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Review article

Attention deficit disorders: Are we barking up the wrongtree?

Pedro Cabral*

Pediatric Neurology Unit, CHLO, Estr. do Forte Alto do Duque, 1400 Lisboa, Portugal

A R T I C L E I N F O

Article history:

Received 15 July 2005

Received in revised form

16 January 2006

Accepted 19 February 2006

Keywords:

Attention

Hyperactivity

Sleep/wake

Neurotransmission

Prefrontal cortex

Co-morbidities

1090-3798/$ - see front matter Q 2006 Europedoi:10.1016/j.ejpn.2006.02.004

E-mail address: vassalocabral@clix.pt

A B S T R A C T

Attention deficit disorder (AAD) and attention deficit/hyperactivity disorder (ADHD) are very

frequent and protean developmental disorders without a definite biologic marker. This

review proposes a framework to understand the enlarged spectrum of its manifestations

based on current knowledge of the mechanisms underlying arousal and attention

variations during sleep/wake cycle. The neuro-modulation’s pivotal role in this process as

well as in the fine tuning of synaptic architecture during development must be taken into

account when trying to understand the marked fuzziness of the symptoms and the very

high prevalence of reported co-morbidities.

The series of related interactions includes a cyclic deactivation of the dorso-lateral portion

of the prefrontal cortex (DLPFC) during sleep, suspending executive functions, co-occurring

with rhythmic periods of decreased noradrenergic tonus. A protracted unbalance in

modulation, with catecholaminergic relative deficiency, could explain less-than-optimum

waking DLPFC activation and the most important manifestations of ADD. Beside the well

documented dopaminergic effects of stimulant medication used in ADD and ADHD, a more

important role must be assigned to noradrenaline (NA). At this light hyperactivity and

impulsivity are less important dimensions. Rather, an attention deficit spectrum disorder

should probably be regarded as a complication of a core defect in prefrontal cortex

dependent inhibitory control, underlying inattention.

Q 2006 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

1. Introduction

ADHD is a very common1,2 heterogeneous developmental

condition which could probably encompass several different

entities. It is, like other developmental disorders, a behaviou-

rally defined syndrome, which integrates three dimensions:

inattention, impulsivity and hyperactivity. There is no definite

biologic marker and, genetically, the evidence is still conflict-

ing.2–10 It is awell-documented cause of learning disabilities at

school age, of behavioural problems in infants and preschoo-

lers, and of social and professional inadequacy in adolescents

an Paediatric Neurology

and adults, with a growing demand for stimulant medication

in these groups.11–14 Claims of increasing incidence of ADD/

ADHD in recent years, perhaps due to changing of speed and

technology of information15 couldmore probably represent an

effect of growing pressure to academic achievement, as

identical prevalence has been shown to occur in deeply varied

social, economic and cultural sets.16

Most ADD patients present co-morbidities:11,17–28 hyper-

activity, tics, anxiety, depression, oppositional and conduct

disorders, developmental motor coordination and perception

disabilities, autistic features and several other specific

developmental troubles. The prevalence of co-pathology, so

Official Journal of the European Paediatric Neurology Society

Society. Published by Elsevier Ltd. All rights reserved.

E U R O P E A N J O U R N A L O F P A E D I A T R I C N E U R O L O G Y 1 0 ( 2 0 0 6 ) 6 6 – 7 7 67

high as to raise the doubt on the existence of the so-called

‘pure’ form of ADD and ADHD, complicates the task of

delineating basic features and does not help the searching

for genetic markers.

Specific developmental disorders present no clear

border separating patients from the normal population,

as opposed to acquired deficits. This was shown by Sally

Shaywitz in dyslexia,29 and even in the so called ‘pervasive

developmental’ (autistic spectrum) disorders, a continuum

with normal performance can be shown in the empathy

ability.30 Moreover, in developmental ADD, three features

should be underlined: symptoms present marked intra-

individual variation during daytime, a different behavioural

expression is to be expected in growth until adulthood,

and there can even be peculiar aspects of genetic

transmission.4

2. Physiopathologic aspects

Multiple hypothesis1,2,26,27,31–35 have been proposed to

explain the enlarged spectrum of symptoms pertaining to

ADD and ADHD, similarly recognized in many monogenic

syndromes, and also as a sequel of trauma, hypoxic–

ischemic encephalopathy, static and progressive neurologi-

cal conditions, and adverse effects of pregnancy and

premature birth.36,37

Until recently, the most widespread hypothesis were

taking into account the well documented dopaminergic

effects of stimulant medication35,38–45 and the role of

dopamine (DA) in prefrontal cognitive processes46 and in

reward mechanisms.27,47 However, some pitfalls in accept-

ing DA as the sole or even the most important neurotrans-

mitter implicated in ADD/ADHD should be pointed. In the

last few years48 a shift has been challenging previous

believes on these topics.47–59 Heterogeneity at the gen-

etic,10,48,53,54,60 physiopathologic31,35,49,55,56,61 and clinical

levels11,49,54,55,62,63 has been commonly accepted. Most

noticeably, very important interactions exist among the

main neurotransmitters involved in diffuse cortical neuro-

modulation.64–68 These dynamic interactions play a docu-

mented role in ongoing cognitive processing, and play a role

in shaping patterns during development. Also, there is most

probably no such thing as a perfectly targeted drug, exerting

its effects on only one system or neurotransmitter.34,69–74 DA

plays a unique role in cognitive functions.32,46,75–77 Its

deficiency in Parkinson disease (a pathologic model perhaps

overused for the study of dopamine cognitive effects) has its

counterpoint in psychotic symptoms in peaks of DA dose.

There is strong correlation of hyperdopaminergic states with

psychosis. As a ‘salience detector’ DA can probably act

either as an ‘attractor’ or as a ‘distractor’.32,78–82 This should

be an important issue, as the role of a neurotransmitter can

change substantially depending on circumstances and stage

of development.64,83,84 It could even be that the arousal state

could modulate the DA circuitry activation, with co-variation

of attraction. The DA absolute role as a motivational

salience detector and reward mechanisms mediator could

probably not justify the whole set of manifestations that

encompass ADD/ADHD.27,47,48,50,55 Also the emergence of

new drugs with more marked noradrenergic effect or of

drugs with less stimulant or non-stimulant effect85–95 can

turn more difficult to accommodate a ‘hypodopaminergic’

model as a sole explanation of ADD/ADHD.47,52,96–100

As new technologies of brain imaging allow functional

and metabolite exams for the purpose of studying circuitry

instead of isolated structures,1,35,101–103 complex dynamic

relations between neurotransmitters,104 the rate of acti-

vation of specific circuits and the way it can be modified by

therapy105–109 need to be addressed. Appearing to work

independently of pre or postsynaptic sensibility modification

mechanisms (as shown by their immediate effect and

absence of tolerance110–114), these stimulants have well-

known cathecolaminergic effects, both DA and NA being

involved. The issue of whether one of them, or both, play a

role in attention mechanisms appears to be an important

one.32–34,97–99

Dopamine, acetylcholine, serotonine and norepinephrine

are the major neurotransmitters that diffusely modulate the

cerebral cortex. From the brainstem, they modify cortical

excitability in different areas depending on rhythms of sub-

cortical pacing. Specifically, serotonine (SE) and norepi-

nephrine (NE) have been shown to present daily rate

variations, regulating sleep/wake cycles. Should not the role

of these neurotransmitters in regulating vigilance and

attention be considered when approaching the spectrum of

developmental disorders where an attention deficit is

documented?

3. Hyperactivity or disorganized activity?

Gillberg115 and other authors have pointed the variability of

the ‘activity’ axis in approaching attention disorders, and

have included hypo-activity and disorganized activity as

very frequent symptoms. Indeed there are well known

gender differences on ADD children’s behaviour, and

declining externalizing motor manifestations is the rule in

adolescence in both sexes.116,117 Perhaps more importantly,

as mentioned, marked intra-individual variations in activity

throughout the day are apparent. Could better knowledge

about pathogenic mechanisms underlying impulsivity con-

tribute to disentangle its nuclear defects? On biological

grounds, should impulsivity be separated from hyperactiv-

ity?.9 Pure ‘phenomenological’ descriptions of the syndrome,

emphasising behaviour, could complicate the search for

‘endophenotypes’35,53,54 and their biological markers. Pyra-

midal tract-dependent hyperactivity as depicted in DSM IV

and Connor’s118–120 list is only part of the symptoms. These

lists ignore, for example, deficits in inhibition of saccadic

ocular movements so often found in attention deficit

children in clinical practice.121–123

Also the search for cognitive differences in neuropsycho-

logical tests in ADHD known subgroups124–127 have been

criticized on methodological grounds.128 Long lasting rel-

evance on impulsivity/hyperactivity as a nuclear deficit does

not appear to have contributed significantly when considering

attention deficit disorders.57,129,130

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4. Attention and the search for core defects

Attention is a complex function, served by segregated

neuronal systems, object of several publications not detailed

in this review.131–134 Sustained attention, mostly related to

vigilance, is dependent on integrity of the (right) prefrontal

cortex. Focused activity (capacity for ruling out irrelevant

stimuli) and executive functions (including inhibitory control,

planning,mental representationworkingmemory, capacity to

postpone an answer to a stimuli)32,121,122,135–141 are supported

mainly or exclusively by anterior attention networks, and

these could possibly be genetically determined.142 Partial

functions integrating this ‘anterior’ attention could be

represented in a bell-shaped curve (author, unpublished

data). Its quantitative evaluation is strongly age-dependent,

in accordance with what is known about developmental

maturation of myelination and synaptic pruning in prefrontal

cortex.127,143,144

Attention deficit is pervasive in the known ADHD sub-

types, and its persistence in adulthood, when impulse and

activity control deficit slow down,make it a likely candidate in

the search of core defects.59 Could inhibitory control deficit

explain most deficiencies in executive function and working

memory currently described? There is evidence that it could

be so.35,47,49,50,121,132,135–138,140

A quite often overlooked feature of attention is its labile

nature. Many children under incomplete arousal circum-

stances can behave in good performance in attention-

requiring tasks, and even in formal evaluation tests (for

example, the ‘towers’) when their responses are dependent of

attention ‘peaks’, normally recruited by salience. Problems

arise usually inmonotonous play or work. This is indeedwhat

is regularly reported by parents and care-givers, when

testifying quiet behaviour in front of TV sets or computer

game screens, mistakenly attributing attention capacities to

this kind of play that, obviously, is not an executive function

hard-demanding task. Recognized difficulty in designing

laboratory tests for ‘anterior’ attention is indeed based on its

marked temporal, even minute to minute variability. The

search for measuring average attention (and behaviour) as

depicted by DSM-IV and Connor’s scales is based on this.

Attention is, evolutionarily, a fragile construct, supposed to be

constantly available. There are well known limits to selective

attention imposed by wake-dependent working memory.145

The need to engage sub-cortical structures (thalami) when the

waking state is not strong enough to maintain a desired level

of attention is documented.146 Limited and vulnerable as it is,

recruiting top–down mechanisms to keep better achievement

should be proof of these unique features.

5. Sleep in ADD children

Among the first models proposed to explain attention deficit

was indeed an arousal deficiency. There is extensive literature

about it.147–152 And there is also some evidence of sleep

behaviour particularities in such patients.153–160 A complaint

of bad sleep during the first 2 years of life is very frequent in

children with attention disorders, and colic behaviour has

been considered a manifestation of sleep consolidation

trouble during the first months,161,162 and is reported to be

more frequent in children who later become attention-

impaired.163,164 Vast and contradictory documentation about

sleep differences in ADD children exists,165,166 and better

understanding of sleep biologic mechanisms is certainly

needed to integrate all this variability as, most probably,

commonly used sleep stage markers are not accurate enough

to measure sleep efficiency.158–160,167–174

Cognitive troubles induced by sleep disturbance have long

been studied175–180 and different memory consolidation

problems in sleep deficits, both in laboratory animals and

humans, have been paving the way for a theorization of sleep

function and sleep ontogeny.

6. Sleep/wake cycle neurochemistry

Hobson’s long-standing work on a model relating neurotrans-

mitter activation and deactivation to sleep/wake cycle and

conscious states181–189 should be considered in this context,

even if much of it has yet to become consensual. For example,

dreams should not be considered as merely a secondary

phenomena, as they are emotionally loaded and emotions

appear to have a pivotal role in driving cognitive contents of

REM sleep (in accordance with what is known about definite

maturity of emotion processing circuits in the human new-

born190). Dopaminergic circuit activity appears essential in

this REM stage, as in other conscious states, either in normal

and pathologic conditions, and there is still a lot to be known

concerning the way it produces its effects.188,189,191–195 But

dopaminergic circuit activity does not presentmajor circadian

variation.196 Its role in mediating waking, vigilance and

attention should not be the primary one.

Cyclic variation of noradrenergic and serotoninergic neuro-

transmitter circuits is, on the contrary, well established.197–203

NE and SEmodulate extensive areas of the brain duringwaking

periods, and are seen to gradually decrease their presence

during periods of decreasingwakefulness and vigilance. During

non-REM sleep NE activity is halved, compared to wakeful

hours, and during REM sleep it is virtually zeroed. Noticeably

there is parallel deactivationof certain brain structures, namely

the DLPFC.204,205 REM sleep, it is well known, presents a special

dream activity, which appears to be activated only after

suspension of DLPFC dependent executive functions. But this

progressive decrease of NE-dependent DLPFC activation co-

occurs with peculiar behaviour of anterior cingulated cortex

(ACC) activation, which is seen to decrease during non-REM

sleep, parallelingDLPFC, butmarkedly reactivatingduringREM-

sleep, to values close to the waking state, instead of deactivat-

ing.184 It looks difficult not to relate this dissociation, with DA-

dependent enhancing of ACC structures during the short

periods of REM-sleep, to what is known of different functions

of these two structures. ACC is said to process options among

differentmotivational values and conflict detection206–213 while

DLPFC is said to play a decision role on material presented by

ACC, with strong interaction.214–218 Some of the features of

dream content, namely the peculiar passivity, could be

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explainedbythisparticularpatternofACCactivationandDLPFC

deactivation.

7. Sleep, dream and memory

REM sleep’s unique vulnerability features of skeletal muscle

decreased tonus, enhanced threshold for sensory stimuli and

loosening of body thermal control must represent a challenge

from an evolutionary point of view and presuppose ontogen-

etically some fundamental yet largely ignored role. Stable

constant temperature is needed in developed brained organ-

isms. Decreased REM sleep latency in sleep deficit physiologic

and pathologic conditions points to its importance. Memory

efficacy could be at least one of these main objectives, and

there is some evidence of experience-dependent and

emotionally oriented REM sleep synaptic reshaping.219–222

Noticeably, autistic spectrum disorder patients, with their

well known difficulty in dealing with changing sets, present

decreased REM sleep.184 Evolved brain structures relying on

very narrow thermal limits for synaptic efficiency in adapting

to different environments seem to depend on cyclic

depression of waking behaviour, even at their own risk, for

what appears to be a moment of central nervous system re-

mapping. This should be accomplished by loosening of stable

synaptic links, and obviously needs inhibitory control and

executive functions suspension.179,181–184,200,219,220

8. Attention and arousal deficiency

Arousal and sleep should not be seen as discrete, ‘all or

nothing’ entities, but integrating a continuum with more or

less extensive transitory states, with marked variation from

person to person and even in the same person. Prolonged

transitory states, and state 1 sleep, present an altered pattern

of response, which is often magnified, to sensory stimuli.

Inhibition deficit and passivity to attractors can then easily be

noticed, and this is a common feature of ADD/ADHD patients,

regardless of motor output.223 Easy habituation to stimuli and

difficulty to automatize are also to be expected under

incomplete arousal situations, and this is indeed what is

seen in clinical ADD practice.115 Habituation can establish

itself very fast in repetitive exposure settings, and be detected

in a few seconds. But even with perfect functional ima-

ging108,224 and with as yet unknown systems allowing

enormous temporal resolution, measuring the state of

vigilance would be useless, as comparisons should not be

made to absolute or median values but intra-individually, and

specific tasks should even be considered.

‘Anterior’ attention225 seems to be particularly sensitive to

the effects of sleep deprivation, and theories about attention

deficit children have stressed for long the relation of

symptoms with poor vigilance.226–230 Only the amount

(duration) and timing of the different sleep states has been

considered when measuring sleep efficiency in cognitive

functions. There are reasons to believe that other markers

should be used in the future in assessing sleep efficacy.231 We

should presumably wait for better knowledge of sleep biology

and sleep repair mechanisms.

9. A link between sleep/wake cycle andattention deficit: prefrontal cortexdependent inhibition

Should ADD/ADHD still be regarded solely as a set of

heterogeneous developmental disorders with very frequent

co-morbidity and fuzzy borders? So far, considering the

previously defined three-dimensional ADD spectrum, the

search for core defects, ‘endophenotypes’ or genetic markers

has been disappointing. Has the phenomenological descrip-

tion of the disorder impaired our insight on its mechanisms?

Among DLPFC executive sub-functions, inhibitory control

serves a very important role of curtailing unnecessary circuitry

activation during a task. This circuitry can potentially relate

widespread sensory, association and motor maps to ongoing

task-related activity. ADD/ADHD being due to aminergic

deficiency, a dysfunction of prefrontal cortex tonus during

waking periods (akin to sleep deficit conditions) should cause a

decrease in inhibition power, and allow irruption of apparently

task-unrelated contents. Inattention, with or without externa-

lizing hyperactive or impulsive behaviour, would be just a by-

product of a more fundamental inhibition core deficit.

10. Implications for brain development:comorbidities?

If an actual deficit in attention and activity control can exert so

deep effects in global performance in children, what is to be

expected if the same causal, genetically determined mechan-

isms are present in foetal, neonatal and growth periods of life?

An early, protracted catecholaminergic, mainly noradren-

ergic, deficit should be profoundly operative in neural systems

sub-serving different functions and proved to be sensitive

during these periods. It looks as if this is indeed the

case.32,224,232–245 Neurotransmitters have very important, yet

largely unknown functions in modulating synaptic contacts.

Even sustained emotions experienced by pregnant females or

infants should have amine-mediated effects on synaptic fine

tuning during foetal life and early infancy.246,247

Functions like perception andmotor control, dependent as

they are on perfect circuitry, should be deeply sensitive to

persistent unbalance in neurotransmitters. This could

explain, at least in part, very frequent motor coordination

and perceptual problems in ADD patients.

On the other hand, relative deficiency in serotonine

activity, that normally parallels rhythmic activity of NE

circuits52,180–183 could, on other way, up-regulate DA circuits66

with hyperdopaminergic effects,248 including detail hypersa-

lience and psychosis. SE is a very ancient and ubiquitous

molecule in nature.64,84,243,249 It was first described as a

neurotransmitter in 1963 by Gerschenfeld and Stefani250,251

and has multiple functions recognized in the nervous system.

In psychiatric clinic there is widespread use of the SE

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re-uptake inhibitors in depression, anxiety, obsessive/com-

pulsive and mood control disorders. It seems that most

psychiatric co-morbidities frequently described in attention

deficit disorders, a putative catecholamine deficit disorder,

could be at least partially related to homologous SE deficit.

11. Improvement in areas other than attention

In clinical practice most strategies that are supposed to

enhance vigilance and DLPFC dependent executive functions

can have positive effects, not only on ‘anterior’ attention

deficits but also, at least in part, on motor control impair-

ments, perception deficits, hyperactivity, impulsive aggres-

sion, opposition and defiant conduct disorders, depression

and anxiety.252,253 Specific learning impairments can be also

helped by stimulant therapy. A significant proportion of

autistic spectrum and Asperger patients can show improve-

ment in several areas, including sociability, under stimulant

medication, perhaps started in much lower dosages (author,

unpublished data). This could also mean that vigilance is an

important dimension in personal, eye-to-eye communication.

It looks as if up-grading vigilance could, in a certain sense,

promote better performance on apparently unrelated areas,

but served by circuits at least partially catecholamine

dependent for optimal functioning.254

12. Routine, creativity andattention/inattention cycling

A question should be addressed about what creativity could

mean in this framework. There is widespread confusion

between talent and genius255,256 and the question has rarely

been addressed, although it is suspected that a strong link

exists between creativity and psychopathology. ‘Savant skills’

have long been recognized in autistic spectrum patients, and

there is undoubtedly unusual performance in half of these

patients in certain areas (namely memory and calculation,

etc.). This appears to represent something different from

creativity, as it is seen to occur in patients to the detriment of

other areas, mostly empathy and socialization, which are

clearly deficient in most of theses cases.257 It is well-known

that in several developmental disorders and autism a defect in

plasticity can be suspected as a major pathologic mechan-

ism.258 It looks as if a distinction should be made between

early, unrelenting, repetitive performance of certain tasks

(mainly memory tasks) which can be noticed in certain

children and herald autistic symptoms, and unusual, unex-

pected ideas which can make their appearance in school

routines or in artistic or scientific domains in some people

that are often considered ‘eccentric’, mainly because they are

inattentive. ADD patients can indeed surprise others by ‘peak’

reply and by bright, unexpected ideas that emerge in a context

of poor response to regular tasks. If in the everyday up-and-

down recurring curve of attention, re-mapping tasks for

updating experience imply cyclic periods of inhibitory control

attenuation, then this can be the opportunity for unexpected,

’creative’ links to emerge. From this viewpoint, attention

deficit patients and artistic personalities would be expected to

spendmore time in ‘less than optimal’ arousal andwould thus

be more prone to unusual associations, such as a deficit in

inhibition state can allow. That is probably why they cannot

easily cope with regular, routine-demanding tasks.

13. Conclusions

This review reconsiders existing hypothesis on pathogenic

mechanisms of ADD, based on current knowledge on the

subject. It recognizes its strong genetic dependency and

stresses its implications in infancy and the search for basic

defects taking into account its protean manifestations.

Attention is a complex function, which implicates sub-

cortical and brain stem circuitry, and pervades several areas

of central nervous system functioning. Its defects can have

deep implications in multiple dimensions, and do not fit well

in an ‘all or nothing’ paradigm. There is evidence of a strong

link between arousal, attention, and sleep/wake cycle neuro-

chemical pacing and of genetic, sub-cortical ‘bottom–up’

mechanisms underlying the efficacy of this pacing.

Attention deficit disorders are specific developmental

impairments that present unique features of marked tem-

poral, circadian variability. Their pharmacological treatment

includes stimulant medication that has strong known ami-

nergic (NA and DA) effects. NA and SE, but not DA, circuits

present important variations during the 24-h cycle, with

decreased activity during sleep, and absent activity during

REM sleep, which parallel congruent deactivation of DLPFC.

‘Anterior’ attention, recruited for learning school tasks, is

strongly dependent on DLPFC executive functions.

An important feature of ADD and ADHD complex is the

frequency of co-morbidities, which can be at least partially

explained by enduring unbalance of these neurotransmitters

during pre and postneonatal life. Positive effects of stimulant

medications on some of these co-morbidities manifestations

should support evidence for sharing part of the same

mechanisms.

Functional imaging intending to study ADD deficits should

have much higher temporal resolution and be directed to

intra-individual comparison. Better knowledge about rest and

sleep biology and ‘sleep genes’ expression is needed to

understand its cognitive effects and efficiency.

Previous views emphasizing impulsivity and hyperactivity

and disregarding inattention should be reconsidered. Instead,

inhibitory control deficit should probably be viewed as the

main defect.

Acknowledgments

The author would like to thank Isabel Pavao Martins,

Carlos Nunes Filipe and Jose Carlos Ferreira for very

helpful discussions, and Ana Gerschenfeld, Margarida

Menezes Ferreira and Ana Isabel Dias for reading of the

manuscript.

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