Striatal Dopamine Transporter Alterations in ADHD: Pathophysiology or Adaptation to Psychostimulants? A Meta-Analysis

Fusar‐Poli, Paolo; Rubia, Katya; Rossi, Giorgio; Sartori, Giuseppe; Balottin, Umberto

doi:10.1176/appi.ajp.2011.11060940

Cited by 203 publications

(167 citation statements)

References 58 publications

(43 reference statements)

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“…The stronger pre‐FU than pre‐post effects may reflect lasting effects of brain self‐regulation training on brain plasticity that may build up over time. The concept of a finite training providing longer‐term persistent changes is particularly attractive given that one of the key limitations of stimulant medication is that effects only last for 24 hours after administration and even with chronic administration longer‐term beneficial clinical effects beyond several years have not been demonstrated [Cunill et al, 2016; Molina et al, 2009], possibly due to evidence for brain dopaminergic adaptation to the medication [Fusar‐Poli et al, 2012; Wang et al, 2013]. …”

Section: Discussionmentioning

confidence: 99%

“…Psychostimulants improve ADHD symptoms in about 70% of patients with effect sizes of 0.6 for parent and up to 0.8 for teacher ratings [Stevens et al, 2013]. Although superior to behavioral treatments in the short‐term, longer‐term efficacy has not been demonstrated [Cunill et al, 2016; Molina et al, 2009], which may be related to evidence from positron emission tomography studies for dopaminergic brain adaptation to psychostimulant medication [Fusar‐Poli et al, 2012; Wang et al, 2013]. Moreover, because of their potential for abuse and diversion, adverse effects, and unknown longer‐term brain effects, non‐pharmacological treatments are preferred, but have limited efficacy [Sonuga‐Barke et al, 2013].…”

Section: Introductionmentioning

confidence: 99%

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Real‐time fMRI neurofeedback in adolescents with attention deficit hyperactivity disorder

Alegría

Wulff

Brinson

et al. 2017

Human Brain Mapping

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Attention Deficit Hyperactivity Disorder (ADHD) is associated with poor self‐control, underpinned by inferior fronto‐striatal deficits. Real‐time functional magnetic resonance neurofeedback (rtfMRI‐NF) allows participants to gain self‐control over dysregulated brain regions. Despite evidence for beneficial effects of electrophysiological‐NF on ADHD symptoms, no study has applied the spatially superior rtfMRI‐NF neurotherapy to ADHD. A randomized controlled trial tested the efficacy of rtfMRI‐NF of right inferior prefrontal cortex (rIFG), a key region that is compromised in ADHD and upregulated with psychostimulants, on improvement of ADHD symptoms, cognition, and inhibitory fMRI activation. To control for region‐specificity, an active control group received rtfMRI‐NF of the left parahippocampal gyrus (lPHG). Thirty‐one ADHD boys were randomly allocated and had to learn to upregulate their target brain region in an average of 11 rtfMRI‐NF runs over 2 weeks. Feedback was provided through a video‐clip of a rocket that had to be moved up into space. A transfer session without feedback tested learning retention as a proximal measure of transfer to everyday life. Both NF groups showed significant linear activation increases with increasing number of runs in their respective target regions and significant reduction in ADHD symptoms after neurotherapy and at 11‐month follow‐up. Only the group targeting rIFG, however, showed a transfer effect, which correlated with ADHD symptom reductions, improved at trend level in sustained attention, and showed increased IFG activation during an inhibitory fMRI task. This proof‐of‐concept study demonstrates for the first time feasibility, safety, and shorter‐ and longer‐term efficacy of rtfMRI‐NF of rIFG in adolescents with ADHD. Hum Brain Mapp 38:3190–3209, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Real‐time fMRI neurofeedback in adolescents with attention deficit hyperactivity disorder

Alegría

Wulff

Brinson

et al. 2017

Human Brain Mapping

Self Cite

112

103

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“…Abnormality of dopamine signaling in the prefrontal cortex contributes to hypoactivation of the ventral prefrontal and inferior parietal regions (see Casey & Durston, 2006). Furthermore, in ADHD patients alterations in striatal dopamine transporter (DAT) density (see Fusar-Poli, Rubia, Rossi, Sartori, & Balottin, 2012 for a meta-analysis of nine receptor imaging studies) as well as reduced volumes of striatal regions, such as the caudate nucleus and the globus pallidus that are rich in dopamine, were observed (Castellanos et al, 2002). Depending on the history of psychostimulant exposures, relative to healthy controls drug naïve ADHD patients tend to show lower DAT density in the striatum (e.g., Hesse, Ballaschke, Barthel, & Sabri, 2009;Volkow et al, 2007), whereas patients with prior medication treatments tend to show higher DAT density (Fusar-Poli et al, 2012).…”

Section: Dopamine and Attention: Clinical And Molecular Genetic Evidencementioning

confidence: 99%

“…Furthermore, in ADHD patients alterations in striatal dopamine transporter (DAT) density (see Fusar-Poli, Rubia, Rossi, Sartori, & Balottin, 2012 for a meta-analysis of nine receptor imaging studies) as well as reduced volumes of striatal regions, such as the caudate nucleus and the globus pallidus that are rich in dopamine, were observed (Castellanos et al, 2002). Depending on the history of psychostimulant exposures, relative to healthy controls drug naïve ADHD patients tend to show lower DAT density in the striatum (e.g., Hesse, Ballaschke, Barthel, & Sabri, 2009;Volkow et al, 2007), whereas patients with prior medication treatments tend to show higher DAT density (Fusar-Poli et al, 2012). Altered dopamine transporter density in ADHD patients could change mechanisms of recycling dopamine back into the presynaptic terminal, and consequently would result in suboptimal extracellular dopamine levels Shumay, Folwer, & Volkow, 2010).…”

Section: Dopamine and Attention: Clinical And Molecular Genetic Evidencementioning

confidence: 99%

Dopamine modulates attentional control of auditory perception: DARPP-32 (PPP1R1B) genotype effects on behavior and cortical evoked potentials

Passow

Nietfeld

et al. 2013

Neuropsychologia

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a b s t r a c tUsing a specific variant of the dichotic listening paradigm, we studied the influence of dopamine on attentional modulation of auditory perception by assessing effects of allelic variation of a single-nucleotide polymorphism (SNP) rs907094 in the DARPP-32 gene (dopamine and adenosine 3′, 5′-monophosphateregulated phosphoprotein 32 kilodations; also known as PPP1R1B) on behavior and cortical evoked potentials. A frequent DARPP-32 haplotype that includes the A allele of this SNP is associated with higher mRNA expression of DARPP-32 protein isoforms, striatal dopamine receptor function, and frontal-striatal connectivity. As we hypothesized, behaviorally the A homozygotes were more flexible in selectively attending to auditory inputs than any G carriers. Moreover, this genotype also affected auditory evoked cortical potentials that reflect early sensory and late attentional processes. Specifically, analyses of eventrelated potentials (ERPs) revealed that amplitudes of an early component of sensory selection (N1) and a late component (N450) reflecting attentional deployment for conflict resolution were larger in A homozygotes than in any G carriers. Taken together, our data lend support for dopamine's role in modulating auditory attention both during the early sensory selection and late conflict resolution stages.

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“…Converging evidence indicates that the pathophysiology of ADHD has multiple origins [26][27][28][29][30][31][32] ; for instance, norepinephrine (NE) has long been implicated [33,34] . In this paper, we review research progress in the relevant fi elds, focusing on the potential relationship between prefrontal α 2A -adrenoceptors and ADHD in nonhuman primates [35][36][37][38][39] .…”

Section: Introductionmentioning

confidence: 99%

Prefrontal cortical α2A-adrenoceptors and a possible primate model of attention deficit and hyperactivity disorder

Sun

Luo

et al. 2015

Neurosci. Bull.

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Attention deficit and hyperactivity disorder (ADHD), a prevalent syndrome in children worldwide, is characterized by impulsivity, inappropriate inattention, and/or hyperactivity. It seriously afflicts cognitive development in childhood, and may lead to chronic under-achievement, academic failure, problematic peer relationships, and low self-esteem. There are at least three challenges for the treatment of ADHD. First, the neurobiological bases of its symptoms are still not clear. Second, the commonly prescribed medications, most showing short-term therapeutic efficacy but with a high risk of serious side-effects, are mainly based on a dopamine mechanism. Third, more novel and effi cient animal models, especially in nonhuman primates, are required to accelerate the development of new medications. In this article, we review research progress in the related fi elds, focusing on our previous studies showing that blockade of prefrontal cortical α 2A -adrenoceptors in monkeys produces almost all the typical behavioral symptoms of ADHD.Keywords: prefrontal cortex; α 2A -adrenoceptors; cognitive functions; attention defi cit and hyperactivity disorder; animal models ·Review· IntroductionAttention deficit and hyperactivity disorder (ADHD) is one of the most prevalent childhood neurodevelopmental conditions, affecting 3-5% of grade-school children worldwide [1] . It is characterized by i nappropriate levels of inattention, i mpulsivity, and/or hyperactivity [2][3][4] . These symptoms develop in childhood, and can persist into adolescence and adulthood [5] . ADHD seriously affects cognitive development [6][7][8] , and, without appropriate treatment, has consequences for the risk of anxiety, substance abuse, and depression in adulthood [ 2, 5, 9] .T he neurobiological bases o f ADHD symptoms are still not clear [10] . Clarifying them can help better understand the biological vulnerabilities that may underlie ADHD in a specifi c patient and how to modulate the responses to treatment, thereby contributing to better and more effective therapy.It has been suggested that the symptoms involve a dopaminergic mechanism in the prefrontal cortex (PFC) and striatum [11, 12] . Experimentally decreased dopamine (DA) release in the PFC results in ADHD-like symptoms [13, 14] .To date, DA dysregulation is thought to be central to the neurobiology of ADHD, and its pharmacological treatment, such as m ethylphenidate (MPH, i.e. Ritalin) [15][16][17] , levels the DA c oncentration in the synapse and extrasynaptic space in the PFC as a blocker of the DA transporter. MPH ameliorates inappropriate inattention [18][19][20] , decreases impulsivity [21] , and enhances inhibitory control [22] . However, as MPH is a prescription psychostimulant, there are strong concerns over drug dependence, paranoia, schizophrenia, and behavioral sensitization that might be caused by longterm therapy, similar to other stimulants [23][24][25].Converging evidence indicates that the pathophysiology of ADHD has multiple origins [26][27][28][29][30][31][32] ; for i...

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Striatal Dopamine Transporter Alterations in ADHD: Pathophysiology or Adaptation to Psychostimulants? A Meta-Analysis

Abstract: Striatal dopamine transporter density in ADHD appears to depend on previous psychostimulant exposure, with lower density in drug-naive subjects and higher density in previously medicated patients.

Cited by 203 publications

References 58 publications

Real‐time fMRI neurofeedback in adolescents with attention deficit hyperactivity disorder

Real‐time fMRI neurofeedback in adolescents with attention deficit hyperactivity disorder

Dopamine modulates attentional control of auditory perception: DARPP-32 (PPP1R1B) genotype effects on behavior and cortical evoked potentials

Prefrontal cortical α2A-adrenoceptors and a possible primate model of attention deficit and hyperactivity disorder

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