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Gene-Jack Wang,
Allan Geliebter,
Nora D Volkow,
Frank W Telang,
Jean Logan,
Millard C Jayne,
Kochavi Galanti,
Peter A Selig,
Hao Han, Wei Zhu,
Christopher T Wong,
Joanna S Fowler
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ABSTRACT: Subjects with binge eating disorder (BED) regularly consume large amounts of food in short time periods. The neurobiology of BED is poorly understood. Brain dopamine, which regulates motivation for food intake, is likely to be involved. We assessed the involvement of brain dopamine in the motivation for food consumption in binge eaters. Positron emission tomography (PET) scans with [(11)C]raclopride were done in 10 obese BED and 8 obese subjects without BED. Changes in extracellular dopamine in the striatum in response to food stimulation in food-deprived subjects were evaluated after placebo and after oral methylphenidate (MPH), a drug that blocks the dopamine reuptake transporter and thus amplifies dopamine signals. Neither the neutral stimuli (with or without MPH) nor the food stimuli when given with placebo increased extracellular dopamine. The food stimuli when given with MPH significantly increased dopamine in the caudate and putamen in the binge eaters but not in the nonbinge eaters. Dopamine increases in the caudate were significantly correlated with the binge eating scores but not with BMI. These results identify dopamine neurotransmission in the caudate as being of relevance to the neurobiology of BED. The lack of correlation between BMI and dopamine changes suggests that dopamine release per se does not predict BMI within a group of obese individuals but that it predicts binge eating.
Obesity 02/2011; 19(8):1601-8. · 4.28 Impact Factor
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Joanna S Fowler,
Jean Logan,
Albert J Azzaro,
Robert M Fielding, Wei Zhu,
Amy K Poshusta,
Daniel Burch,
Barry Brand,
James Free,
Mahnaz Asgharnejad, [......],
Pauline Carter,
Scott Carter,
Youwen Xu,
Colleen Shea,
Lisa Muench,
David Alexoff,
Elena Shumay,
Michael Schueller,
Donald Warner,
Karen Apelskog-Torres
[show abstract]
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ABSTRACT: Reversible inhibitors of monoamine oxidase-A (RIMA) inhibit the breakdown of three major neurotransmitters, serotonin, norepinephrine and dopamine, offering a multi-neurotransmitter strategy for the treatment of depression. CX157 (3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin-10,10-dioxide) is a RIMA, which is currently in development for the treatment of major depressive disorder. We examined the degree and reversibility of the inhibition of brain monoamine oxidase-A (MAO-A) and plasma CX157 levels at different times after oral dosing to establish a dosing paradigm for future clinical efficacy studies, and to determine whether plasma CX157 levels reflect the degree of brain MAO-A inhibition. Brain MAO-A levels were measured with positron emission tomography (PET) imaging and [(11)C]clorgyline in 15 normal men after oral dosing of CX157 (20-80 mg). PET imaging was conducted after single and repeated doses of CX157 over a 24-h time course. We found that 60 and 80 mg doses of CX157 produced a robust dose-related inhibition (47-72%) of [(11)C]clorgyline binding to brain MAO-A at 2 h after administration and that brain MAO-A recovered completely by 24 h post drug. Plasma CX157 concentration was highly correlated with the inhibition of brain MAO-A (EC(50): 19.3 ng/ml). Thus, CX157 is the first agent in the RIMA class with documented reversible inhibition of human brain MAO-A, supporting its classification as a RIMA, and the first RIMA with observed plasma levels that can serve as a biomarker for the degree of brain MAO-A inhibition. These data were used to establish the dosing regimen for a current clinical efficacy trial with CX157.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2009; 35(3):623-31. · 6.99 Impact Factor
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Nora D Volkow,
Gene-Jack Wang,
Scott H Kollins,
Tim L Wigal,
Jeffrey H Newcorn,
Frank Telang,
Joanna S Fowler, Wei Zhu,
Jean Logan,
Yeming Ma,
Kith Pradhan,
Christopher Wong,
James M Swanson
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ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD)--characterized by symptoms of inattention and hyperactivity-impulsivity--is the most prevalent childhood psychiatric disorder that frequently persists into adulthood, and there is increasing evidence of reward-motivation deficits in this disorder.
To evaluate biological bases that might underlie a reward/motivation deficit by imaging key components of the brain dopamine reward pathway (mesoaccumbens).
We used positron emission tomography to measure dopamine synaptic markers (transporters and D(2)/D(3) receptors) in 53 nonmedicated adults with ADHD and 44 healthy controls between 2001-2009 at Brookhaven National Laboratory.
We measured specific binding of positron emission tomographic radioligands for dopamine transporters (DAT) using [(11)C]cocaine and for D(2)/D(3) receptors using [(11)C]raclopride, quantified as binding potential (distribution volume ratio -1).
For both ligands, statistical parametric mapping showed that specific binding was lower in ADHD than in controls (threshold for significance set at P < .005) in regions of the dopamine reward pathway in the left side of the brain. Region-of-interest analyses corroborated these findings. The mean (95% confidence interval [CI] of mean difference) for DAT in the nucleus accumbens for controls was 0.71 vs 0.63 for those with ADHD (95% CI, 0.03-0.13, P = .004) and in the midbrain for controls was 0.16 vs 0.09 for those with ADHD (95% CI, 0.03-0.12; P < or = .001); for D(2)/D(3) receptors, the mean accumbens for controls was 2.85 vs 2.68 for those with ADHD (95% CI, 0.06-0.30, P = .004); and in the midbrain, it was for controls 0.28 vs 0.18 for those with ADHD (95% CI, 0.02-0.17, P = .01). The analysis also corroborated differences in the left caudate: the mean DAT for controls was 0.66 vs 0.53 for those with ADHD (95% CI, 0.04-0.22; P = .003) and the mean D(2)/D(3) for controls was 2.80 vs 2.47 for those with ADHD (95% CI, 0.10-0.56; P = .005) and differences in D(2)/D(3) in the hypothalamic region, with controls having a mean of 0.12 vs 0.05 for those with ADHD (95% CI, 0.02-0.12; P = .004). Ratings of attention correlated with D(2)/D(3) in the accumbens (r = 0.35; 95% CI, 0.15-0.52; P = .001), midbrain (r = 0.35; 95% CI, 0.14-0.52; P = .001), caudate (r = 0.32; 95% CI, 0.11-0.50; P = .003), and hypothalamic (r = 0.31; CI, 0.10-0.49; P = .003) regions and with DAT in the midbrain (r = 0.37; 95% CI, 0.16-0.53; P < or = .001).
A reduction in dopamine synaptic markers associated with symptoms of inattention was shown in the dopamine reward pathway of participants with ADHD.
JAMA The Journal of the American Medical Association 09/2009; 302(10):1084-91. · 30.03 Impact Factor
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Nora D Volkow,
Joanna S Fowler,
Jean Logan,
David Alexoff, Wei Zhu,
Frank Telang,
Gene-Jack Wang,
Millard Jayne,
Jacob M Hooker,
Christopher Wong,
Barbara Hubbard,
Pauline Carter,
Donald Warner,
Payton King,
Colleen Shea,
Youwen Xu,
Lisa Muench,
Karen Apelskog-Torres
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ABSTRACT: Modafinil, a wake-promoting drug used to treat narcolepsy, is increasingly being used as a cognitive enhancer. Although initially launched as distinct from stimulants that increase extracellular dopamine by targeting dopamine transporters, recent preclinical studies suggest otherwise.
To measure the acute effects of modafinil at doses used therapeutically (200 mg and 400 mg given orally) on extracellular dopamine and on dopamine transporters in the male human brain.
Positron emission tomography with [(11)C]raclopride (D(2)/D(3) radioligand sensitive to changes in endogenous dopamine) and [(11)C]cocaine (dopamine transporter radioligand) was used to measure the effects of modafinil on extracellular dopamine and on dopamine transporters in 10 healthy male participants. The study took place over an 8-month period (2007-2008) at Brookhaven National Laboratory.
Primary outcomes were changes in dopamine D(2)/D(3) receptor and dopamine transporter availability (measured by changes in binding potential) after modafinil when compared with after placebo.
Modafinil decreased mean (SD) [(11)C]raclopride binding potential in caudate (6.1% [6.5%]; 95% confidence interval [CI], 1.5% to 10.8%; P = .02), putamen (6.7% [4.9%]; 95% CI, 3.2% to 10.3%; P = .002), and nucleus accumbens (19.4% [20%]; 95% CI, 5% to 35%; P = .02), reflecting increases in extracellular dopamine. Modafinil also decreased [(11)C]cocaine binding potential in caudate (53.8% [13.8%]; 95% CI, 43.9% to 63.6%; P < .001), putamen (47.2% [11.4%]; 95% CI, 39.1% to 55.4%; P < .001), and nucleus accumbens (39.3% [10%]; 95% CI, 30% to 49%; P = .001), reflecting occupancy of dopamine transporters.
In this pilot study, modafinil blocked dopamine transporters and increased dopamine in the human brain (including the nucleus accumbens). Because drugs that increase dopamine in the nucleus accumbens have the potential for abuse, and considering the increasing use of modafinil, these results highlight the need for heightened awareness for potential abuse of and dependence on modafinil in vulnerable populations.
JAMA The Journal of the American Medical Association 03/2009; 301(11):1148-54. · 30.03 Impact Factor
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Gene-Jack Wang,
Nora D Volkow,
Frank Telang,
Millard Jayne,
Yeming Ma,
Kith Pradhan, Wei Zhu,
Christopher T Wong,
Panayotis K Thanos,
Allan Geliebter,
Anat Biegon,
Joanna S Fowler
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ABSTRACT: Although impaired inhibitory control is linked to a broad spectrum of health problems, including obesity, the brain mechanism(s) underlying voluntary control of hunger are not well understood. We assessed the brain circuits involved in voluntary inhibition of hunger during food stimulation in 23 fasted men and women using PET and 2-deoxy-2[(18)F]fluoro-D-glucose ((18)FDG). In men, but not in women, food stimulation with inhibition significantly decreased activation in amygdala, hippocampus, insula, orbitofrontal cortex, and striatum, which are regions involved in emotional regulation, conditioning, and motivation. The suppressed activation of the orbitofrontal cortex with inhibition in men was associated with decreases in self-reports of hunger, which corroborates the involvement of this region in processing the conscious awareness of the drive to eat. This finding suggests a mechanism by which cognitive inhibition decreases the desire for food and implicates lower ability to suppress hunger in women as a contributing factor to gender differences in obesity.
Proceedings of the National Academy of Sciences 02/2009; 106(4):1249-54. · 9.68 Impact Factor
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ABSTRACT: Acute alcohol administration decreases overall brain glucose metabolism, which serves as a marker of brain activity. The behavioral effects of alcohol, however, are likely to reflect not only changes in regional brain activity but also the patterns of brain functional organization. Here we assessed the effects of a moderate dose of alcohol on the patterns of brain activity and cerebral differentiation. We measured brain glucose metabolism in 20 healthy controls with positron emission tomography and fluorodeoxyglucose during baseline and during alcohol intoxication (0.75 g/kg). We used the coefficient of variation (CV) to assess changes in brain metabolic homogeneity, which we used as a marker for cerebral differentiation. We found that alcohol decreased the CV in the brain and this effect was independent of the decrements in overall glucose metabolism. Our study revealed marked disruption in brain activity during alcohol intoxication including decreases in global and regional brain differentiation, a loss of right versus left brain metabolic laterality and a shift in the predominance of activity from cortical to limbic brain regions. The widespread nature of the changes induced by a moderate dose of alcohol is likely to contribute to the marked disruption of alcohol on behavior, mood, cognition and motor activity.
Psychiatry Research 05/2008; 162(3):205-13. · 2.52 Impact Factor
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Joanna S Fowler,
Nelly Alia-Klein,
Aarti Kriplani,
Jean Logan,
Benjamin Williams, Wei Zhu,
Ian W Craig,
Frank Telang,
Rita Goldstein,
Nora D Volkow,
Paul Vaska,
Gene-Jack Wang
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ABSTRACT: A functional polymorphism in the promoter region of the monoamine oxidase A (MAO A) gene has two common alleles that are referred to as the high and low MAO A genotypes. We report the first in vivo human study to determine whether there is an association between MAO A genotype and brain MAO A activity in healthy male subjects.
Brain MAO A activity was measured with positron emission tomography and [(11)C]clorgyline in 38 healthy adult male nonsmokers genotyped for MAO A polymorphism.
There was no significant difference in brain MAO A activity between the high (n = 26) and low (n = 12) MAO A genotypes.
The lack of an association between the high and low MAO A genotype and brain MAO A activity suggests that this polymorphism by itself does not contribute to differences in brain MAO A activity in healthy adult male subjects.
Biological Psychiatry 09/2007; 62(4):355-8. · 8.28 Impact Factor
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ABSTRACT: The neurobiological mechanisms underlying overeating in obesity are not understood. Here, we assessed the neurobiological responses to an Implantable Gastric Stimulator (IGS), which induces stomach expansion via electrical stimulation of the vagus nerve to identify the brain circuits responsible for its effects in decreasing food intake. Brain metabolism was measured with positron emission tomography and 2-deoxy-2[18F]fluoro-D-glucose in seven obese subjects who had the IGS implanted for 1-2 years. Brain metabolism was evaluated twice during activation (on) and during deactivation (off) of the IGS. The Three-Factor Eating Questionnaire was obtained to measure the behavioral components of eating (cognitive restraint, uncontrolled eating, and emotional eating). The largest difference was in the right hippocampus, where metabolism was 18% higher (P < 0.01) during the "on" than "off" condition, and these changes were associated with scores on "emotional eating," which was lower during the on than off condition and with "uncontrolled eating," which did not differ between conditions. Metabolism also was significantly higher in right anterior cerebellum, orbitofrontal cortex, and striatum during the on condition. These findings corroborate the role of the vagus nerve in regulating hippocampal activity and the importance of the hippocampus in modulating eating behaviors linked to emotional eating and lack of control. IGS-induced activation of regions previously shown to be involved in drug craving in addicted subjects (orbitofrontal cortex, hippocampus, cerebellum, and striatum) suggests that similar brain circuits underlie the enhanced motivational drive for food and drugs seen in obese and drug-addicted subjects, respectively.
Proceedings of the National Academy of Sciences 10/2006; 103(42):15641-5. · 9.68 Impact Factor
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ABSTRACT: Feature extraction or biomarker selection is a critical step in disease diagnosis and knowledge discovery based on protein MS. Many studies have discussed the classification methods applied in proteomics; however, few could be found to address feature extraction in detail. In this paper, we developed a systematic approach for the extraction of mass spectrum peak apex and peak area with special emphasis on noise filtration and peak calibration. Application to a head and neck cancer data generated at the Eastern Virginia Medical School [Wadsworth, J. T., Somers, K. D., Cazares, L. H., Malik, G. et al.., Clin. Cancer Res. 2004, 10, 1625-1632] revealed that the new feature extraction method would yield consistent and highly discriminatory biomarkers.
PROTEOMICS 05/2006; 6(7):2095-100. · 4.51 Impact Factor
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Joanna S Fowler,
Jean Logan,
Gene-Jack Wang,
Nora D Volkow,
Frank Telang, Wei Zhu,
Dinko Franceschi,
Colleen Shea,
Victor Garza,
Youwen Xu,
Yu-Shin Ding,
David Alexoff,
Donald Warner,
Noelwah Netusil,
Pauline Carter,
Millard Jayne,
Payton King,
Paul Vaska
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ABSTRACT: Smokers have reduced levels of brain monoamine oxidase A (MAO A) leading to speculation that MAO A inhibition by tobacco smoke may underlie some of the neurophysiologic effects of smoking. Because smoking exposes peripheral organs as well as the brain to MAO A-inhibitory compounds, we determined whether smokers would also have reduced MAO A in peripheral organs.
We measured MAO A in peripheral organs in a group of 9 smokers and compared it with a group of nonsmokers studied previously. MAO A was measured using PET and serial scans with the MAO A-specific radiotracers (11)C-clorgyline and deuterium-substituted (11)C-clorgyline ((11)C-clorgyline-D2) using the deuterium isotope effect to assess binding specificity. The time course of radiotracer in the arterial plasma was also measured and data from the tissue time-activity curves and the arterial input function were analyzed using a 3-compartment model to estimate k(3), which represents the rate-limiting step for the irreversible binding of labeled clorgyline to MAO A.
Tracer uptake at plateau was reduced with deuterium substitution for the heart, lungs, and kidneys, indicating specificity for MAO. There was no difference in organ uptake at plateau between nonsmokers and smokers though, for the smokers, the efflux of tracer from peak uptake to plateau was slower for the lungs. The area under the time-activity curve for the arterial plasma was also significantly reduced for smokers versus nonsmokers and the reduction occurred in the first few minutes after radiotracer injection. Smokers had an approximately 50% reduction in k(3) when compared with nonsmokers; however, k(3) did not differ for nonsmokers and smokers for the heart and the kidneys.
Because MAO A breaks down serotonin, norepinephrine, dopamine, and tyramine, and because the lung is a major metabolic organ in degrading some of these substances, reduced lung MAO A may contribute to some of the physiologic effects of smoking. This study also revealed that the concentration of the radiotracers in the arterial plasma is significantly lower for the smoker versus the nonsmoker and that this appears to be caused in part by retention of the radiotracer in lungs. If this is generally true for other substances that are administered intravenously, then this needs to be considered as a variable that may contribute to different short-term behavioral responses to intravenously administered drugs for nonsmokers versus smokers.
Journal of Nuclear Medicine 10/2005; 46(9):1414-20. · 6.38 Impact Factor
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Nora D Volkow,
Gene-Jack Wang,
Joanna S Fowler,
Susan Learned-Coughlin,
Julia Yang,
Jean Logan,
David Schlyer,
John S Gatley,
Christopher Wong, Wei Zhu,
Naomi Pappas,
Michael Schueller,
Millard Jayne,
Pauline Carter,
Donald Warner,
Yu-Shin Ding,
Colleen Shea,
Youwen Xu
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ABSTRACT: (2S,3S)-2-(3-Chlorophenyl)-3,5,5,-trimethyl-2-morpholinol hydrochloride (radafaxine) is a new antidepressant that blocks dopamine transporters (DAT). A concern with drugs that block (DAT) is their potential reinforcing effects and abuse liability. Using positron emission tomography (PET) we have shown that for DAT-blocking drugs to produce reinforcing effects they must induce >50% DAT blockade and the blockade has to be fast (within 15 minutes). This study measures the potency and kinetics for DAT blockade by radafaxine in human brain.
PET and [11C]cocaine were used to estimate DAT blockade at 1, 4, 8, and 24 hours after radafaxine (40 mg p.o.) in 8 controls. Plasma pharmacokinetics and behavioral and cardiovascular effects were measured in parallel.
DAT blockade by radafaxine was slow, and at 1 hour, it was 11%. Peak blockade occurred at about 4 hours and was 22%. Blockade was long lasting: at 8 hours 17%, and at 24 hours 15%. Peak plasma concentration occurred about 4 to 8 hours. No behavioral or cardiovascular effects were observed.
The relatively low potency of radafaxine in blocking DAT and its slow blockade suggests that it is unlikely to have reinforcing effects. This is consistent with preclinical studies showing no self-administration. This is the first utilization of PET to predict abuse liability of a new antidepressant in humans based on DAT occupancy and pharmacokinetics.
Biological Psychiatry 03/2005; 57(6):640-6. · 8.28 Impact Factor
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ABSTRACT: High-throughput mass spectrometry and statistical analysis methodologies are promising technologies to aid the medical diagnostics field by detecting the cancer-related proteomic markers. We propose statistical methods to cull the potential markers by ranking them in relations to their power of separability distinguishing cancerous patients from normal persons or among different cancer stages. To assess the training variability, resampling via bootstrap strategy is adopted to select stable markers which show the potential of a large probability to classify specific groups. Selected marker pattern is validated by a combined classifier. Methods are demonstrated by a colon cancer dataset screened by SELDI technology.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 02/2005; 5:4775-8.
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ABSTRACT: Many prediction studies of medical research lead to discrete longitudinal data with repeated measurement and categorical outcomes. Therefore the traditional likelihood-based methods for continuous outcome measures are no longer suitable. With the development of modern computing technologies and improved scope for estimation via iterative sampling methods, Bayesian analysis is becoming increasingly popular among biostatisticians. Markov Chain Monte Carlo (MCMC), for the implementation of Bayesian methods has rendered the implementation of complex Bayesian models a reality. In addition, the availability of software like WinBUGS has made the utilization of MCMC straightforward. In this study, we developed a full Bayesian version of generalized linear models for binary longitudinal data and applied it to a longitudinal prediction study of Alzheimer's disease conducted at New York University School of Medicine.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 02/2005; 2:1204-7.
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[show abstract]
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ABSTRACT: Many prediction studies of medical research lead to discrete longitudinal data with repeated measurement and categorical outcomes. Therefore the traditional likelihood-based methods for continuous outcome measures are no longer suitable. With the development of modern computing technologies and improved scope for estimation via iterative sampling methods, Bayesian analysis is becoming increasingly popular among biostatisticians. Markov chain Monte Carlo (MCMC), for the implementation of Bayesian methods has rendered the implementation of complex Bayesian models a reality. In addition, the availability of software like WinBUGS has made the utilization of MCMC straightforward. In this study, we developed a full Bayesian version of generalized linear models for binary longitudinal data and applied it to a longitudinal prediction study of Alzheimer's disease conducted at New York University School of Medicine
Engineering in Medicine and Biology Society, 2005. IEEE-EMBS 2005. 27th Annual International Conference of the; 02/2005
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Nora D Volkow,
Gene-Jack Wang,
Joanna S Fowler,
Frank Telang,
Laurence Maynard,
Jean Logan,
Samuel J Gatley,
Naomi Pappas,
Christopher Wong,
Paul Vaska, Wei Zhu,
James M Swanson
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ABSTRACT: Methylphenidate is the most commonly prescribed drug for attention deficit hyperactivity disorder (ADHD), yet its therapeutic mechanisms are poorly understood. The objective of this study was to assess if methylphenidate, by increasing dopamine (neurotransmitter involved in motivation) in brain, would enhance the saliency of an academic task, making it more interesting.
Healthy subjects (N=16) underwent positron emission tomography with [(11)C]raclopride (dopamine D(2) receptor radioligand that competes with endogenous dopamine for binding) to assess the effects of oral methylphenidate (20 mg) on extracellular dopamine in the striatum. The authors compared the effects of methylphenidate during an academic task (solving mathematical problems with monetary reinforcement) and a neutral task (passively viewing cards with no remuneration). In parallel, the effects of methylphenidate on the interest that the academic task elicited were also evaluated.
Methylphenidate, when coupled with the mathematical task, significantly increased extracellular dopamine, but this did not occur when coupled with the neutral task. The mathematical task did not increase dopamine when coupled with placebo. Subjective reports about interest and motivation in the mathematical task were greater with methylphenidate than with placebo and were associated with dopamine increases.
The significant association between methylphenidate-induced dopamine increases and the interest and motivation for the task confirms the prediction that methylphenidate enhances the saliency of an event by increasing dopamine. The enhanced interest for the task could increase attention and improve performance and could be one of the mechanisms underlying methylphenidate's therapeutic effects. These findings support educational strategies that make schoolwork more interesting as nonpharmacological interventions to treat ADHD.
American Journal of Psychiatry 08/2004; 161(7):1173-80. · 12.54 Impact Factor
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Gene-Jack Wang,
Nora D Volkow,
Frank Telang,
Millard Jayne,
Jim Ma,
Manlong Rao, Wei Zhu,
Christopher T Wong,
Naomi R Pappas,
Allan Geliebter,
Joanna S Fowler
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ABSTRACT: The increased incidence of obesity most likely reflects changes in the environment that had made food more available and palatable. Here we assess the response of the human brain to the presentation of appetitive food stimuli during food presentation using PET and FDG.
Metabolic changes in response to food presentation were done in 12 healthy normal body weight subjects who were food deprived before the study.
Food presentation significantly increased metabolism in the whole brain (24%, P < 0.01) and these changes were largest in superior temporal, anterior insula, and orbitofrontal cortices. The increases in the right orbitofrontal cortex were the ones that correlated significantly with the increases in self-reports of hunger and desire for food.
The marked increase in brain metabolism by the presentation of food provides evidence of the high sensitivity of the human brain to food stimuli. This high sensitivity coupled with the ubiquitousness of food stimuli in the environment is likely to contribute to the epidemic of obesity. In particular, the activation of the right orbitofrontal cortex, a brain region involved with drive, may underlie the motivation to procure food, which may be subjectively experienced as "desire for food" and "hunger" when exposed to food stimuli.
NeuroImage 05/2004; 21(4):1790-7. · 5.89 Impact Factor
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Joanna S Fowler,
Jean Logan,
Gene-Jack Wang,
Nora D Volkow,
Frank Telang,
Yu-Shin Ding,
Colleen Shea,
Victor Garza,
Youwen Xu,
Zizhong Li,
David Alexoff,
Paul Vaska,
Richard Ferrieri,
David Schlyer, Wei Zhu,
S John Gatley
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ABSTRACT: The monoamine oxidase A and B (MAO A and B) radiotracers [(11)C]clorgyline (CLG) and [(11)C]L-deprenyl (DEP) and their deuterium labeled counterparts (CLG-D and DEP-D) were compared to determine whether their distribution and kinetics in humans are consistent with their physical, chemical and pharmacological properties and the reported ratios of MAO A:MAO B in post-mortem human tissues. Irreversible binding was consistently higher for DEP in brain, heart, kidneys and spleen but not lung where CLG >DEP and not in thyroid where there is no DEP binding. The generally higher DEP binding is consistent with its higher enzyme affinity and larger free fraction in plasma while differences in regional distribution for CLG and DEP in brain, heart, thyroid and lungs are consistent with different relative ratios of MAO A and B in humans.
Nuclear Medicine and Biology 04/2004; 31(3):313-9. · 3.02 Impact Factor
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ABSTRACT: Methamphetamine is a highly addictive drug of abuse that is neurotoxic to dopamine terminals. The authors recently reported that decreases in dopamine transporters (used as markers of dopamine terminals) in the striatum of methamphetamine abusers recover with protracted abstinence and that relative to comparison subjects, recently detoxified methamphetamine abusers have lower metabolism in the striatum and thalamus. In this study, the authors assessed whether metabolism recovers with protracted abstinence.
Brain glucose metabolism was measured with positron emission tomography and [18F]fluorodeoxyglucose in five methamphetamine abusers who were evaluated after both a short (<6 months) and protracted (12-17 months) abstinence interval, eight methamphetamine abusers tested only after protracted abstinence, and 11 comparison subjects who were not drug users.
Significantly greater thalamic, but not striatal, metabolism was seen following protracted abstinence relative to metabolism assessed after a short abstinence interval, and this increase was associated with improved performance in motor and verbal memory tests. Relative to the comparison subjects, the methamphetamine abusers tested after protracted abstinence had lower metabolism in the striatum (most accentuated in the caudate and nucleus accumbens) but not in the thalamus.
The persistent decreases in striatal metabolism in methamphetamine abusers could reflect long-lasting changes in dopamine cell activity, and decreases in the nucleus accumbens could account for the persistence of amotivation and anhedonia in detoxified methamphetamine abusers. The recovery of thalamic metabolism could reflect adaptation responses to compensate for the dopamine deficits, and the associated improvement in neuropsychological performance further indicates its functional significance. These results suggest that while protracted abstinence may reverse some of the methamphetamine-induced alterations in brain function, other deficits persist.
American Journal of Psychiatry 02/2004; 161(2):242-8. · 12.54 Impact Factor
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Nora D Volkow,
Gene-Jack Wang,
Yemin Ma,
Joanna S Fowler, Wei Zhu,
Laurence Maynard,
Frank Telang,
Paul Vaska,
Yu-Shin Ding,
Christopher Wong,
James M Swanson
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ABSTRACT: The reinforcing effects of drugs of abuse result from the complex interaction between pharmacological effects and conditioned responses. Here we evaluate how expectation affects the response to the stimulant drug methylphenidate in 25 cocaine abusers. The effects of methylphenidate (0.5 mg/kg, i.v.) on brain glucose metabolism (measured by [18F]deoxyglucose-positron emission tomography) and on its reinforcing effects (self-reports of drug effects) were evaluated in four conditions: (1) expecting placebo and receiving placebo; (2) expecting placebo and receiving methylphenidate; (3) expecting methylphenidate and receiving methylphenidate; (4) expecting methylphenidate and receiving placebo. Methylphenidate increased brain glucose metabolism, and the largest changes were in cerebellum, occipital cortex, and thalamus. The increases in metabolism were approximately 50% larger when methylphenidate was expected than when it was not, and these differences were significant in cerebellum (vermis) and thalamus. In contrast, unexpected methylphenidate induced greater increases in left lateral orbitofrontal cortex than when it was expected. Methylphenidate-induced increases in self-reports of "high" were also approximately 50% greater when subjects expected to receive it than when they did not and were significantly correlated with the metabolic increases in thalamus but not in cerebellum. These findings provide evidence that expectation amplifies the effects of methylphenidate in brain and its reinforcing effects. They also suggest that the thalamus, a region involved with conditioned responses, may mediate the enhancement of the reinforcing effects of methylphenidate by expectation and that the orbitofrontal cortex mediates the response to unexpected reinforcement. The enhanced cerebellar activation with expectation may reflect conditioned responses that are not linked to conscious responses.
Journal of Neuroscience 01/2004; 23(36):11461-8. · 7.11 Impact Factor
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ABSTRACT: We propose a comprehensive pattern recognition procedure that will achieve best discrimination between two or more sets of subjects with data in the same coordinate system. Applying the procedure to MS data of proteomic analysis of serum from ovarian cancer patients and serum from cancer-free individuals in the Food and Drug Administration/National Cancer Institute Clinical Proteomics Database, we have achieved perfect discrimination (100% sensitivity, 100% specificity) of patients with ovarian cancer, including early-stage disease, from normal controls for two independent sets of data. Our procedure identifies the best subset of proteomic biomarkers for optimal discrimination between the groups and appears to have higher discriminatory power than other methods reported to date. For large-scale screening for diseases of relatively low prevalence such as ovarian cancer, almost perfect specificity and sensitivity of the detection system is critical to avoid unmanageably high numbers of false-positive cases.
Proceedings of the National Academy of Sciences 01/2004; 100(25):14666-71. · 9.68 Impact Factor
