The dual pathway model proposes the existence of separate and neurobiologically distinct cognitive (inhibitory and more general executive dysfunction) and motivational (delay aversion) developmental routes to AD/HD. The study reported in this paper explores the relation between inhibitory deficits and delay
aversion and their association with AD/HD in a group of three-year-old children. Children identified as having a pre-school equivalent of AD/HD (N=19) and controls (N=19), matched for gender and IQ, completed a battery of inhibition and delay tasks. Correlational and factor analysis supported a dissociation between inhibitory deficits (go-no-go, set shifting) and delay aversion (choice delay) with delay of gratification cross-loading. Children
with AD/HD displayed more inhibitory deficits and were more delay averse than controls. The data support the value of the distinction between motivational and cognitive pathways to AD/HD. Furthermore, the data suggest that
such a distinction is apparent relatively early on during development.

Lindy Dalen

Edmund J. S. Sonuga-Barke

Martin Hall

Bob Remington

Inhibitory Deficits, Delay Aversion and Preschool AD/HD:
Implications for the Dual Pathway Model

This paper brings together two recent insights into attention deficit/hyperactivity disorder (AD/HD) to provide the rationale for a novel approach to treatment. First is the suggestion, backed up by data from randomized
trials, that training and practice in carefully selected cognitive activities (executive and attentional training) and tasks can provide a way of modifying the processes underlying cognitive, especially executive, deficits in
AD/HD. Second, is the idea that AD/HD is a neuropsychologically heterogeneous disorder resulting from motivational alterations, specifically an increased intolerance for delay, as well as executive deficits. The paper builds
on these two insights to explore the possibility that the motivational alterations underpinning delay aversion can be modified through specific training regimes in a way equivalent to that found with executive and attentional training. The requirements for such an approach are set out. Delay fading is proposed as a possible basis for reorganizing delay experience, altering the incentive value of delay (e.g., increasing tolerance for delay), thereby reducing AD/HD symptoms.

On the Reorganization of Incentive Structure to Promote
Delay Tolerance: A Therapeutic Possibility for AD/HD?

We analyzed the molecular mechanisms
involved in the acquisition and maturation of
dopaminergic (DA) neurons generated in vitro
from rat ventral mesencephalon (MES) cells in the
presence of mitogens or specific signaling
molecules. The addition of basic fibroblast growth
factor (bFGF) to MES cells in serum-free medium
stimulates the proliferation of neuroblasts but
delays DA differentiation. Recombinant Sonic
hedgehog (SHH) protein increases up to three fold
the number of tyrosine hydroxylase (TH)-positive
cells and their differentiation, an effect abolished
by anti-SHH antibodies. The expanded cultures
are rich in nestin-positive neurons, glial cells are
rare, all <mml:math id="E1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:msup><mml:mrow><mml:mtext>TH</mml:mtext></mml:mrow><mml:mo>+</mml:mo></mml:msup></mml:mrow></mml:math> neurons are DA, and all DA and
GABAergic markers analyzed are expressed.
Adding ascorbic acid to bFGF/SHH-treated
cultures resulted in a further five- to seven-fold
enhancement of viable DA neurons. This
experimental system also provides a powerful tool
to generate DA neurons from single embryos. Our
strategy provides an enriched source of MES DA
neurons that are useful for analyzing molecular
mechanisms controlling their function and for
experimental regenerative approaches in DA
dysfunction.

Floriana Volpicelli

Claudia Consales

Massimiliano Caiazzo

Luca Colucci-D'Amato

Carla Perrone-Capano

Umberto di Porzio

Enhancement of Dopaminergic Differentiation in Proliferating Midbrain Neuroblasts by Sonic Hedgehog and Ascorbic Acid

Sixty-six male infants participating in the Ben-Gurion Infant Development Study of familial risk for attention deficit hyperactivity disorder (ADHD)were assessed at 7 months of age using observational and mother report measures. Risk for ADHD was based on ADHD symptoms in the father. Infants whose fathers had seven or more symptoms formed the ADHD risk group; infants whose fathers had three or less symptoms formed the comparison group. The ADHD risk group significantly differed from the comparison group on measures of interest, anger, and activity level and showed less interest in block play and more anger reactivity but less directed anger in a
barrier task. According to mother report, the ADHD risk group had higher levels of activity
than the comparison group. Measures of neonatal immaturity and activity were related to behavior at 7 months. The findings suggest that possible developmental pathways to ADHD may be emerging in early infancy.

Judith G. Auerbach

Naama Atzaba-Poria

Andrea Berger

Rivka Landau

Emerging Developmental Pathways to ADHD: Possible Path Markers in Early Infancy

The underlying defects in ADHD (AttentionDeficit/Hyperactivity Disorder) are not yet clear.The current paper tests three existing theories:State Regulation, Cognitive Deficit, andTemporal Difference (TD) learning. We presentcomputational simulations of the MatchingFamiliar Figures Task and compare these withthe experimental results reported by Sonuga-Barke (2002). The TD model contains fourparameters: the learning rate, discounting forfuture rewards, brittleness (randomness) ofbehavior, and action bias. The results show thatthe basic TD model accounts well for controlperformance in trials of 5 sec, 10 sec, and 15 secduration; but not for the deficits in ADHDperformance at 5 sec and 15 sec. Extending theTD model to incorporate either a stateregulation deficit, or working memory deficitand delay in starting trials, can provide a goodaccount of both control and ADHD results, atall trial-lengths. We discuss the significance ofthe results for theories of ADHD and makesuggestions for future experimentation.

Jonathan  Williams

Eric  Taylor

Dopamine Appetite and Cognitive Impairment in Attention Deficit/Hyperactivity Disorder

Animal models are useful for characterizing
neural substrates of neuropsychiatric disorders.
Several models have been proposed for the
study of Attention Deficit Hyperactivity Disorder
(ADHD). The models can be divided into various
groups: (i) genetically derived hyperactivity/
inattention, (ii) animal models showing symptoms
after pharmacological intervention, and (iii)
those based on spontaneous variations in a
random population. Spontaneously hypertensive
(SHR) and Naples High Excitability (NHE) rats
show behavioral traits featuring the main
aspects of ADHD in humans but show different
changes in dopamine (DA) systems. In fact, the
enzyme tyrosine hydroxylase is hyperexpressed
in NHE rats and hypoexpressed in SHR. The DA
transporter is hyperexpressed in both lines,
although in the SHR, DAT activity is low
(reduced DA uptake). The DA levels in the
striatum and prefrontal cortex are increased in
the juvenile SHR, but are decreased in handled
young and non-handled older animals. The
mRNA of the D1 DA receptor is upregulated
in the prefrontal cortex of SHR and downregulated
in NHE. The D2 DA receptors are
likely to be hypofunctioning in SHR, although
the experimental evidence is not univocal,
whereas their mRNA is hyperexpressed in
NHE. Thus, in SHR both the mesocortical and
mesolimbic DA pathways appear to be
involved, whereas in NHE only the mesocortical
system. To understand the effects of
methylphenidate, the elective ADHD drug
treatment in humans, in a dysfunctioning DA
system, we realized a simple mathematical
model of DA regulation based on experimental
data from electrophysiological, cyclic
voltammetry, and microdialysis studies. This
model allows the estimation of a higher firing
frequency of DA neurons in SHR rats and
suggests that methylphenidate increases
attentive processes by regulating the firing rate
of DA neurons.

Davide Viggiano

Daniela Vallone

Adolfo Sadile

Dysfunctions in Dopamine Systems and ADHD: Evidence From Animals and Modeling

Clinical, Experimental, and Modeling Studies in AD/HD

To determine the strength and nature of the association between hydrocephalus and hyperactivity
and to test the dual pathway model (DPM) of AD/HD, we compared a group of 51 children and adolescents with hydrocephalus with 57 normally developing controls from the general population on a battery of neuropsychological
assessments. The mean hyperactivity scores were significantly greater in the group with hydrocephalus (effect size =0.94). This association was not just part of a general elevated rate of behavior problems and was not
affected by sex or age. Variation in the clinical features of hydrocephalus was not related to the severity of hyperactivity. Path analysis was used to examine the relation between IQ, delay aversion, and executive function. In accordance with the DPM, the effect of hydrocephalus on hyperactivity was completely mediated via delay aversion and executive functions.

Jim Stevenson

Ineke Pit-ten Cate

The Nature of Hyperactivity in Children and Adolescents With Hydrocephalus: A Test of the Dual Pathway Model

The aim of this review is to compare the
experimental evidence obtained from in vitro
studies on the effect of amphetamine and
methylphenidate on dopamine transmission with
the results obtained in animal models of
attention deficit hyperactivity disorder (ADHD).
This comparison can extend the knowledge on
the mechanism of action of the drugs used in
the therapy of ADHD and provide insight into
the etiology of ADHD. In particular, we
considered the results obtained from in vitro
methods, such as synaptosomes, cells in culture,
and slices and from in vivo animal models of
ADHD, such as spontaneous hypertensive rats
(SHR) and the Naples high-excitability (NHE)
rat lines. The different experimental approaches
produce consonant results and suggest that in
SHR rats, in contrast to Wistar Kyoto rats
(WKY), amphetamine and depolarization by
high <mml:math id="E1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:msup><mml:mtext>K</mml:mtext><mml:mo>+</mml:mo></mml:msup></mml:mrow></mml:math> might release different pools of
dopamine-containing vesicles. The pool depleted
by amphetamine might represent dopamine
that is stored in large dense core vesicles,
whereas dopamine released by high <mml:math id="E2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:msup><mml:mtext>K</mml:mtext><mml:mo>+</mml:mo></mml:msup></mml:mrow></mml:math> might
be contained in small synaptic vesicles (SSV).
The sustained dopamine transmission observed
in the nucleus accumbens of SHR but not WKY
rats can be supported by an elevated synthesis
and release, which also might explain the
stronger effect of methylphenidate on dopamine
release in SHR but not in WKY rats. This
hypothesis might enlighten the common
therapeutic effect of these drugs, although their
action takes place at different levels in
catecholaminergic transmission.

Ezio Carboni

Alessandra Silvagni

Experimental Investigations on Dopamine Transmission Can Provide Clues on the Mechanism of the Therapeutic Effect of Amphetamine and Methylphenidate in ADHD

To investigate the mechanisms underlyingmotor hyperactivity, we performed intracisternalinjection of 6-hydroxydopamine orendocrine disruptors in rats on postnatal day 5.6-Hydroxydopamine (100 &#956;g, 488 nmol) causeda significant increase in spontaneous motoractivities at 4 weeks of age. Gene-expressionprofiling using a cDNA membrane arrayrevealed alterations in several classes of gene at8 weeks of age. In the midbrain, gene expressionwas enhanced in dopamine transporter 1; aplatelet-derived growth factor receptor;dopamine receptor D4; galanin receptor 2;arginine vasopressin receptor 2; neuropeptide Y;tachykinin 2; and fibroblast growth factor 10.Expression was also enhanced in theglutamate/aspartate transporter gene in thestriatum. Rats received an endocrine disruptor(87 nmol), such as bisphenol A, nonylphenol, p-octylphenol,or diethylhexylphthalate, whichalso caused motor hyperactivity at 4 weeks.The effects of bisphenol A on motor activitywere dose-dependent from 0.87 to 87 nmol. Thephenols caused a deficit in dopamine neurons,similarly to the deficit caused by 6-hydroxydopamine.Gene-expression profiles aftertreatment with endocrine disruptors showedvariation and differed from those of 6-hydroxydopamine. The results suggest thatneonatal treatment with environmentalchemicals can generate an animal model ofattention-deficit hyperactivity disorder, inwhich clinical symptoms are pervasive.

Yoshinori  Masuo

Masami  Ishido

Masatoshi  Morita

Syuichi  Oka

Effects of Neonatal Treatment With 6-Hydroxydopamine and Endocrine Disruptors on Motor Activity and Gene Expression in Rats

About this journal

Neural Plasticity is an interdisciplinary journal dedicated to the publication of articles related to all aspects of neural plasticity, with special emphasis on its functional significance as reflected in behavior and in psychopathology.

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Chief Editor, Professor Baudry, is currently University Professor at Western University of Health Sciences in Pomona, CA. His research focuses on understanding the molecular/cellular mechanisms of learning and memory and neurodegeneration.

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Clinical, Experimental, and Modeling Studies in AD/HD

Clinical, Experimental, and Modeling Studies in AD/HD

Articles

Inhibitory Deficits, Delay Aversion and Preschool AD/HD: Implications for the Dual Pathway Model

On the Reorganization of Incentive Structure to Promote Delay Tolerance: A Therapeutic Possibility for AD/HD?

Enhancement of Dopaminergic Differentiation in Proliferating Midbrain Neuroblasts by Sonic Hedgehog and Ascorbic Acid

Emerging Developmental Pathways to ADHD: Possible Path Markers in Early Infancy

Dopamine Appetite and Cognitive Impairment in Attention Deficit/Hyperactivity Disorder

Dysfunctions in Dopamine Systems and ADHD: Evidence From Animals and Modeling

Clinical, Experimental, and Modeling Studies in AD/HD

The Nature of Hyperactivity in Children and Adolescents With Hydrocephalus: A Test of the Dual Pathway Model

Experimental Investigations on Dopamine Transmission Can Provide Clues on the Mechanism of the Therapeutic Effect of Amphetamine and Methylphenidate in ADHD

Effects of Neonatal Treatment With 6-Hydroxydopamine and Endocrine Disruptors on Motor Activity and Gene Expression in Rats