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      Motivation Deficit in ADHD is Associated with Dysfunction of the Dopamine Reward Pathway

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          Abstract

          ADHD is typically characterized as a disorder of inattention and hyperactivity/impulsivity but there is increasing evidence of deficits in motivation. Using PET we showed decreased function in the brain dopamine reward pathway in adults with ADHD, which we hypothesized could underlie the motivation deficits in this disorder. To evaluate this hypothesis we performed secondary analyses to assess the correlation between the PET measures of dopamine D2/D3 receptor and dopamine transporter availability (obtained with [ 11C]raclopride and [ 11C]cocaine, respectively) in the dopamine reward pathway (midbrain and nucleus accumbens), and a surrogate measures of trait motivation (assessed using the Achievement scale on the Multidimensional Personality Questionnaire or MPQ) in 45 ADHD participants and 41 controls. The Achievement scale was lower in ADHD participants than in controls (11±5 vs 14±3, p<0.001) and was significantly correlated with D2/D3 receptors (accumbens: r=0.39, p<0.008; midbrain: r=0.41, p<0.005) and transporters (accumbens: r=0.35, p < 0.02) in ADHD participants, but not in controls. ADHD participants also had lower values in the Constraint factor and higher values in the Negative Emotionality factor of the MPQ but did not differ in the Positive Emotionality factor - and none of these were correlated with the dopamine measures. In ADHD participants scores in the Achievement scale were also negatively correlated with symptoms of inattention (CAARS A, E and SWAN-I). These findings provide evidence that disruption of the dopamine reward pathway is associated with motivation deficits in ADHD adults, which may contribute to attention deficits and supports the use of therapeutic interventions to enhance motivation in ADHD.

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          Most cited references32

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          Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects.

          A graphical method of analysis applicable to ligands that bind reversibly to receptors or enzymes requiring the simultaneous measurement of plasma and tissue radioactivities for multiple times after the injection of a radiolabeled tracer is presented. It is shown that there is a time t after which a plot of integral of t0ROI(t')dt'/ROI(t) versus integral of t0Cp(t')dt'/ROI(t) (where ROI and Cp are functions of time describing the variation of tissue radioactivity and plasma radioactivity, respectively) is linear with a slope that corresponds to the steady-state space of the ligand plus the plasma volume,.Vp. For a two-compartment model, the slope is given by lambda + Vp, where lambda is the partition coefficient and the intercept is -1/[kappa 2(1 + Vp/lambda)]. For a three-compartment model, the slope is lambda(1 + Bmax/Kd) + Vp and the intercept is -[1 + Bmax/Kd)/k2 + [koff(1 + Kd/Bmax)]-1) [1 + Vp/lambda(1 + Bmax/Kd)]-1 (where Bmax represents the concentration of ligand binding sites and Kd the equilibrium dissociation constant of the ligand-binding site complex, koff (k4) the ligand-binding site dissociation constant, and k2 is the transfer constant from tissue to plasma). This graphical method provides the ratio Bmax/Kd from the slope for comparison with in vitro measures of the same parameter. It also provides an easy, rapid method for comparison of the reproducibility of repeated measures in a single subject, for longitudinal or drug intervention protocols, or for comparing experimental results between subjects. Although the linearity of this plot holds when ROI/Cp is constant, it can be shown that, for many systems, linearity is effectively reached some time before this. This analysis has been applied to data from [N-methyl-11C]-(-)-cocaine ([11C]cocaine) studies in normal human volunteers and the results are compared to the standard nonlinear least-squares analysis. The calculated value of Bmax/Kd for the high-affinity binding site for cocaine is 0.62 +/- 0.20, in agreement with literature values.
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            Neurobiology of the structure of personality: dopamine, facilitation of incentive motivation, and extraversion.

            Extraversion has two central characteristics: (1) interpersonal engagement, which consists of affiliation (enjoying and valuing close interpersonal bonds, being warm and affectionate) and agency (being socially dominant, enjoying leadership roles, being assertive, being exhibitionistic, and having a sense of potency in accomplishing goals) and (2) impulsivity, which emerges from the interaction of extraversion and a second, independent trait (constraint). Agency is a more general motivational disposition that includes dominance, ambition, mastery, efficacy, and achievement. Positive affect (a combination of positive feelings and motivation) is closely associated with extraversion. Extraversion is accordingly based on positive incentive motivation. Parallels between extraversion (particularly its agency component) and a mammalian behavioral approach system based on positive incentive motivation implicate a neuroanatomical network and modulatory neurotransmitters in the processing of incentive motivation. A corticolimbic-striatal-thalamic network (1) integrates the salient incentive context in the medial orbital cortex, amygdala, and hippocampus; (2) encodes the intensity of incentive stimuli in a motive circuit composed of the nucleus accumbens, ventral pallidum, and ventral tegmental area dopamine projection system; and (3) creates an incentive motivational state that can be transmitted to the motor system. Individual differences in the functioning of this network arise from functional variation in the ventral tegmental area dopamine projections, which are directly involved in coding the intensity of incentive motivation. The animal evidence suggests that there are three neurodevelopmental sources of individual differences in dopamine: genetic, "experience-expectant," and "experience-dependent." Individual differences in dopamine promote variation in the heterosynaptic plasticity that enhances the connection between incentive context and incentive motivation and behavior. Our psychobiological threshold model explains the effects of individual differences in dopamine transmission on behavior, and their relation to personality traits is discussed.
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              The dual pathway model of AD/HD: an elaboration of neuro-developmental characteristics.

              The currently dominant neuro-cognitive model of Attention Deficit Hyperactivity Disorder (AD/HD) presents the condition as executive dysfunction (EDF) underpinned by disturbances in the fronto-dorsal striatal circuit and associated dopaminergic branches (e.g. meso-cortical). In contrast, motivationally-based accounts focus on altered reward processes and implicate fronto-ventral striatal reward circuits and those meso-limbic branches that terminate in the ventral striatum especially the nucleus accumbens. One such account, delay aversion (DEL), presents AD/HD as a motivational style-characterised by attempts to escape or avoid delay-arising from fundamental disturbances in these reward centres. While traditionally regarded as competing, EDF and DEL models have recently been presented as complimentary accounts of two psycho-patho-physiological subtypes of AD/HD with different developmental pathways, underpinned by different cortico-striatal circuits and modulated by different branches of the dopamine system. In the current paper we describe the development of this model in more detail. We elaborate on the neuro-circuitry possibly underpinning these two pathways and explore their developmental significance within a neuro-ecological framework.
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                Author and article information

                Journal
                9607835
                20545
                Mol Psychiatry
                Molecular psychiatry
                1359-4184
                1476-5578
                30 August 2010
                21 September 2010
                November 2011
                1 May 2012
                : 16
                : 11
                : 1147-1154
                Affiliations
                [1 ]National Institute on Drug Abuse, Bethesda, MD 20892
                [2 ]Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892
                [3 ]Medical and Chemistry Departments, Brookhaven National Laboratory, Upton, NY 11973
                [4 ]Department of Psychiatry, Mount Sinai Medical Center, New York, NY 10029
                [5 ]Department of Psychiatry, Department of Psychiatry, Duke University Medical Center, Durham, NC 27701
                [6 ]Child Development Center, University of California, Irvine, CA 92612
                Author notes
                Corresponding Author: Nora D. Volkow, National Institute on Drug Abuse, 6001 Executive Boulevard, Room 5274, MSC 9581, Bethesda, MD 20892, Tel. (301) 443-6480, Fax (301) 443-9127, nvolkow@ 123456nida.nih.gov
                Article
                nihpa229585
                10.1038/mp.2010.97
                3010326
                20856250
                c48c7362-111b-4035-b4a9-1226d31c97f9
                History
                Funding
                Funded by: National Institute on Alcohol Abuse and Alcoholism : NIAAA
                Award ID: ZIA AA000550-06 ||AA
                Categories
                Article

                Molecular medicine
                psychiatric disorder,brain imaging,pet,attention,catecholamines,personality
                Molecular medicine
                psychiatric disorder, brain imaging, pet, attention, catecholamines, personality

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