Positron emission tomography neuroimaging for a better understanding of the biology of ADHD

PET Department, CERMEP-Imagerie du Vivant, 69003 Lyon, France.
Neuropharmacology (Impact Factor: 5.11). 09/2009; 57(7-8):601-7. DOI: 10.1016/j.neuropharm.2009.08.001
Source: PubMed


Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by inappropriate symptoms of inattention, impulsivity and motor restlessness. Converging data from neuropsychological, genetic, neurochemical and pharmacological studies have implicated fronto-striatal network abnormalities as the likely cause of ADHD. The functional imaging field has evolved rapidly providing unprecedented tools to examine questions regarding the pathophysiology of ADHD and the biological effects of medications used to treat it. Positron emission tomography (PET) provides unique quantitative information on the spatial resolution of radiolabelled molecules in the brain of patients or healthy subjects allowing the longitudinal assessment of physiological parameters such as binding potential over extended periods of time. The main goal of this review is to provide an overview of PET studies performed in ADHD patients, discuss their relative strengths and weaknesses and show how they can complement one another to enable a better understanding of the neurobiology and the neuropharmacology of this disease.

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Available from: Luc Zimmer
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    • "1.3. Support for a DAT connection to ADHD: brain imaging studies Positron emission tomography (PET) methods have afforded a direct inspection of DAT levels in the brain of human ADHD subjects (Varrone and Halldin, 2010; Zimmer, 2009). However, the findings with this approach have been mixed, possibly due to prior drug exposure in some studies (Fusar-Poli et al., 2012). "
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    ABSTRACT: Alterations in dopamine (DA) signaling underlie the most widely held theories of molecular and circuit level perturbations that lead to risk for attention-deficit hyperactivity disorder (ADHD). The DA transporter (DAT), a presynaptic reuptake protein whose activity provides critical support for DA signaling by limiting DA action at pre- and postsynaptic receptors, has been consistently associated with ADHD through pharmacological, behavioral, brain imaging and genetic studies. Currently, the animal models of ADHD exhibit significant limitations, stemming in large part from their lack of construct validity. To remedy this situation, we have pursued an effort to create a mouse model derived from functional nonsynonymous variation in the DAT gene (SLC6A3) of ADHD probands. We trace our path from the identification of these variants to in vitro biochemical and physiological studies to the production of the DAT Val559 mouse model. We discuss our initial findings with these animals and their promise in the context of existing rodent models of ADHD.
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    • "The underlying mechanisms of impulsivity are not well understood but putatively involve deficiencies in norepinephrine and dopamine (DA) transmission (5–8), together with functional abnormalities in the prefrontal cortex (PFC) and striatum (9–15). Research has implicated the nucleus accumbens (NAcb) as a key brain region involved in the expression of impulsive behavior (1,16), a function postulated to involve glutamatergic inputs from the amygdala, hippocampus, midline thalamus, and PFC, together with DA inputs from the mesolimbic DA system (17) that impinge on its core (NAcbC) and shell (NAcbS) subterritories (1,16). "
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    ABSTRACT: Pathological forms of impulsivity are manifest in a number of psychiatric disorders listed in DSM-5, including attention-deficit/hyperactivity disorder and substance use disorder. However, the molecular and cellular substrates of impulsivity are poorly understood. Here, we investigated a specific form of motor impulsivity in rats, namely premature responding, on a five-choice serial reaction time task. We used in vivo voxel-based magnetic resonance imaging and ex vivo Western blot analyses to investigate putative structural, neuronal, and glial protein markers in low-impulsive (LI) and high-impulsive rats. We also investigated whether messenger RNA interference targeting glutamate decarboxylase 65/67 (GAD65/67) gene expression in the nucleus accumbens core (NAcbC) is sufficient to increase impulsivity in LI rats. We identified structural and molecular abnormalities in the NAcbC associated with motor impulsivity in rats. We report a reduction in gray matter density in the left NAcbC of high-impulsive rats, with corresponding reductions in this region of glutamate decarboxylase (GAD65/67) and markers of dendritic spines and microtubules. We further demonstrate that the experimental reduction of de novo of GAD65/67 expression bilaterally in the NAcbC is sufficient to increase impulsivity in LI rats. These results reveal a novel mechanism of impulsivity in rats involving gamma aminobutyric acidergic and structural abnormalities in the NAcbC with potential relevance to the etiology and treatment of attention-deficit/hyperactivity disorder and related disorders.
    Full-text · Article · Aug 2013 · Biological psychiatry
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    • "Although many of these studies support hypofunctioning or compromised white matter integrity within these networks , results have been inconsistent and some studies have found increased rather than decreased regional brain activation, especially throughout the DMN. Each of these neuroimaging techniques provides unique information regarding the pathophysiology of ADHD, but they also are characterized by unique methodological limitations (Rubia, 2002; Zimmer, 2009). Both fMRI and PET, for example, are indirect measures of brain activity and do not immediately assess neuronal brain activity. "
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    ABSTRACT: Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by pervasive and developmentally inappropriate levels of inattention, impulsivity, and hyperactivity. There is no conclusive cause of ADHD although a number of etiologic theories have been advanced. Research across neuroanatomical, neurochemical, and genetic disciplines collectively support a physiological basis for ADHD and, within the past decade, the number of neuroimaging studies concerning ADHD has increased exponentially. The current selective review summarizes research findings concerning ADHD using functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and diffusion tensor imaging (DTI). Although these technologies and studies offer promise in helping to better understand the physiologic underpinnings of ADHD, they are not without methodological problems, including inadequate sensitivity and specificity for psychiatric disorders. Consequently, neuroimaging technology, in its current state of development, should not be used to inform clinical practice.
    Full-text · Article · May 2013 · Developmental Neuropsychology
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