monkeys. In socially experienced monkeys, a significant positive correlation was observed between caudate nucleus D2 receptor availability and latencies to touch the novel object. Although chronic cocaine self-administration blunts the ability of social dominance to alter D2 receptor availability and sensitivity to the reinforcing effects of cocaine, this influence reemerges during abstinence. In addition, the data suggest that prior experience with social dominance can lead to longer latencies in reaction to novelty--a personality trait associated with low vulnerability to cocaine abuse.
    Psychopharmacology 03/2010; 208(4):585-92. · 4.06 Impact Factor
  • Haiyong Xu, H. Donald Gage, Pete Santago
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    ABSTRACT: Most colon CAD (computer aided detection) software products, especially commercial products, are designed for use by radiologists in a clinical environment. Therefore, those features that effectively assist radiologists in finding polyps are emphasized in those tools. However, colon CAD researchers, many of whom are engineers or computer scientists, are working with CT studies in which polyps have already been identified using CT Colonography (CTC) and/or optical colonoscopy (OC). Their goal is to utilize that data to design a computer system that will identify all true polyps with no false positive detections. Therefore, they are more concerned with how to reduce false positives and to understand the behavior of the system than how to find polyps. Thus, colon CAD researchers have different requirements for tools not found in current CAD software. We have implemented a module in 3D Slicer to assist these researchers. As with clinical colon CAD implementations, the ability to promptly locate a polyp candidate in a 2D slice image and on a 3D colon surface is essential for researchers. Our software provides this capability, and uniquely, for each polyp candidate, the prediction value from a classifier is shown next to the 3D view of the polyp candidate, as well as its CTC/OC finding. This capability makes it easier to study each false positive detection and identify its causes. We describe features in our colon CAD system that meets researchers' specific requirements. Our system uses an open source implementation of a 3D Slicer module, and the software is available to the pubic for use and for extension (http://www2.wfubmc.edu/ctc/download/).
    Proc SPIE 03/2010;
  • Haiyong Xu, H. Donald Gage, Peter Santago, Yaorong Ge
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    ABSTRACT: Automated polyp segmentation is important both in measuring polyp size and in improving polyp detection performance in CTC. We present a polyp segmentation method that is based on the combination of geodesic active contours and a shape-prior model of polyps. To train the shape model, polyps identified by radiologists are grouped by morphologic characteristics. Each group of polyps is used for building a shape-prior model. Then the geodesic active contours method is employed to segment polyps constrained by this shape-prior model. This method can reliably segment polyp boundaries even where the image contrast is not sufficient to define a boundary between a polyp and its surrounding colon tissue. As a pilot study, we developed one polyp shape-prior model for sessile polyps that are located on a relatively flat colon wall. We use the model to segment similar polyps, and the results are evaluated visually.
    Virtual Colonoscopy and Abdominal Imaging. Computational Challenges and Clinical Opportunities - Second International Workshop, Held in Conjunction with MICCAI 2010, Beijing, China, September 20, 2010, Revised Selected Papers; 01/2010
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    ABSTRACT: Islet cell adaptation to insulin resistance in type 2 diabetes mellitus may be due in part to increased stimulation of beta cells by the autonomic nervous system. The parasympathetic neurotransmitter acetylcholine (ACh) mediates insulin release via M3 muscarinic receptors on islet beta cells. The vesicular ACh transporter (VAChT) receptor correlates with cholinergic activity in vivo. The positron emission tomography (PET) radiotracer (+)-4-[18F]fluorobenzyltrozamicol ([18F]FBT) binds to the VAChT receptor on presynaptic cholinergic neurons and can be quantified by PET. In this study, we utilize [18F]FBT PET to demonstrate pancreatic cholinergic activity before and after dextrose infusion in nonhuman primates with normal (NGT) and impaired (IGT) glucose tolerance. Seven adult female vervet (Chlorocebus aethiops) monkeys were maintained on an atherogenic Western diet. They were divided into two groups: four with NGT and three with IGT. Each subject underwent [18F]FBT PET twice: first, a baseline PET under fasting conditions; and second, PET under fasting conditions but after intravenous infusion of dextrose solution. Quantitative analysis of pancreatic uptake at 60 min post-injection was performed. There was no difference in pancreatic uptake of [18F]FBT on baseline scans between the two groups. Pancreatic uptake of [18F]FBT increased in every subject after dextrose infusion (P = 0.03). On post-dextrose PET scans, pancreatic uptake of [18F]FBT was significantly higher in IGT subjects compared with NGT subjects (P = 0.03). The post-dextrose to pre-dextrose uptake ratios were higher in IGT subjects (P = 0.08). Acute increases in pancreatic cholinergic activity in vivo were detected in the pancreata of nonhuman primates with NGT and IGT after intravenous dextrose infusion on [18F]FBT PET. In subjects with IGT, this activity was significantly higher, suggesting increased autonomic nervous system stimulation of the pancreatic islets in insulin-resistant subjects.
    Diabetes Technology &amp Therapeutics 08/2009; 11(7):451-5. · 2.21 Impact Factor
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    ABSTRACT: Pancreatic neuronal changes associated with beta cell loss in type 1 diabetes mellitus are complex, involving, in part, parasympathetic mechanisms to compensate for preclinical hyperglycemia. The parasympathetic neurotransmitter acetylcholine (ACh) mediates insulin release via M3 muscarinic receptors on islet beta cells. The vesicular ACh transporter (VAChT) receptor has been shown to be a useful marker of cholinergic activity in vivo. The positron emission tomography (PET) radiotracer (+)-4-[(18)F]fluorobenzyltrozamicol ([(18)F]FBT) binds to the VAChT receptor on presynaptic cholinergic neurons and can be quantified by PET. The compound 4-diphenylacetoxy-N-methylpiperidine (4-DAMP), available in a tritiated form, binds to M3 muscarinic receptors on beta cells and is a potential target for assessing pancreatic beta cell mass. In this study, we investigate the feasibility of dual radiotracer analysis in identifying neurofunctional changes that may signify type 1 diabetes mellitus in its early preclinical state. Ex vivo determinations of pancreatic uptake were performed in prediabetic nonobese diabetic mice and controls after intravenous injection of [(18)F]FBT or 4-[(3)H]DAMP. Beta cell loss in prediabetic mice was confirmed using immunohistochemical methods. [(18)F]FBT uptake was significantly higher in prediabetic pancreata than controls: 3.22 +/- 0.81 and 2.51 +/- 1.04, respectively (P < 0.03). 4-[(3)H]DAMP uptake was significantly lower in prediabetic pancreata than controls: 0.612 +/- 0.161 and 0.968 +/- 0.364, respectively (P = 0.01). These data suggest that a combination of radiotracer imaging agents that bind to neuronal elements intimately involved in insulin production may be an effective method of evaluating changes associated with early beta cell loss using PET.
    Diabetes Technology &amp Therapeutics 02/2009; 11(2):107-11. · 2.21 Impact Factor
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    ABSTRACT: Sex differences have been reported in a variety of affective and neurodegenerative disorders that involve dysfunctional dopamine (DA) neurotransmission. In addition, there is evidence for differences in sensitivity to the abuse-related effects of psychostimulants across the menstrual cycle which may result from effects of ovarian hormones on DA function. The goal of the present study was to extend previous work examining menstrual cycle-related changes in DA D2 receptor availability in humans to drug-naive female cynomolgus monkeys (n=7) using the selective D2-like receptor ligand [(18)F]fluoroclebopride (FCP) and a high-resolution microPET P4 scanner. Menstrual cycle phase was characterized by daily vaginal swabs and measurements of serum progesterone levels. PET studies were conducted once during the luteal phase and once during the follicular phase. Regions of interest in the caudate nucleus, putamen, and cerebellum were defined on coregistered MRIs. Distribution volumes were calculated for FCP in each structure and the distribution volume ratio (DVR) for both brain regions relative to the cerebellum was used as a measure of D2 receptor availability. FCP DVRs were significantly higher in the luteal phase compared to the follicular phase in both the caudate nucleus (11.7% difference, p=0.02) and putamen (11.6% difference, p=0.03). These findings extend earlier work in humans and suggest that changes in DA receptor availability may be involved in the variation in symptoms of various neuropsychiatric disorders across the menstrual cycle, including differences in sensitivity to the abuse-related effects of stimulants.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 03/2008; 34(3):548-54. · 8.68 Impact Factor
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    ABSTRACT: Although serotonin (5-HT) can interact with dopamine (DA) systems to modulate the subjective and reinforcing effects of psychostimulants such as cocaine and 3,4-methyldioxymethamphetamine (MDMA, ecstasy), the long-term effects of exposure to psychostimulants on brain 5-HT systems are not well characterized. The present study assessed 5-HT transporter (SERT) availability using positron emission tomography (PET) in rhesus monkeys with the SERT-specific radioligand [(11)C]3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB). SERT availability was assessed in regions of interest including the caudate nucleus, putamen, anterior cingulate cortex, and cerebellum. [(11)C]DASB distribution volume ratios (DVRs) were calculated using the cerebellum as the reference region. DVRs were calculated in control monkeys and in cocaine or MDMA self-administering monkeys approximately 24 h after the last self-administration (SA) session. SERT availability did not differ between monkeys with a history of MDMA SA and control monkeys in any region examined. In contrast, monkeys with a history of cocaine SA showed significantly higher levels of SERT availability in the caudate nucleus and putamen compared to control subjects. These results suggest that chronic SA of cocaine, but not MDMA, leads to alterations in serotonergic function in brain areas relevant to drug abuse. The higher level of SERT availability in cocaine-experienced monkeys may lead to a reduced inhibitory tone of 5-HT on the DA system, which may explain, in part, differences in the abuse liability between cocaine and MDMA.
    Neuropsychopharmacology 02/2008; 33(2):219-25. · 8.68 Impact Factor
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    ABSTRACT: Previous studies have demonstrated that cocaine use alters availability of brain dopamine D2 receptors (D2R) and transporters (DAT). The present study examined the effects of low doses of cocaine on this neuroadaptation. Using positron emission tomography (PET), D2R and DAT availability in the caudate nucleus (Cd), putamen (Pt), anterior cingulate cortex (ACC), and amygdala (AMY) were assessed before and after monkeys acquired cocaine self-administration. Twelve rhesus monkeys were trained to self-administer intravenous cocaine (0.03 mg/kg per injection) under conditions that resulted in low drug intakes. PET scans using radiotracers targeting D2R ([F]fluoroclebopride, FCP) or DAT ([F]-(+)-N-(4-fluorobenzyl)-2β-propanoyl-3β-(4-chlorophenyl)tropane, FCT) were performed when monkeys were cocaine naive and after 9 weeks of self-administration. Before self-administration, D2R availability was significantly higher only in left vs. right Cd, whereas DAT availability was higher in left vs. right Cd, Pt, and ACC. Nonetheless, after cocaine exposure, left-right differences in D2R were apparent in 3 of 4 regions, but only in the ACC for DAT availability. Self-administration of this dose of cocaine did not significantly affect DAT availability in any region and only decreased D2R availability in the ACC. These results demonstrate lateralization of D2R and DAT availability in brain areas that mediate cocaine self-administration, even under conditions in which cocaine does not affect overall receptor availability.
    Journal of Addiction Medicine 03/2007; 1(1):33-9. · 1.73 Impact Factor
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    ABSTRACT: Dopamine neurotransmission is associated with high susceptibility to cocaine abuse. Positron emission tomography was used in 12 rhesus macaques to determine if dopamine D2 receptor availability was associated with the rate of cocaine reinforcement, and to study changes in brain dopaminergic function during maintenance of and abstinence from cocaine. Baseline D2 receptor availability was negatively correlated with rates of cocaine self-administration. D2 receptor availability decreased by 15-20% within 1 week of initiating self-administration and remained reduced by approximately 20% during 1 year of exposure. Long-term reductions in D2 receptor availability were observed, with decreases persisting for up to 1 year of abstinence in some monkeys. These data provide evidence for a predisposition to self-administer cocaine based on D2 receptor availability, and demonstrate that the brain dopamine system responds rapidly following cocaine exposure. Individual differences in the rate of recovery of D2 receptor function during abstinence were noted.
    Nature Neuroscience 09/2006; 9(8):1050-6. · 15.25 Impact Factor

Publication Stats

1k Citations
202.77 Total Impact Points

Institutions

  • 1994–2013
    • Wake Forest School of Medicine
      • • Department of Physiology and Pharmacology
      • • Department of Biostatistical Sciences
      • • Division of Radiologic Sciences
      • • Department of Radiology
      Winston-Salem, NC, United States
  • 2010
    • Wake Forest University
      • Department of Physiology and Pharmacology
      Winston-Salem, NC, United States
  • 2004
    • Boston Children's Hospital
      Boston, Massachusetts, United States