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UNIVERSITY OF COPENHAGEN

Department of Psychology

Master Thesis
Jimmy Jensen

Advancing ADHD Diagnosis through Neuroimaging

Supervisor: Signe Vangkilde, Associate Professor

Submitted: October 2014
161.386 characters, equivalent to 67,2 pages

Abstract

Objective:Attention Deficit/HyperactivityDisorder(ADHD)isaprevalentchilddisorder
with alargesocialandeconomicimpact.ThediagnosisofADHDispresentlybased on
subjective evaluation of behavioral symptoms.An affordable and easyto use objective
diagnosisof ADHD isdesirableto ensure high accuracy as wellaseffectivetreatment
fortheindividual. Neuroimagingtechnologieshaveprovidedgreatstridesinneuroand
cognitive science, but translationof research findingsinto clinical utilityis lacking.This
thesisexamines and discusses issuessurroundingtheuseofneuroimagingtoimprove
ADHDdiagnosis,includingpotentialtechnologiesandbiomarkers.
Method: A review of the research data on neuroimaging for the diagnosis of ADHD
was conducted,and biomarkerswere evaluatedaccording to criteriadevelopedbythe
task force on biological markers of the World Federation of Societies of Biological
Psychiatry(WFSBP)andtheWorldFederationofADHD.
Results: No biomarkers evaluated complied with the full range ofcriteria, but several
promising results were found. In particular, eventrelated potential (ERP) recording,
machine learning, and eye movement tracking, are technologies with potential as
diagnostic tools. Further research is needed to ensure reliability and unravel the
influenceofADHDsubtypesandpsychiatriccomorbiditiesondiagnosis.

TableofContents

1.Introduction...1
1.1.Researchquestion...........2
1.2.Insearchofbiomarkers......2

2.ADHD..........8
2.1.History.........9
2.2.Diagnosis......11
2.3.Treatment......15
2.4.NeurobiologyofADHD......16
2.5.NeuropsychologyofADHD......19
2.5.1.Reactiontimevariability..19
2.5.2.Workingmemorydeficits.22
2.6.ModelsofADHD..23
2.6.1.ADHDasadeficitinbehavioralinhibition23
2.6.2.ADHDashypoarousal.25
2.6.3.ADHDasdelayaversion....26
2.6.4.ADHDasaneurodevelopmentaldisorder...28
2.6.5.ADHDasdysfunctionalnetworks......31
2.6.6.Summary.......34

3.Neuroimaging.....34
3.1.Electroencephalography...35
3.1.1.Eventrelatedpotential...40
3.2.Magneticresonanceimaging...41
3.2.1.Functionalmagneticresonanceimaging..42
3.2.2.Diffusiontensorimaging.....43
3.3.Positronemissiontomography...45
3.4.Combiningmodalities45


4.Researchdata........46
4.1.EEGstudies......46
4.1.1.Metaanalyses......50
4.1.2.Singlestudies52
4.2.MRIstudies...55
4.2.1.Machinelearningstudies57
4.2.2.Restingstatefunctionalconnectivitystudies...60
4.3.Eyemovementtracking....62

5.Discussion......64
5.1.TBRasadiagnosticmarker.64
5.2.Age,subtypeandcomorbidity....68
5.3.OtherEEGfindings.69
5.4.FindingsfromMRIstudies...71
5.5.Structuralvsfunctionalimaging....72
5.6.Frontocentralthetaandoccipitalalphaabnormalities...73
5.7.Summary...74

6.Perspectiveandfuturesuggestions......75

References......79

1.Introduction

An increasing number of children are being diagnosed with Attention

Deficit/Hyperactivity Disorder (ADHD), which has now become the most commonly
diagnosed child psychiatric disorder (Sundhedsstyrelsen, 2014). Despite being now
regarded as a neurodevelopmental disorder, with evidence of both structural and
functional impairments, the diagnosisof ADHDiscurrently clinical,basedonsubjective
evaluations of behavioral symptoms as defined inthe classificationsystem DSM. The
primary symptoms inattention and hyperactivity/impulsivity are nonspecific and
observed in a range of psychiatric disorders, making it difficult to distinguish ADHD
fromotherdisorders.

Because of the heterogeneity of research findings, there are presently no accepted

biomarkers to helpguidethe clinician in his diagnosis(Botteron etal.,2012Thomeet
al., 2012), and many patients are therefore misdiagnosed. According to research by
Weiler et al. (2000), the sensitivity of a DSMIV based ADHD screener (Diagnostic
Rating Scale, DRS) is 7090% in children, which means that 1030% ofADHDcases
are missed and therefore left untreated. An affordable, noninvasive test based on
objective biomarkerscouldmakediagnosismorepreciseandefficient,leadingto more
effectivetreatmentandfasterrecoveryforpatients,andisthereforehighlydesirable.

TheclassificationsystemsICD andDSMbasepsychiatricdiagnosisontheobservation
of behavioral symptoms, andbiologicalmeasuresarenotpartofthediagnosticcriteria.
A controversy regarding thisissue has emerged,especiallyduring thedevelopment of
version V of the DSM (NLM, 2013). The American National Institute of Mental Health
(NIMH), the countrys largest mental health research institute,hascriticizedthe current
method of diagnosing psychiatric disorders and in response launched the Research
Domain Criteria (RDoC) project, which seeks to develop methods for objective
diagnosis of mental disorders. NIMH argues that patients with mental illnesses have
equal rights toobjectiveand effective diagnosisaspatientswithphysiologicalillnesses
where testable biomarkers exist. The methods proposed in RDoC for improving
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psychiatric diagnosis include the utilization of 1) neuroimaging technologies, 2)

geneticsresearch,and3)cognitivetesting(Insel,2013).

Neuroimaging technologies, including electroencephalography (EEG) and magnetic

resonance imaging(MRI), haveprovided significant progressin the domainsof neuro
andcognitivescience inthelastdecades,butin spite ofaverylargebodyofresearch,
this data is not being utilized clinically to improve psychiatric diagnosis (Farah &
Gillihan, 2012). This lack of translation from research data into clinical utility is both
puzzling and disappointing, as improving the quality of life for patients is one of the
primary(andperhapsthemostnoble)goalsofneurocognitiveresearch.

This thesis will examineand discussthe issues surroundingtheimprovementofADHD

diagnosis through neuroimaging, including technologies employed, research data and
potential biomarkers, by a review of the empirical data in the field. Do reliable
neuroimaging biomarkers aidingdiagnosis presently exist? Ifso,howdotheycompare
to traditionalclinicaldiagnosis?Howcanexistingtechnologiesbeemployedtoimprove
diagnosis?

1.1.Researchquestion
Can current neuroimaging technologies improvethe accuracy ofADHDdiagnosis,and
if not,in what waysdoweneedtoimprovetheuseofthesetechnologiestoachievethis
goal?

1.2.Insearchofbiomarkers
In the 2012 Consensus Report ofthe APA Work GrouponNeuroimaging Markers of
Psychiatric Disorders, the American Psychological Association (APA) state that
currently no brain imaging biomarkers exist that areclinically usefulforany diagnostic
category inpsychiatry(Botteronet al., 2012).This isdespitethefactthatneuroimaging
has shown clear abnormalities of brain structure and function associated with
psychiatric disorders. The authors continue by concluding that the data found

corroborate the conclusions reached from genetic, endocrine, and clinical

pharmacology research involving these disorders to suggest that under the current
nosology the majorpsychiatricdisorderslikelyreflectheterogenousgroupsofdisorders
with respectto pathophysiologyandetiology (Botteronet al.,2012,p.1).Thisineffect
means thatin the authorsopinion,the biologicalfindingsin researchcannotbedirectly
mapped to the existing diagnostic categories as they are defined in the current
diagnostic systems(i.e.,DSM,ICD),butinsteadreflectamorediverse setofdisorders.
As such, it may not be possible to utilize research technologies to diagnose patients
based on present classification systems,and insteadnew systemsbased on different
categoriesmayhavetobeinvented.

The clinical advantages afforded by objective, biologicallybased diagnosis of

psychiatricdisordersare vast,andaccordingtotheAPAworkgroupincludepredicting
treatment response, differentiating between related diagnostic categories, and
potentially treating atrisk patients prophylactically to prevent neurotoxicity and clinical
deterioration (Botteron et al.,2012,p.1).However,theevidencereviewedleadstothe
conclusionthat imagingmeasuresdonotprovidesufficientspecificityandsensitivityto
accuratelyclassify individual caseswithrespecttothepresenceofapsychiatricillness
(Botteron et al., 2012, p. 1). Of note, the evidence reviewed included only MRIbased
studiesanddidnotincludestudiesusingEEGmeasures.

Similarly, the 2012 consensus report by the task force on biological markers of the
World Federation of Societies of Biological Psychiatry (WFSBP) and the World
Federation of ADHD concluded that most likely, no single ADHD biomarker can be
identified. However, the use of a combination of markers may help to reduce
heterogeneity andto identifyhomogeneous subtypes of ADHD (Thomeetal.,2012,p.
379). The criteria of the task force for biomarkercandidate evaluation were: (1)
sensitivity > 80%, (2) specificity > 80%, (3) the candidate is reliable, reproducible,
inexpensive, noninvasive, easy to use, and (4)confirmed by at least two independent
studies in peerreviewed journals conducted by qualified investigators (Thome et al.,
2012, p. 379).In contrast to theAPAreport, thisreportdidincludeevidencefromEEG
studies, however although criteria for the successful evaluation of biomarkers were
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clearly defined, it is not clear from the report how the reviewed studies wereselected
(i.e., noinclusion/exclusion criteria were defined), and thismakes it difficultto evaluate
the task forces conclusions. The authors did acknowledge that neurophysiological
measures from EEG, nearinfrared spectrography (NIRS) and transcranial magnetic
stimulation (TMS) techniques do provide objective measurements of abnormalities in
ADHD,but the specificityand sensitivityof these measures arecurrentlyinadequateto
functionasreliablebiomarkersfordiagnosis.

In contrast to these reports, Bansal et al. (2012) claims that identifying anatomical
variations using MRI can accurately diagnose chronic neuropsychiatric illnesses. The
authors developed a classification algorithm, based on machine learning, that
discriminated with high specificity and nearly perfect sensitivity the brains of persons
who had one specific neuropsychiatric disorder from thebrains ofhealthy participants
andthe brains ofpersonswho hadadifferentneuropsychiatric disorder(Bansaletal.,
2012, p. 1). However,thesefindingswillhavetobereplicatedbyindependentresearch
groupstoconfirmtheirutility.Furthermore,MRIscanning,thoughitisnoninvasive,does
not fulfill the thirdcriteriaoftheWFSBPtaskforce,asitisneitherinexpensive,noreasy
to use. In this thesisI will use the fourcriteriaset forth by the WFSBP taskforce when
evaluating the clinical utility of biological research findings. Besides findings being
replicated by independent groups of researchers, as well as being noninvasive,
inexpensive and easy to use, both high sensitivity and specificity is required for a
biologicalbiomarkertocarrydiagnosticvalue.

In clinical terms,sensitivity refers totheabilityofatesttocorrectlyidentifypeoplewitha

given disorder, and specificity refers to the ability of a test to correctlyidentify people
without a givendisorder. Arequirement of a sensitivityand specificityof >80% means
that a given test should be able to return a positive result for at least 80 out of 100
peoplewith agivendisorder,aswellasreturnanegativeresultforatleast80outof100
people withoutagivendisorder. Lowervalues of sensitivityaswellasspecificitywould
produceunacceptable high numbers offalsepositivesandnegatives,renderingsucha
testclinicallyuseless.

Boutros, Fraenkel and Feingold (2005) has proposed a fourstep approach for
developing diagnostic tests inpsychiatry.In Step1,abiologicalanomalyisobservedin
apatient population. Thereliability of this anomalyis essential,andreplicationmustbe
confirmed by independent groups of researchers. In Step 2, the clinical usefulness of
the research finding must be demonstrated. The most important objective here is the
demonstration of difference between the target patient group and differential
diagnoses. If an anomaly is equally observed in for instance Bipolar Disorder and
Schizophrenia, twodisordersthat commonly needto bedifferentiated,the observation
islikely not clinically useful. In Step 3,thesensitivityandspecificityofthetestshouldbe
established. Boutrosetal.findsitunlikelythata biologicaltestwillbeabletoidentifythe
DSMbased categories inpatients, and believesitmore likelythat thetest willinstead
beable to identify subgroups. Factorssuchasillnessseverity,durationandmedication
effects shouldalsobedefinedinthisstep.Finally,Step4definestheclinicalapplication
andstandardization ofthetestthroughlargermulticentertrials.Thisshouldprovidedata
such as cost effectiveness and short/longtermclinicaloutcomes.Step 4 alsoincludes
thebeginningofthedevelopmentofnormativedatabases.

One area of candidate biomarker research is genetics, asgenes arebotheasilyand

affordably testable through sequencing of a blood or saliva sample. Genes are
heritable,hardwired deoxyribonucleicacid(DNA)codes,algorithmsfortheconstruction
(folding) of proteins, through the differential assembly of amino acids, the building
blocks ofproteins. Every cell in thehumanbody containsthe exact same DNA copy, a
unique combination ofgenesforeverypersonontheplanet.Thisuniquecombinationof
genes, or DNA, is known as the genotype of the person, and is established at
conception, through the combinationof the parents genotypes. The genotypeincludes
mutations ofgenes,eitherinheritedfromparents orlateracquiredthrough life.Common
gene mutations are known as polymorphisms, and are largely responsible for the
differences inappearance and behavior observed at birth. However,notallgenes and
polymorphisms need be expressed in an individual the environment modulates which
genesand polymorphismsare switched on (expressed)orswitchedoff(silenced).This
modulation of the environment of gene expression is known as epigenetics. Thefinal
expression of the genes, mutations and environmental modulation is the persons
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phenotype. Phenotype is the appearance and behavior of the individual that we can
observe or measure. Since the environment changesgene expression, the phenotype
of any given individual is not directly translatable to his genotype. This distinction
between phenotype andgenotypeis important, as it means that we areunlikely to find
direct geneticcausesformostcomplexbehaviorsanddisorders(suchasADHD)atthe
genotypic level. In other words, we have to look to the phenotype in order to find
sufficientlysatisfactoryanswersaboutcomplexbehaviors.

Studying phenotypes in relationtopsychiatricillnessischallengingbecauseofthehuge

individual variability displayed, as individuals suffering from psychiatric disorders
display a wide range of different phenotypes. This is likely explained both by the
influence of epigeneticsonbehavior,aswellasthefactthatthehumanbrainisthemost
complex of all organs, involving an extraordinary number of genes in its phenotypical
expression compared to other organs. To make things simpler, we can look at
intermediate levels between phenotype and genotype. These intermediate levels are
known as endophenotypes and according to Gottesman and Gould (2003) can be
either neurophysiological,biochemical,endocrinological,neuroanatomical,cognitive,or
neuropsychological representations of their genetic underpinnings. Endophenotypes
canalsobesaidtobebiomarkers,whichareendogenous,measurable characteristics
thatmark either riskforormanifestationofpsychiatricillness(Beauchaine,2009,p.1).
Though all endophenotypes can be said to be biomarkers, not all biomarkerscan be
said to be endophenotypes, as thereareimportant distinctions. Gottesman and Gould
(2003) outline five required characteristics ofendophenotypes: 1)The endophenotype
must segregate (be associated with) illness in the population. 2) The endophenotype
must be heritable. 3) The endophenotype must be state independent (manifesting
whetherillness is present ornot).4)The endophenotypemust cosegregate withillness
in families. 5) The endophenotype must be present at a higher rate in nonaffected
family members than the general population. A biomarker must fulfill these criteria in
ordertobecharacterisableasanendophenotype.

In the case of ADHD, twin studies have shown that genetic effects can explain up to
80% of the variance seen in ADHD, and siblings and parents of children with ADHD
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have a 28 fold increased risk of ADHD (Biederman, 2005 Matthew et al., 2014).
However,a studyof twin boys showedhigherheritabilityofimpulsivity/hyperactivitythan
inattention, again pointing to different endophenotypes as comprising the present
ADHD diagnostic category. Asearchforgenomewidesignificantassociationshasso
far been disappointing as resultsaccountfor verylittle variance,but severalcandidate
geneshave beenresearched andidentified.Examplesoftheseincludepolymorphisms
in genesthatcodefordopaminereceptors, orthedopaminetransporter(DAT),butalso
these candidate genes account for less than 5% of variance of the ADHD phenotype
(Matthewsetal.,2014).

Itseems at this point,inspiteoftheapparentlyhighheritabilityofADHD,wecannotuse

genes as biomarkers for the diagnosis of ADHD. This mightbe becausethe study of
the genotype of ADHDexcludestheinfluenceoftheenvironmentonthedevelopmentof
the disorder (epigenetics), or because of the great heterogeneity of the different
subtypes.Inanycase,atpresentwehavetolookelsewhereforeffectivebiomarkers.

Besidesneuroimagingandgenetics,neuropsychologicalassessmentprovidesanother
area of interestfor biomarkeridentification.KoziolandStevens(2012,p.80)statethat
although impairment on various executive cognitive tests was conclusivelylinked to
the disorder, impairment on any single test, or even multiple tests, has not yet been
proventoreliablydifferentiateanygivenpersonwithADHDfromapersonwhodoesnot
have ADHD. According to the authors, a central issue is that the DSM system is
behaviorally definedratherthanneuroanatomicallyorganized, making it difficultto map
DSM categories onto brain networks and systems. This is in line with the criticisms
provided by the NIMH mentioned earlierin this thesis. TheDSMisbasedonamedical
model of etiology in which a disorder or syndrome is caused by a single identifiable
cause. However, in the case of ADHD this search for one cause/one disorder has
been less than fruitful, andonthisbackground Kozioland Stevens (2012,p. 80) argue
thatADHD itself likelyis nota unitarydisorderbutinsteadisabehavioralpresentation
that arises in any given individual from one (or more) different abnormalities in key
neural systems. This again leads us back to neuroimaging as the most likely focus
area in which to discover clinically useful biomarkers for diagnosing ADHD, and also
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highlights the heterogeneity of the disorder. The divergence of research findings

suggest thatmultiplefactorsare involvedin the psychopathogenesis ofADHD, and for
this reason it seems unlikely that a single unique biomarker of ADHD can be found.
Instead it is likely that multivariate analysis (the simultaneous statistical analysis of
multiple variables) willprovesuperiortounivariate analysis (thestatistical analysis ofa
singlevariable)inthesearchforbiomarkers.

2.ADHD

In this section I will give a brief introductionto ADHD,including history,diagnosis and

treatment, as well as an overview oftheprevailing models developedto describeand
explainthedisorder.

According to Brne og Ungdomspsykiatrisk Selskab (2008), ADHD is a common

disorder affecting 35% of children in Denmark. Untreated, the disorder can continue
into adulthood, affecting 24% of adults. A higher number of boys than girls are
diagnosed,witharatioof4:16:1inclinicalpopulations,andaratioof1:13:1insurveys
of the general population, which would seem to indicate underdiagnosis of ADHD in
girls. Comorbidities, such as behavioral disorders, depression, anxiety, drug abuse,
Tourette syndrome and learning disorders are commonly seen in conjunction with
ADHD.

Risk factors fordeveloping ADHDinclude prenatal smokingand alcohol exposure,low

birth weight as wellaspregnancy ordeliverycomplicationssuchastoxemiaorhypoxia
(Biederman, 2005). Severalsubcorticalbrainregionsincludingthecerebellum,aregion
heavilyinvolved in ADHD,areespeciallyvulnerabletoearlyneuronalinsults(Halperin &
Schulz, 2006) that canoccurbefore,duringor afterbirth.FamilialADHDisariskfactor,
as the disorder is highly heritable (Biederman, 2005 Matthews et al., 2014).
Psychosocial factors, such as an adverse familial environment, seems to predispose
children to psychiatric disorders (Biederman, 2005). However, this is a general
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condition, and do not predispose to ADHD in particular, but rather a wide range of
cognitiveandaffectivedisorders.

According to a metaanalysis by Polanczyk et al. (2007) the worldwide estimated

prevalence ofADHD forsubjects aged18yearsor youngerwas 5.29%. This estimate
was based onananalysisof171,756subjectsfromallworldregions.Theauthorsfound
large variability in the studies of ADHD prevalence, but ascribe this mainly to
methodological differences (e.g., diagnostic criteria), whileonly little variationcould be
ascribed directly to geographical differences. Variation was found mainly between
North American and African and Middle Eastern studies, and no variation was found
between North American and European studies. The authors conclude that their
findings argue against ADHD being a culturallybased construct, but simultaneously
stressthatcultureandenvironmentalfactorsmustbeinvolvedinthepathogenesisofthe
disorder,asstudieshaveshown80%heritability.

Theprevalenceof ADHDdiagnoses is rising.Accordingto Sundhedsstyrelsen(2014),

the Danish Health and Medicine Authority, the number of children and adolescents
diagnosed with ADHD in 2001 and 2011 wereapprox. 1,000 and8,000respectively,
an 8fold increase. At the same time, the number of patients receiving ADHD
medication has increasedfromapprox.3,000 in 2002 to 35,000 in2011,more than a
10fold increase (Statens Serum Institut, 2012). Acommon argumentis thatteachers,
parents and health care personnel have become more adept at spotting and
diagnosing ADHD, but this argument (though probably true) seems unlikely to explain
the huge increase in prevalence, as the diagnostic tools available have not changed
considerably during the last decade. Others believe that ADHD as a disorder has
simply become morefashionable(Politiken,2013), andSundhedsstyrelsen(2014)has
calledforarevisionofdiagnosticguidelines.

2.1.History
Matthews etal.(2014) discuss whether ADHDis actuallyarecentpsychiatriccondition
(such as anorexia) or an ancient disorder (such as schizophrenia). Did people suffer
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attention or hyperactivity problems in paleolithic times, or is it a modernphenomena?

Wedonotknowthis,butitisclearthatthedefinitionofADHDhaschangedovertime.In
recent history it was noted that after the encephalitis epidemic between 191520
surviving children expressed symptoms of defiance, impulsivity and hyperactivity.
Eventually, the term braininjured child syndrome (Strauss and Lehtinen, 1947 in
Matthews etal.,2014)wascoined.Thistermlaterevolvedintominimalbraindamage,
andagainlater intominimal braindysfunction (MBD).In the 1950sitwaslearnedthat
MBD responded well to psychostimulants, which seemed to suppress hyperactive
behavior. This finding marked a shift in the understanding of the disorder, towards
hyperactivity as the central characterization, and labels such as hyperkinetic impulse
disorder and hyperactive child syndrome started being used. The models of the
disorder ranged from neuronal overstimulation to underarousal, as well as several
psychologybased models. Progress in cognitive and experimental psychology during
the 1970sled toan emphasisonproblemswithsustainedattentionandimpulsecontrol
in addition tohyperactivity(Douglas, 1972 inMatthews etal.,2014),andintheDSMIII
the disorder was renamedasAttentionDeficit Disorder(ADD). Thiswasrevisedinthe
DSMIIIR to Attention Deficit Hyperactivity Disorder (ADHD), the term we use today.
Finally,intheDSMIV,thesubtypesofADHDwereincluded.

Itisinterestingtoobservethechangeinnamingconventionofthedisorderthroughtime.
What started out as a disorder clearly defined as braininjury later evolved into a
disorderofattentionandhyperactivity,which aresymptomsonahigherbehaviorallevel.
In other words, the naming changed from a focus on a neurophysiological
endophenotype to a cognitive endophenotype. The early models of ADHD (e.g.,
Barkley,1997)reflects this,with their emphasisonafunctionaldescriptionofADHDon
a cognitive and behavioral level. Later models (e.g., Halperin &Schulz, 2006 Menon,
2011) focus more on the neurophysiological characteristics of ADHD, and seem to
markareturntothebeginningoftheclassificationofthedisorder.

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2.2.Diagnosis
Generally the classification system ICD is employed in Denmark, but in the case of
ADHD the American classification system DSM is used, most likely because the
research into the disorder utilizes thissystem. Since thisthesiswillreviewtheresearch
literature on ADHD and neuroimaging in relation to diagnosis, onlythe DSM definition
willbeused.

According to the DSM, the key feature of ADHD isapersistent pattern ofinattention
and/or hyperactivityimpulsivity that interfereswith functioningordevelopment(DSMV,
p. 61).Theprimarysymptomsareinattention,hyperactivityandimpulsivity.Toqualifyfor
anADHD diagnosis, impairments must havebeen presentbeforetheageof12(age7
according toDSMIV), and mustbepresent in more than onedomain (e.g.,bothhome
and school environments). The impairments must clearly interfere with the quality of
social or school/work functioning, and must not be better accounted for by another
mentaldisorder.

DSMIV defines three subtypes of ADHD: Predominantly Inattentive Type,

Predominantly HyperactiveImpulsive Type and Combined Type in the DSMV these
are updated to Presentations.Sixor moresymptoms from thelistofinattentiveand/or
hyperactive/impulsive symptoms must be present to qualify for a diagnosis of the
relevantsubtypeifsixormoresymptomsfrombothlistsarepresent,CombinedTypeis
diagnosed.

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12

Figure1.ThediagnosticcriteriaofADHD(DSMV).

In Denmark the normal procedure for diagnosing ADHD is as follows. First, an initial
evaluation of the child as well as an anamnesis (medical case history) is done. The
anamnesis includes anyneuronal insults, traumaor illnessessincebirthaswellasafull
history of behavioral symptoms.A diagnosticinterview(usinge.g.,theKiddieSchedule
for Affective Disorders and Schizophrenia (KSADS) rating scale) is then performed,
and parent as well as teacher rating scales, usually employing ADHD Rating Scale
(ADHDRS)and Behavior RatingInventoryofExecutiveFunction(BRIEF),areobtained
through questionnaires. There are no ADHD specific tests, but several nonspecific
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cognitive tests can be performed, often Test of Variables of Attention (TOVA) and
Conners ContinuousPerformanceTest(CPT).WechslerIntelligenceScaleforChildren
(WISC) is regularly employedto distinguishADHD from mental retardation (Brneog
Ungdomspsykiatrisk Selskab, 2008), and finally, a somatic evaluation by a doctor is
normallydonetoruleoutotherillnesses.

There have been criticisms of the ADHD diagnosis as it is presently defined and
utilized. While fewquestionthevalidityofADHDasarealdisorder,andmostclinicians
and researchers agree to a neurobiological underpinning, the lack of biomarkers and
objective criteria makes the diagnosis of ADHD a grey area. Parens and Johnston
(2009) have presented eight points about what they call the zone of ambiguity in
current ADHD diagnosis. 1) The diagnosis of ADHD is based on a subjective
interpretation of a heterogeneous set of behavioral symptoms. 2) Becausesymptoms
are dimensional (existona spectrum), ratherthan categorical (either/or), thereexistsa
grey area, or zone of ambiguity, in diagnosis. 3) Factors such as differences in
diagnostic systems, parenting styles and social normsinfluencethe rateof diagnosis,
resulting in both over and underdiagnosing. 4) Parents and teachers hold different
views and attitudes towards the goals of parenting as well as psychiatric treatments,
influencing therate ofdiagnosis as wellaschoiceof treatmentfor thosein the zone of
ambiguity. 5) The importance of recognizing that at present, because of it being a
subjective interpretationofsymptomsinagreyzone,thediagnosisofADHDisasocial
construct. 6) There is a lack of consensus on which treatment is most effective in
treating ADHD, and how efficacy is defined and measured. 7) People have different
values concerning the treatment of ADHD, for example some prefermedicationwhile
others would choosebehavioraltreatments.8) Theimportanceof everyoneinvolvedin
diagnosis and treatment to be truly wellinformed when making decisions about
children.

Taken together, the eight points of Parens and Johnston (2009) clearly describe the
current issues surrounding the diagnosis of ADHD and why a method for objective
diagnosis, as well as a better consensus on treatment is urgently needed. The
diagnoses in ICD and DSM are not mirrored in nature, unlike the diagnosis of, for
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example,the HIVvirus. Abloodtestcan determineifthevirusispresentinthebloodor

not, but this is not the case for ADHD or other psychiatric disorders. This condition
makes the diagnosis of ADHD a construct, open to debate and interpretation. As
described by Parens and Johnston (2009), no clear demarcation exists between
children suffering from ADHD and healthy, typicallydeveloping children, as the
behavioral symptoms of the disorder are dimensional rather than categorical. All
children exhibit some degree ofinattention and/orhyperactivity/impulsivity, and exactly
when the imaginarylinebetweennormalityanddisorderiscrossedisacentralquestion
which, untilnow, has beenvery muchopentointerpretation.Ofcourse,sciencedislikes
interpretation as it is subjective and inconsistent, but until we can define diagnoses
whicharemirroredinnature,itseemslikelythatwemustsufferthiscondition.

2.3.Treatment
ThestandardtreatmentofchildrenwithADHDispharmacological,specificallyusingthe
stimulant drugs methylphenidate and dexamphetamine(BrneogUngdomspsykiatrisk
Selskab, 2008).Thesedrugsworkbyincreasingtheavailabilityoftheneurotransmitters
dopamine and noradrenalinein the synaptic cleft, thereby activating dopaminergic and
noradrenergic circuits in the brain, leading to the behavioral amelioration of the
symptoms associated with ADHD. A nonstimulant drug, atomoxetine, is occasionally
used. Atomoxetine works exclusively on noradrenergic reuptake, and has noeffecton
the central dopaminergic reward circuit in the striatum, thus avoiding
stimulantassociatedhypomaniaandaddiction.
In cases of mild ADHD,orwhen drugs are not tolerated, psychological treatmentsare
employed (Brneog UngdomspsykiatriskSelskab,2008).Thesetreatmentsconsistof
variousbehavioral interventions,such ascognitiveandsocialtraining,aswellasparent
training.Occasionallypharmacological andpsychologicaltreatmentsarecombined,for
further effect. Whilesome 80% of children gaineffectfrompharmacological treatment,
there is still a remaining 20% who do not, and these are obvious candidates for
psychological treatment. Also,itis worthnotingthattheMTAstudy(Jensenetal.,2007)
found that although initially pharmacological treatment has higher effect, after three
yearstheeffectofpharmacologicalandbehavioralinterventionsissimilar.
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Anexample of a newand specificbehavioral interventionissuggestedbyHalperinand

Healey (2011), who believes ADHD to be fundamentally a neurodevelopmental
disorder. Theauthors recommenddirectedplay, a structured form ofplay therapyasa
way of providing adequate neuronal stimulation forchildrensuffering from ADHD. The
neuronal stimulation obtained through directed play is hypothesized to increase
neuronal development of the child, leading to an amelioration of ADHD symptoms.
Halperin and Schulzs (2006) model of ADHD as a neurodevelopmental disorder is
describedinsection2.6.4ofthisthesis.

2.4.NeurobiologyofADHD
Theneurobiological basisofADHDisnotfullyunderstoodatthistime,butfindingsfrom
the pharmacological treatment of the disorder have provided important clues.
Psychostimulants commonly used in treatment ameliorate both the inattention and
hyperactivitysymptomsof ADHD, leadingresearchers to hypothesizethat theneuronal
circuitsinvolved in the mechanism ofactionofpsychostimulantsarealsoinvolvedinthe
generationofthesymptomsofthedisorder.Sohowdopsychostimulantswork?

The psychostimulants methylphenidate and dexamphetamine both increase the

available levels ofdopamine(DA)andnorepinephrine(NE)inthesynapticcleft,through
the inhibition of the DA and NE transporters, proteins that reuptake the
neurotransmitters from thesynapse.Besidesinhibitingreuptake,dexamphetaminealso
facilitates the release of neurotransmitters DA and NE from presynaptic terminals,
making it a stronger medication compared to methylphenidate (Del Campo et al.,
2011).

According to a hypothesis by Seeman and Madras (2002) the reuptake inhibition of

psychostimulantsleads to highertonic(basal) levelsofDAandNEacrossthebrain,as
wellas a dampeningofphasic (stimulusinduced)levels. This mighthelpto explainthe
seemingly opposite dual effects of psychostimulants, namely their simultaneous
amelioration of bothinattention and hyperactivity.Highertonic,andlowerphasic levels
16

of neurotransmitter transmission leads to a higher level of overall arousal, but

simultaneously less variance in arousal, creating a more biochemically stable
environmentoverall.

Severalpositronemissiontomography(PET)studieshavefoundincreasedlevelsofthe
dopamine transporter(DAT) inADHD patients,leading researchersto suggest this as
aneurochemical basis for the disorder, however these findings havebeeninconsistent
(Del Campoet al.,2011). Thetheory isalsochallenged by the fact that DA has higher
affinity (binding capability) for the norepinephrine transporter (NET) in the prefrontal
cortex (PFC), meaning that NET terminates DA molecules in this region. It is this
condition thatallowsatomoxetine,aNEreuptakeinhibitor,toincreaselevelsofbothDA
andNEinthePFC.

The DA D1 receptors and NE alpha2A adrenoceptors in the PFC seem largely

responsiblefor theeffectsof DA and NE on cognition (Arnsten,2011).Severalstudies
have found these receptors implicated in attention, working memory and executive
function. The effect oftheavailabilityofthecatecholaminesoncognitiontypicallyfollows
an inverted Ushaped curve too little or too much availability (due to e.g., fatigue or
stress) causes under and overstimulation respectively, while optimal neurotransmitter
availability leads to optimal arousal levels for the environmental demands. Anoptimal
arousal level is required for effective functioning ofthePFC, and soboth hypoarousal
as well as hyperarousal will have detrimental effects on executive function and
behavioral control. The PFC is innervated by DA projectionsfromthesubstantianigra
and ventral tegmental area in the midbrain, as well as NE projections from the locus
coeruleusinthebrainstem.

CorticostriatothalamocorticalcircuitsfromthePFCthrough the cortex connectsback

to the subcortical areas of the brain, creating structural and functional loops, or
networks. Severalof thesenetworkshavebeen identifiedandhereIwillbrieflydescribe
three,namelytheaffective,cognitiveandmotornetworks.
The affective network is involved with emotional control and connects the orbitofrontal
cortex with the amygdala, hippocampus and basal ganglia region. The cognitive
17

network is involved with executive function and connects the prefrontal, parietal and
temporal cortices with basal ganglia structures. Finally, the motor network is involved
with motor control and connects premotor, motor and somatosensory cortices with
basal ganglia and cerebellar structures. All three networks complete their loops by
connecting their respective cortical andsubcorticalregionsthroughthethalamus,which
functionsasacentralneuronalhub(Arnsten,2011).

The PFC regulates motor, cognitive and emotional responsesthrough its connections
with other cortices and subcortical structures, such as the basal ganglia and the
cerebellum. By creating a mental sketch pad of representations, often referred to as
working memory, the PFC is able to use information for the regulation of behavior,
thought and emotion. A key function of the PFC is the handling of selectiveattention,
the focusing of resources on taskrelevant stimuli, while filtering out both external and
internal distractions.Anotherkeyfunctionis attentionalsetshifting,theabilityto flexibly
respondtothechangingdemandsof theenvironment,byalteringbehavioranddecision
making. Finally, the PFC is involved witherror monitoring,themonitoringoffeedback
informing us that our behavioris inappropriateandthat a shift instrategies isneeded.
Dysfunctionsof these PFCdependentoperations(workingmemory,selectiveattention,
setshifting,errormonitoring)areassociated withADHD.Perhapsofspecialrelevance
to ADHD is that optimal functioning of the PFC is necessary to inhibit responding for
smallrewards,andinsteadfocusingresourcesonlongtermgoals(Arnsten,2011).

18

Figure2.Theaffective,cognitiveandmotornetwork(Arnsten,2011).

2.5.NeuropsychologyofADHD
As previously stated, neuropsychological assessment is an area of interest for
biomarker identification. If possible, neuropsychological profiles or endophenotypes,
could both providevaluableinsightsinto thepsychopathologyofADHDaswellasserve
as an efficient discrimination marker. However, the search for consistent as well as
unique neuropsychological traitsin subjectswith ADHDhas so far beendisappointing.
In this section I will briefly discuss two promising and commonly reported
neuropsychological traits, namely intraindividual reaction time variability and working
memorydeficits.

2.5.1.Reactiontimevariability
One very consistent finding in the neuropsychological assessment of ADHD is
increased intraindividualvariability,whichreferstomomenttomoment(withinsubject)
fluctuations in behavior and task performance occurring over a period of seconds or
19

milliseconds rather than hours or days (Kofler et al., 2013, p. 796). In particular,
intraindividual variabilityof reaction time (RT)hasbeendocumentedacrossarangeof
computerized cognitive tests, including working memory, attention, inhibitory control,
and choice discrimination tasks, in both child and adult samples (Tammet al., 2012).
However, increased RT variability is notspecific to ADHD, and hasbeen observed in
individuals with other disorders, including autism, schizophrenia, bipolar disorder,
traumaticbraininjuryanddementia.

A recent andcomprehensive metaanalysis revealed that both children/adolescents as

wellas adults withADHD demonstrated robust,mediumtolarge magnitudeincreases
in intraindividual RT variability relative to typically developing individuals, even after
accounting for sampling error, measurement unreliability, publication bias,andADHD
subtype (Kofler et al., 2013, p. 807). The effect sizes were 0.76 (Hedges g) for
children/adolescents and 0.46 for adults, meaning that only 47% of
children/adolescents and 32% of adults had RT variability scores outside the typically
developing range. The drop in effect size in relation to age is unsurprising as ADHD
symptoms often abate in adulthood, but speaks against RT variability as an
endophenotypic marker. In addition, in a comparison with clinical control groups
(subjects with other psychiatric disorders) subjects were hardlydistinguishable,asthe
results showed a 78% overlap between ADHD and clinical control groups of children,
and a 100% overlap between ADHD and clinical adolescents/adults. The authors
conclude that increased RT variability is a robust and relatively consistent, albeit not
unique finding inADHD, and as suchlacksspecificityandisunsuitableasadiagnostic
marker. Instead of being a biomarker for ADHD, Kofler et al. (2013) speculates that
increased RT variability may be a general marker for psychopathology, which is
supported by the consistent findings across disorders as well as ADHD subtypes.
Lastly, it was found that psychostimulants attenuate, and in manycases normalize, RT
variability.

Thequestion of theneurophysiological basisofincreasedRTvariabilityinADHDisstill

unclear at this point, but several ideas have been put forward. The RT variability in
ADHD groups isexplained by a subset ofintermittent,abnormallyslowresponsetimes
20

(Tamm et al., 2012 Kofler et al., 2013). As such, subjects with ADHD are not on
averageslowerthantheirtypicallydevelopingpeers,butvarymoreintheirperformance.
Kofleret al.(2013)describeitasbeingconsistentlyinconsistentinperformance.This
inconsistency in performance has traditionally beenexplained as occasionallapsesin
attention i.e., failures of sustained attention (Tamm et al., 2012), which could reflect
hypoarousal (as suggested by Sergeant, 2000) in ADHD cohorts. Shortereventrates
(timebetween stimulusrepresentation) normallyreducesthe increasedRTvariabilityin
ADHDsubjects,anditisspeculatedthatthemore frequentstimulikeepthesubjects on
their toes. However,Kofler etal.(2013) found nosupport forthistheory,aseventrate
variedgreatlyacrosstrials in their metaanalysis. Also,thefactthatADHDcohortsvary
more inresponsetimes,butarenotactuallyonaverageslowerthantypicallydeveloping
peers,argueagainsthypoarousalasacausativemechanism.

Another proposed mechanism for increased RT variability in ADHD is behavioral

inhibition deficits (as suggested byBarkley,1997). Again, Kofler etal.(2013)foundno
support for this hypothesis,asthelevelofinhibitorydemandoftrialtasksvariedgreatly.
Finally, it has been suggested that higher resting state activity as well as a
dysfunctionally connected default mode network (DMN) would result in poor
signaltonoise ratio when processingexternalstimuli (Tammet al., 2012),also known
as the defaultmode hypothesis of ADHD (SonugaBarke & Castellanos, 2007).
However, based on the recommended cutoff of .10 Hz for default mode oscillations
(SonugaBarke & Castellanos, 2007), the current results suggest that potential
periodicity in ADHDresponsetimedistributionsisnotattributablespecificallytodefault
mode network intrusions, Kofler et al. (2013, p. 808) conclude. More on the
defaultmodehypothesiscanbefoundintheneuroimagingsectionofthisthesis.
McLoughlin et al. (2014), in an analysis using multivariate twin modeling and
computationalneurosciencemethods,foundevidencethatinefficientphasicsignalingin
the frontal midline cortex (medial PFC and anterior cingulate cortex) were strongly
associated with RT variability and ADHD symptoms, both phenotypically and
genetically. The authors suggest that eventrelated midline theta oscillations can be
used as an endophenotypic marker for ADHD, but the findings of Kofler etal.(2013)

21

speak against this, since RT variability was neither present in all ADHDsubjects,nor
specifictoADHDasadisorder.

2.5.2.Workingmemorydeficits
Asecond consistent finding ofcognitiveimpairmentinADHDisworkingmemory(WM)
deficits. The functional WM model ofADHD isbased on Baddeleyand Hitchs (1974)
originalWM model. According toBaddeley,WMreferstoabrainsystemthatprovides
temporary storage and manipulation of the information necessary for such complex
cognitive tasksaslanguagecomprehension,learning,andreasoning(Baddeley,1992,
p. 556). The WM model consist of a central executive (CE) component, and two
subcomponents, the visuospatial sketchpad (VS) andthe phonological loop (PH).The
CE is an attentional control system, involved with overseeing the subsidiary
components as well as focusing and dividing attention among tasks. TheVS andPH
subsystems areinvolved withstorage andmanipulationofvisualinformationandverbal
information,respectively.

In a metaanalysis by Kasperetal.(2012), theauthors found significantlylarge effects

sizes (Hedges g,VS=0.74, PH=0.69) forWM tasksperformed by childrenwithADHD
relative to controls. This shows that children with ADHD generally perform poorer on
WM task than typically developing children. Furthermore, the authors found evidence
suggesting that several methodological variables were associated with larger effects
sizes, while other variables were associated with smaller effect sizes. The variables
increasing effect size included greater trial number, recall tasks, fewer females and
greater CE demands, while the variables decreasing effect size included fewer trial
numbers, recognition tasks, more females, fewer CE demands. When conditions
maximizing effect size were employed, trials showed exceptionally high effect sizes
(Hedges g, VS=2.15, PH=2.01). WM deficits have been associated with other
psychiatric disorders including major depression disorder and generalized anxiety
disorder, and as such are not unique to ADHD(Kasperet al., 2012).Forthisreason,
wecannotrelyonWMdeficitsalonefordiscriminationpurposes.

22

However,several research teams, includingLenartowicz et al. (2014) andMissonieret

al.(2013)havefoundevidenceofEEGabnormalitiesinsubjectswithADHDduringWM
tasks. These findings include increased frontocentral theta activity, and reduced
occipitalalpha activitysuppression.Thesignificanceofthesefindingswillbediscussed
laterinthisthesis.

2.6.ModelsofADHD
In thefollowing, theleadingmodelsofADHDwillbedescribed,namelyBarkleysmodel
of behavioral inhibition, Sergeants cognitiveenergetic model, SonugaBarkes dual
pathway model and Halperin and Schulzs neurodevelopmental model. Finally, a
largescale neurocognitive networksbased model, as presented by Menon, will be
described. Though thereareimportant differencesbetween the models, someoverlap
do exist and it is likely that they each in their own way contribute to the overall
understanding of ADHD. The models included describe ADHD at different
endophenotypic levels, and bycombiningtheinsightsfromeachitbecomespossibleto
mapADHDatmultiplelevels,fromtheneurophysiologicaltothecognitive.

2.6.1.ADHDasadeficitinbehavioralinhibition
Barkley(1997)haspresentedhisnowfamousmodelofADHDasadeficitinbehavioral
inhibition. According to Barkley, the deficits in behavioral inhibition central to ADHD
leads tosecondary impairmentsinexecutivefunctionsandmotorcontrol.Theexecutive
functions affected by behavioral inhibition are defined as: a) working memory, b)
selfregulation of affectmotivationarousal, c) internalization of speech, and d)
reconstitution.

Working memory impairment is predicted by the model to cause problems with the
abilityto recall and retaininformationaboutpasteventsandtointerfere withforethought
andplanning forthefuture.ThiscausesindividualswithADHDtobemoreinfluencedby
immediate events and theirconsequences ratherthandistant ones, leadingto a focus
onshorttermoutcomes, as well assignificant deficienciesinsocialskillsandadaptive
behaviors(Barkley,1997).
23

Selfregulation is defined as the ability to selfregulate and even induce emotional

states as needed in theservice ofgoaldirected behavior, and involvesthe regulation
and induction of motivation, drive, and arousal states (Barkley, 1997, p. 74).
Conversely, according to the model, a deficit of behavioral inhibition would cause
individuals with ADHD to display an impaired capacity to induce and regulate said
states. It isimportant tonotethatdeficitsinselfregulationandemotionalcontrolcanbe
attributed to a wide range of psychiatric disorders, and as such are not specific to
ADHD. However, when combined with the other dimensions (working memory,
internalizationofspeech,reconstitution)themodeldoesbecomespecific.

Internalizationof speechis characterized by Skinner (1953in Barkley,1997, p.74)as

the influence of language on behavior that happens in three stages. First,behavior is
controlled by the languageofothers,laterthe individualdevelopsprogressivecontrolof
behavior by selfdirected (private) speech, and finally the individual is able to create
new behavioral rulesthrough theuseof selfdirectedspeech.Similarly,Cerutti(1989in
Barkley, 1997, p. 74) has hypothesized that by formulating rules, the individual can
construct novel, complex (hierarchically organized), and prolonged behavioral chains.
These rules can then providethetemplate forreadingofftheappropriatesequencesof
behavioral chains and can guide behavior toward the attainment of a future goal.
According to the model, individuals with ADHD display a declinein task performance
asreinforcementsbecomemoredistantintime,orinother wordsdisplayagratification
delayaversion,similartowhatSonugaBarke(2003)laterdescribes.

Finally,reconstitutionisdefinedasthefacilityforthecreationofmultiplenovel,complex
alternative response sequences, whether in language or motor behavior (Barkley,
1997, p. 82). Againthe modelpredictsthat individuals withADHDdisplayimpairment
inareasinvolvingtheutilizationofthesebehavioralrulesandtemplates,causingdeficits
insocialandadaptivebehaviors.

Taken together, Barkleys model predicts that deficits in behavioralinhibition leads to

executive function impairments in selfregulation, as well as impaired ability of the
24

individualto direct behaviortowardslongtermgoals.ThemodelexplainsADHDonthe

cognitivebehaviorallevel,andbyitsemphasisonbehavioralinhibition ismore suitedto
explainthehyperactive/impulsiveratherthantheinattentivesubtypeofADHD.

2.6.2.ADHDashypoarousal
Sergeants (2000) cognitiveenergetic model is generally known as a model of
hypoarousal. The model consists of three levels. The first (lower) level of the model
comprises four computational stages of attention: encoding, search, decision and
motororganization. Onthislevel,SergeantfindsthatADHDisgenerallyassociatedwith
deficitsinmotororganization,butnotwithdeficits inencodingorsearchprocesses. The
second(middle) level ofthemodel comprises threeenergeticpools:effort,arousaland
activation. Effort is defined as the necessary energy to meet the demands ofagiven
task, and encompasses factors such as cognitive load, motivation and contingency
responses. Arousal is definedas thephasic responding to stimulus processing, which
is influenced by signal intensity and novelty. Activation is defined as the tonic
physiological readiness to respond, and influenced by variables such as preparation,
alertness, time of day and timeontask. The energetic pools are all located in
subcortical structures: the effort pool is associated with thehippocampus, thearousal
pool with the amygdala and mesencephalicreticularformation,and theactivation pool
with thebasal gangliaand striatum.Finallythe third (upper)levelof the modelconsists
of a management or executive system,associated with planning, monitoring anderror
detection/correction.

According to Sergeant (2000), ADHD includes defects at all three levels: cognitive
mechanisms, energetic mechanisms and management system (executive function)
deficits, howeverthe models focus on energetic mechanismsareunique comparedto
other models. Sergeant hypothesizes that the executive dysfunction and disinhibition
described by Barkley (1997) is, at least partially, due to dysfunction of the energetic
pools.

The

model

describes

deficits

in

both

topdown

processes

(management/executivesystem)aswell as bottomup processes(energeticpools),but

the emphasis is on faulty bottomup processes stemming from dysfunctions in the

25

energetic pools located in subcortical structures. This is in contrast toBarkleysfocus

on a prefrontal cortical dysfunction causing a deficit in topdown behavioralinhibition.
Consequently, where Barkleys model seems more suited towards explaining the
hyperactive symptoms of ADHD, Sergeants model seems more suited towards
explaining the inattentive. This again puts focus on the heterogeneity of the disorder,
and questions whether a single model can explain all subtypes of ADHD. Sergeants
model explains ADHD at the neurocognitive level, including descriptions on the
neuroanatomicallevel.

Figure 3. The cognitiveenergetic model. The central stage on the lowerlevel includes both search and
decisionstages(Sergeant,2000).

2.6.3.ADHDasdelayaversion
The dual pathway model of SonugaBarke (2003) combines models of topdown and
bottomup deficits. Whereas Barkleys (1997) model describes a deficit in topdown
behavioral control, and Sergeant (2000) focuses on bottomup energetic dysfunction,
SonugaBarkes model combines deficits in topdown inhibition as well as bottomup
motivation, thelatter characterized by behavioral delayaversion(attemptstoescapeor
avoiddelayofreward).
26

SonugaBarke (2003) argues that executive dysfunctionis not consistently associated

with ADHD but also observed in other disorders, and that itis therefore possible that
dysregulationof behaviourandcognitionareindependentaspectsofADHD.Thiswould
seem to render Barkleys (1997) model of deficits in behavioral inhibition leading to
executive dysfunctionas a basisfor ADHDinadequate, and socausesSonugaBarke
toemphasizemotivationalaspectsasacausativefactorinstead.

The SonugaBarke (2003) model focuses on delay aversion as a central factor in

causing ADHD behaviors. Wheredelay averse childrencannotescapeoravoidactual
delay (i.e., under fixed time conditions) is it hypothesized that they will allocate their
attention to aspects of the environment that speed upthe perceived passageof time
and so avoid or escape the subjective experience of delay (SonugaBarke, 2003, p.
595), leading to inattention, impulsivity and hyperactivity. The delay aversion causes
impairments in goaldirected behavior, causing children with ADHD to become
hypersensitive towards environmental stimuli that will provide escapefromdelay and
shorttermgratificationoverlongtermrewards.

SonugaBarke (2003)describestwodistinctneurobiologicalcircuitsunderlyingthedual
pathway model, one is the executive dysfunction (EDF) pathway, and the other is the
delay aversion (DEL) pathway. The EDF pathway originates in the dorsolateral
prefrontal cortex and connects to the dorsal striatum (caudate), andthe DEL pathway
originates in the orbitofrontal cortex and connects to the ventral striatum (nucleus
accumbens). Both circuits connect back to the PFC from the basal gangliastructures
and through the thalamus, indicating that the two circuits are not entirely distinct but
containa degree ofinterconnection andoverlap.DysfunctionofboththeEDFandDEL
neurobiological pathways as well as the interaction between the two circuits is the
underlyingbasisforSonugaBarkesdualpathwaytheory.

Asamodel,thedual pathwaytheory presented by SonugaBarke (2003)is similarlyto

Sergeants (2000) focused on both the neuroanatomical as wellastheneurocognitive
level, explaining both the structural and functional factors that leads to ADHD. By
27

incorporating both topdown and bottomup processes as causative, the modelseeks

to explain the fullrangeof symptomsseenin ADHD,including both the inattentive and
hyperactivesubtypes.

Figure4.Thedualpathwaymodel(SonugaBarke,2003).

2.6.4.ADHDasaneurodevelopmentaldisorder
While earlier models have held the idea of a dysfunction of the PFC in providing
topdown inhibitory control over subcortical structures as a central factor in causing
ADHD, Halperin and Schulz (2006) turn this idea upside down by theorizing the core
pathology as originating from those subcorticalstructures, and the PFC as providing a
compensatory mechanisminamelioratingthedysfunction.HalperinandSchulzpropose
that early brain insults (e.g., anoxia, hypoxia) to subcortical structures results in the
cognitive and behavioral disturbances observed inADHD. Thisis reminiscent of early
theoriesonADHDasminimalbraininjury/damage.

28

Traditionally,the basal gangliahasbeen implicated inADHD,andHalperinandSchulz

(2006) agrees thatthe striatum islikelyinvolved,asthedopaminergicinnervationofthe
striatum is susceptible to early brain insults, which produces longterm changes in
dopamine activity. However, Halperin and Schulz argue that the caudate is likely
uninvolved, asthe developmental trajectory of thecaudate anomaliesseemstoparallel
the reduction of hyperactivity often seen during adolescence. Similarly, early insults to
the locus coeruleus in the brainstemcanproducelongterm changesto noradrenergic
innervation of the brain, leading to insufficient activation andarousal,asdescribedby
Sergeant (2000). Finally, the interdependence of the catecholamine system and the
cerebellum,and thefactthatthisstructureisamongthemostvulnerableregionstoearly
insults,makeitlikelytobeinvolvedinthecausationofADHD.

Halperin and Schulz (2006) argue that children with early damage to the PFC do not
show symptoms of ADHD, and that the developmental trajectory of ADHD is
inconsistent with the ontogenetic development of the PFC. The evidence cited by
Halperinand Schulz isabundantand notthefocus of this thesis, however Iwillmention
evidence showingthattheneurodevelopmentofthePFCand its connectionsparallelsa
reduction in ADHD symptoms, with individuals who have recovered from ADHD in
adolescence showing the most pronounced neurodevelopment. Figure 5 shows the
corresponding(orparallel)trajectoriesofremissionofADHDsymptoms withage,along
with thedevelopment ofexecutive functions,aswellasthedevelopmentofwhitematter
inthedorsolateralPFC.

29

Figure 5. Corresponding trajectories of A) remission of ADHD symptoms, B) development of executive

functions (measured by Stroop, StopSignal Reaction Time andVerbal Fluency),andC) developmentof
white matter in the dorsolateral PFC (Hill & Schoener,1996 Paus, 2005BarneaGoraly et al.,2005 in
Halperin&Schulz,2006).FA=fractionalanisotrophySSRT=stopsignalreactiontime.

Rather than being a syndrome ofprefrontaldysfunction,ADHDisaccordingtoHalperin

and Schulz (2006) a syndrome of subcortical dysfunction, paired with immaturationof
corticalstructures. Adelayinneurodevelopmentofcorticalstructurescausesadeficitin
topdown regulatory control over dysfunctional subcortical structures. As the PFC and
other cortical structures mature, regulatory control is increased, and subcortical
dysfunction is (at least partially) compensated. As such dysfunction of the PFC is not
causative of ADHD, but insufficient neurodevelopment of the region is involved in the
pathogenesisofthedisorder.

AstudybyShawetal.(2007)confirmsthatADHDischaracterizedbyadelayincortical
development. Measuring the cortical thickness in over 40,000 cerebral points using
MRI,they identified a delayincorticalmaturationin223childrenwithADHDversus223

30

healthy controls. The median age of peak cortical thickness was 10.5 years for the
ADHDgroup,versus7.5yearsforthecontrols.

Halperin and Schulzs (2006) neurodevelopmental model is clearly focused on the

neuroanatomical level, and the double whammy of insults to subcortical structures
paired with insufficientmaturationofthecortexissuitabletoexplainbothinattentiveand
hyperactivesubtypesof ADHD. In myviewitis a modern model of ADHD, withasolid
body of evidence behind it. However, it is a regionbased model, with perhaps
insufficient focus on distributed networks. This leads us to the final model, which is a
networkbased model, explaining ADHD as dysfunctions in largescale distributed
neurocognitivenetworks.

2.6.5.ADHDasdysfunctionalnetworks
Menon (2011) has presented a triple network model of psychopathology, including
ADHD.The model is basedondysfunctionsinlargescaleneurocognitivenetworksthat
are distributed across the brain, as opposed to dysfunctions in local networks or
regions. These largescale networks include thethree core networks central executive
network(CEN),defaultmodenetwork(DMN)andsaliencenetwork(SN).

TheCENisafrontoparietalnetworkanchoredindorsolateralPFCandlateralposterior
parietal cortex. The network is crucial for actively maintaining and manipulating
information inworkingmemory, forrulebasedproblemsolvingandfordecisionmaking
in the context of goaldirected behavior (Menon, 2011, p. 495). Dysfunctions of the
CEN has been identified in several psychiatric disorders, including schizophrenia,
depression, dementia and autism. Interestingly, Menon does not specifically mention
ADHD in relation to CEN dysfunction, although he does state that CEN disruption is
widespread in virtually every major psychiatric and neurological disorder (Menon,
2011, p. 495). It is important to stress that Menons model does not focus on ADHD
specifically,but targets psychiatricpsychopathologyin general.Itwouldseemlikelythat
CEN dysfunction is somehow involved inADHD,given the disordersassociationwith
executive dysfunction, however it is at this point unclear whether the executive

31

dysfunction is due to defects intrinsic to the CEN itself, or perhaps initsengagement

withothernetworks.Menon(2011,p.496)describesthreewaysdeficitsintheCENcan
arise: 1) through weak intrinsic connections between the networks nodes, 2) through
abnormalrecruitmentof nodesextrinsictothenetwork,and3)throughimpairedaccess
tosalientstimuli(aprocesswhichheavilyinvolvestheSN).

The DMN is anchored in medial PFC and posterior cingulate cortex, with prominent
nodesin medial temporal lobeand angulargyrus.InoppositiontotheCEN,theDMNis
typically disengaged during stimulusdriven cognitive tasks,and isinstead associated
with functions such as episodicandautobiographicmemory,semanticmemoryrelated
to internal thoughts, selfrelated and social cognitiveprocesses,valuebased decision
making and emotional control. Thedisorders includingdysfunctionof the DMNinclude
dementia, schizophrenia, epilepsy, anxiety, depression, autism and ADHD (Menon,
2011).

TheSNisanchoredindorsalanteriorcingulatecortex(ACC)andtheanteriorinsula(AI)
and is involved in detection, integration and filtration of relevant interoceptive,
autonomous and emotional information (Menon, 2011, p. 498). SN includes two
subcortical structures, the amygdala and the substantia nigra/ventral tegmental area,
both of which are important forthe detection of reward saliency.Dysfunction of theSN
has been found to beinvolved inanxiety,pain conditions,dependency, schizophrenia,
autism,dementia,depressionandADHD(Menon,2011).

Menon(2011) arguesthatabnormalintrinsicorganizationofthesecore networks(CEN,

DMN,SN)aswellasabnormal interconnectivitybetweenthemistheunderlyingbasisof
most psychiatric disorders. As earlier stated, Menons triple network model of
psychopathology doesnot specifically focusonADHD,butthemodelsfocusontheSN
as a central component makes it especially interesting as an explanatory model of
ADHD.The SNis involvedwiththedetectionandfilteringofsalientinternaland external
stimuli, as well as initiating the relevant control signals necessary for engaging the
attentional and working memory resourcesneeded forcognitivetasks.When salience
detection andmapping of goalrelevantstimuli isweak,appropriateengagementofthe
32

CEN is compromised, leading to impairment of cognition and goaloriented behavior.

Similarly, ineffective disengagement of the DMN leadsto inappropriate selfreferential
mental activity (such as excessive rumination), further compromising cognition and
goalrelevant behavior. Furthermore, the couplingof the AI and the ACC within the SN
facilitatesaccesstothemotorsystemtoregulatebehavior,andsoreducedeffectivityof
thisnetworkleadstoimpoverishedpsychomotorcontrol.

Figure6.Thetriplenetworkmodel(Menon,2011).

A study supporting Menons model was conducted byLopezLarsonet al. (2012) who
found reducedinsular volumein 19adolescents withADHD versus25healthy controls,
using MRI. The reductions of the left AI correlated with oppositional symptoms, while
reductions of the right AI correlated with attentionproblems and increased impulsivity.
Similarly, Bledsoe, SemrudClikeman and Pliszka (2013) foundreductionsin the right
ACC compared to controls, which predicted a significant amount of the variance in
parent and teacherreported symptoms of ADHD. Interestingly, SonugaBarke and
Castellanos(2007)hasproposed that the DMNis notbeingadequatelydisengagedin
ADHDcohorts.

33

Overall, Menons(2011)triplenetworkmodel serves wellto explainboth theinattentive

and hyperactive symptoms of ADHD on a neurocognitive levels, including both
neuroanatomical level descriptions as well as their impact on cognition andbehavior.
As Halperin and Schulzs (2006) neurodevelopmental model, Menons model is a
modern neuroscientifically oriented approach to explaining the psychopathology of
ADHD, but where Halperin and Schulzs model is focused on dysfunctions ofspecific
regions,Menons model isfocusedon theinteractionofdistributednetworks.However,
in contrast to earlier models, Menons model posits neuropsychiatric dysfunctions on
the cortical layer, seemingly leaving out any subcortical regions as important
components.

2.6.6.Summary
Combined, the different ADHD models describe dysfunctions of both topdown and
bottomup processes, located in both cortical and subcortical structures. The
differences between models indicate that the heterogeneity of symptoms in ADHD
might be too large for it to be defined as a single disorder, even when including
subtypes. As we shall later see, imaging studies likewise have found huge
heterogeneityinbothstructuresandfunctionsinvolvedinADHD.

3.Neuroimaging

Neuroimagingis the use ofvarious technologiestoimagethebrain.Theimagingofthe

brain can be divided into two general categories, structural and functional imaging.
Structural imaging provides imagesofthe structural (anatomical) featuresof the brain,
whereas functional imaging provides images of its functional(chemical)features, such
as metabolismor neurotransmission. Thetechnologies used vary incomplexity ofuse,
cost,risk/sideeffects,aswellasbothtemporalandspatialresolution.

Neuroimaging has been used in psychiatric research for decades. Particularly,

functional neuroimaging technologies such as EEG, PET and functional MRI have
34

provided many important new insights into the psychopathology of mental disorders.
However,so far this hastranslated intovery littleuseclinically,andneuroimagingisnot
currently being employedinthediagnosticprocess.Giventhatpsychiatricdisordersare
brain disorders, and given the enormous research literature on the subject, it seems
quitepuzzlingwhyneuroimagingisnotusefulfordiagnosticpurposes.

While psychiatric diagnosis utilizing neuroimaging presently seems to be halting,

neuroimaging excels today inthe examination ofthe effects of genes onneurobiology.
Genetic polymorphisms are found in nature and therefore both categorical and easily
testable. Furthermore, using neuroimaging to observe a psychiatrically relevant
polymorphisms effects directly onthe neural level is scientifically moreinterestingthan
observing its effect on thebehavioral level,whichis moreunspecific(Farah&Gillihan,
2012). Another area where neuroimaging is providing clinical utilityis throughmaking
new treatment modalities possible. For example, deep brain stimulation, transcranial
magneticstimulation (TMS)andneurofeedback has onlybecome possible becauseof
imagingtechnologies(Farah&Gillihan,2012).

Beforewecandiscusstheissuessurroundingtheuseofneuroimagingindiagnosis,we
mustfirsthavearudimentary understandingofthe technologiesinvolved. Inthefollowing
I will briefly describe the neuroimaging technologies being employed today, how they
work, and their advantages and limitations in relation to the diagnosis of psychiatric
disorders.

3.1.Electroencephalography
Electroencephalography (EEG) is the detection and recording of cortical brainactivity
using electrodes consisting of flat metal discs connected tothescalp.The electrodes
are connected to EEG devices which record, amplify, filter, present and store the
electricbrainactivity(Boutros,2011).

The electrical activity of neurons consists mainly of actionpotentials and postsynaptic

potentials. Action potentialsare electrical signals whichtravel along nerve axonstothe
35

presynaptic terminal where they cause release of neurotransmitters that pass the
synaptic cleft. In turn the neurotransmitters bind to receptors on the membrane of the
postsynaptic neuron, leading to a change in membrane potential. These postsynaptic
membrane potentials can be either excitatory (EPSP) or inhibitory(IPSP), depending
on the presynaptic fiber type. Action potentials have a very short temporal duration of
about one millisecond, whereas postsynaptic potentials can last tens to hundreds of
milliseconds. For this reason EEG recordings always reflect postsynaptic potentials,
ratherthanactionpotentials(Boutros,2011Luck,2005).

Theplacement ofthe electrodesduring studies followsthe 1020 ElectrodePlacement

System, an international standardised system. 1020 describes the distance in
percentage between the electrodes and fixed points on the skull, such as the nasion
andinion. Each electrode point is identifiedwithanameindicating its generalarea(Fp
frontalpole,Ffrontal, Ccentral,Pparietal,Ttemporal,Ooccipital,Aearlobes)
and a number, where higher numbers indicate more lateral placement. Electrodes
placed on thelefthemispherearedesignatedoddnumbers,andthoseontherighteven
numbers.Themidlineisreferencedwithaz(e.g.,Cz)(Boutros,2011).

36

Figure7.The1020ElectrodePlacementSystem(Boutros,2011).

The differential amplification can beobtained usingone oftwo different setups,known

as montages. In referential montage each electrode wire is paired with a reference
electrode, placed on a neutral spot on the head, such as the earlobes, and the
difference in voltage between the two is recorded. In bipolar montage, electrodes are
longitudinally connectedoneachhemisphere,andthedifferenceinvoltagebetweentwo
neighboring electrodes is recorded. Thus referential montage investigate differences
between an active and an inactive (the reference) electrode, and bipolar montage
investigates differences between two active electrodes. Referential montage is better

37

suited at detecting general alterations, whereas bipolar montage is better suited at

detectingfocalabnormalities(Boutros,2011).

In orderto avoid external electromagnetic disturbancesonly thedifferenceinamplitude

between two input signals is amplified and processed by the EEG devices, and any
signalthat is similar atbothinput points issuppressed.Furthermore,EEGdevicesare
equippedwithlowandhighfrequency filters,commonlyfilteringoutsignalsbelow0.5Hz
andabove70Hz,andalsofiltersthatremove50or60Hzcyclesfrompowerlines.EEG
recordingsshouldbeperformedin asound attenuated,electrically shieldedroom.Still,
even with these precautions, artefacts are common. Artefacts are noise, or
disturbancesof the EEG recordingsbyelectricalsignalsunrelatedtobrainactivity,and
canbeof either technical or biological origin.Technical artefacts arerelated tosignals
from the environment, and can be power sources, current inductions, and changes in
conductanceor impedance oftheelectrodes.Biologicalartefactsarerelatedtosignals
stemming from the subjects, such as from the eyes, tongue, heart, arteries/pulse,
skin/sweatingandmuscles(Boutros,2011).

Therecordedbrain activity istraditionallydivided into the frequencybandsdelta,theta,

alpha, beta and gamma, as described below. The specific presentation depends on
age, wakefulness and other conditions. For example, some activities are considered
abnormalinawakeadults,butconsiderednormalinchildren(Boutros,2011).

Deltaactivity
Includes frequencies below 4 Hz, with amplitudes ranging between 50350 microvolt.
Delta activity is common in infancy and childhood, as well as represented in
drowsiness, deep sleep, hyperventilation and during use of psychotropic drugs
(sedatives).Delta activity is consideredabnormalinawakehealthyadults.Deltaactivity
isrelatedtocerebralbloodflow,increasingwhencerebralperfusionisreduced.

Thetaactivity
Includes frequencies between 4 and 7.5 Hz, with amplitudes varying between 10150
microvolt. It ishighlyrepresentedininfancyandchildhood,aswellasduringdrowsiness
38

andsleep, and isincreased during mental tasksandhyperventilation. In normal awake

adults there is a small amount of theta activity, but never organized in rhythms. Theta
activityisrelatedtocerebralbloodflow,increasingwhencerebralperfusionisreduced.

Alpharhythm
Is defined from 8 to 13 Hz, with a distributioncurvecenteringaround 10 Hz. Analpha
frequency of 8 Hz occurs in less than 1% of normal adults, and so should raise
suspicionon measurement.Theamplituderangeis20100microvolt,withanamplitude
asymmetry in approx. 60% of normal individuals, tending towards higher voltage in the
right hemisphere. This asymmetryonlyreachesclinicalsignificance whenthedifference
between hemispheres is over 50%. Any amplitude asymmetries would indicate
lateralized brain dysfunction (primarily affecting only one hemisphere), however
asymmetry can also be induced by intracranial haematomas. In lateralized brain
dysfunction,thedysfunctionisnormallyonthesidewiththeloweramplitude.

In contrast to amplitude, frequency is very similar in the two hemispheres, with a

persistent difference of 1 Hz being considered abnormal on the slower hemisphere.
Alphafrequency isassociated withcerebral bloodflow,withlessperfusionleadingtoa
reduction in frequency. It is maximized with eyes closed during relaxed wakefulness,
and is attenuated by eyes opening, sensory stimuli and sustained attention. Alpha
rhythm is mostly dominant in posterior regions, including the parietal and occipital
cortex.

Simultaneously recording of EEG and fMRI signalsfoundthat increased alpha power

was correlated with decreased fMRI signal in multiple regions of occipital, superior
temporal,inferiorfrontal andcingulatecortex,andwithincreasedsignalinthethalamus
and insula, suggesting that alpha rhythm is an index of cortical inactivity that may be
generatedinpartbythethalamus(Boutros,2011,p.38).

Betarhythm
Is defined as any frequency above 13 Hz, with the most commonly observed
frequencies being 18 to 25 Hz, less commonly 14 to 16 Hz, and rarely above 35 Hz.
39

Amplitudes range from 1030 microvolt. Beta activity is mostly dominant in frontal
regions and near the motor cortex. It is represented during cognitivetasks,sustained
attention and motor activity. Absence of beta activity is not considered abnormal, but
asymmetricalbetaactivityis.

Gammaactivity
Includes the frequencies between 30 and 70 Hz, commonly centered around 40 Hz. It
can be classified into induced, evoked, emitted and spontaneous activity (Boutros,
2011). Synchronization of neuronal gamma activity is likely related to feature
integration, the integration of different features of a visual object in the visual cortex.
Furthermore, it has been proposed that gamma synchronization is associated with
selectiveattention,inparticularperceptualselection(Felletal.,2003).

3.1.1.Eventrelatedpotential
The eventrelated potential (ERP) technique is the measurement of the
electrophysiological response to a stimulus, using an EEG device. In contrast to
standard EEG measurement, which isacontinuous recording, the ERP isrecorded at
short, specific intervals in relationto a given stimulus. The measured ERPs from each
electrodeis then averaged tocreate averagedERPwaveforms foreachstimulustype.
Theresulting averagedERPwaveforms consistofasequenceofpositiveandnegative
voltagedeflections calledpeaks,orwaves.ThepeaksaretraditionallylabelledPandN
followed by a sequence number, used to indicate positivegoing and negativegoing
peaks, as well as the peaks position within the waveform (P1, P2, P3, N1, N2 etc).
Commonly, the precise latency is also given, for example P300, which indicates a
positive peak at 300 ms following the stimulus (Luck, 2005). In relation toADHD and
cognition, P300isbelievedtoreflectworkingmemoryupdatingaswellasrepresentthe
allocation of executive control resources to a given task, and P300 amplitude and
latencyhavebeenfoundtobeabnormalinADHD(Karalunasetal.,2014).

40

Figure8.ExampleERPwaveform(Luck,2005).

Themain advantages of EEG are lowcostofequipment,lowrisk/sideeffects,andhigh

temporal solution. The equipment is inexpensive compared to other neuroimaging
devices such as MRor PETscanners,anddonotrequireasmuchspace.Subjectsare
not exposed to contrast agents, radioactive tracers or highintensity magnetic fields.
TheEEG signal isrelativelytolerant ofsubject movement, which can beanissuewhen
trying todiagnosehyperactivechildren.Finally,thehightemporalresolution (intheorder
ofmilliseconds)makesitpossibletofinelytrackchangesinneuronaltransmission.

The main disadvantages of EEG are low spatial resolution, poor signaltonoiseratio
andthe limitation of EEG onlymeasuring neuronalactivitynearthescalp(outercortex).
Low spatial resolution makes it difficultto localizetheneuronal signalcoming from the
brain, thus not allowing different structures or regions involved to be easily identified.
The fact that EEG only measures neuronal activitycoming from the outerlayersofthe
cortex further limits the localization capabilities of this technology. Finally, the low
signaltonoiseratiorequiresintensepostrecordinganalysisbeforethedataareuseful.

3.2.Magneticresonanceimaging
Magnetic resonance imaging (MRI) is a neuroimaging technology used to provide
clinicians and researchers withvisual images of thestructureof the brain. The images
are created by placing the subject in a scanner which induces a very strong magnetic
field, whichmagnetizesthecoresof hydrogen atomsin the body. The hydrogencores,

41

which spin around their own axes, are in turn oriented along the magnetic field
generated by the scanner.Through the use ofmagnetic coils,another electromagnetic
field is then induced at specific radio frequencies, causing the hydrogen atoms to
reorient themselves towards this second field. When the second magnetic field is
switched off, the hydrogen cores gradually return to their original orientation along the
main magnetic field of the MR scanner the period of time this takes isknown asthe
relaxation time. During relaxation hydrogen cores oscillate, emittingradio signals at a
resonant frequency (the frequency induced by the second magnetic field), and these
radiosignals are in turnpickedupbythescanner.Duetothedensityandwatercontent
of different tissue types, the relaxation times differ depending on the form of tissue
beingscanned,andthiscreatesthevisualcontrastintheimages(Buxton,2009).

MRI is utilized in the measurement and visualization of the structural features of the
brain, including shape, mass and volume. ThemeasurementofbrainvolumeusingMRI
isknownasvolumetryandisoftenemployedinthediagnosisofneurologicaldisorders
such as Alzheimers disease, Parkinsons disease and multiple sclerosis. Volumetry
can be performed either manually or (semi)automatically through the use of computer
algorithms (Giorgio & De Stefano, 2013). Manual volumetry is a timeconsuming
process involving the outlining of regions of interest (ROIs) on scanned images, and
then calculating volume from parameters such as diameter. Automated volumetry
through the use of computer algorithms, a technique known as machine learning,
involvesexposingthecomputeralgorithmstoaseries ofexampledatasets,allowingthe
algorithms to learn patterns in the data. Automated volumetry using machine learning
hasthe advantageof speedofprocessingcomparedtothemanualmethod,andallows
researcherstouselargerdatasets,improvingthevalidityandreliabilityoffindings.

3.2.1.Functionalmagneticresonanceimaging
Functional magnetic resonance imaging (fMRI) is a MR technique used to create
functional visual images of the brain, as opposedto the structural imagesof standard
MR. FMRI utilize the blood oxygen dependent (BOLD) contrast,which is apropertyof
the oxygenation level of the blood to exhibit different relaxation times. Deoxygenated

42

hemoglobin in the blood inhibits the MR signal, creating longer relaxation times as
compared to oxygenated hemoglobin. The theory behind thefunctionalimagingoffMRI
is that active neurons utilizes more oxygen than nonactive neurons, andsothevisual
imagery created by the level ofoxygenation of neurons reflecttheiractivitylevelduring
taskbasedorrestingstatescans(Buxton,2009).

While taskbased functional imaging has been utilized traditionallyto identify neuronal
activity during tasks, resting state scanning, also known as resting state functional
connectivity(RSFC)imaging, has become increasingly popular. Restingstate imaging
studies has made it apparent that neural systems exhibit synchronous highamplitude
fluctuations at frequencies 10100times slower than regular EEG signals(Castellanos
& Proal, 2012). The patterns of spontaneous neuronal activity seem robust across
distinct populations as well as different scanning parameters, and can be statistically
mapped and displayed in a manner similar to taskbased activity maps. Through the
use of resting state fMRI, seven primary cortical networks have been identified,
including the default mode network, the dorsal and ventral attentional networks, the
motor network, the visual network and the executive control network (Castellanos &
Proal,2012). TherobustnessofRSFCpatternscombinedwithsensitivitytoagefactors
during development as well as topsychopathologymake themuseful for the purposes
ofidentifyingneuralsignaturesofpsychiatricdisorders.

3.2.2.Diffusiontensorimaging
Besides the more standard structural and functional imaging techniques, magnetic
resonance is also used to create tractographies through the application of diffusion
tensor imaging (DTI). DTI is a technique used for measuring the diffusion of water
molecules inside tissues. In an isometric medium, water molecules diffuse freely and
randomlyin all directions, as opposed towater in an anisotropicmedium,where water
diffuses more unidirectionally. Because of the principle of diffusion, water molecules
move more freely in the less dense white matter (axons, nerve tracts) than the more
dense grey matter (nerve cell bodies). Similarly, water molecules move more freely
along the axes ofaxons rather than perpendicular to them. It istherefore assumedthat

43

the diffusivity of different tissues can be used to differentiate them by measuring it at

discrete points (voxels) in the brain, thereby making it possible to create a visual
representation ofthewhite matterofthebrain.Thistechniquemakesitpossibletomap
the network connections of the brain, socalled tractographies, rather than the
regionbasedmappingofstandardMRI(Giorgio&DeStefano,2013).

The raw image data from the MR scanner is not immediately ready for analysis, but
needto bepreprocessed, whichincludescorrectionofdifferentpropertiesoftheimage
data.Becauseof the natureof MR technologies, noise(distortion) isintroducedduring
scans and needs to be corrected. The twolargestsourcesof noise arethermal noise
and physiological noise. Thermalnoise pertainsto the magnetic fielditself, with higher
strength field causing increasing levels of distortion. Physiological noise pertains to
movementof the headandotherphysiologicalparameters(bloodflow,oxygenuse,etc)
stemming fromthesubject.BecauseofthehyperactivenatureofADHD,havingchildren
with ADHDliestillin a MR scannerfortwentyminutesormoreisahugechallenge,and
therefore physiological noise is a significant source of error in MRbased ADHD
research.Finally, different formsoffilteringsuchasthefilteringofunwantedfrequencies
(temporal filtering) and the averaging of intensities (spatial filtering) are employed,
beforetheimagesarereadyforstatisticalanalysis(Buxton,2009).

The main advantages of MRI are the high spatial resolution and the low side effect
profile. High spatial resolution makes MRI an excellent technology for identifying and
visualizingthe complete rangeof structures ofthe brain, includingthedifferentlayersof
the cortex, the subcortical areas andthe brainstem.Thismakesitusefulfordiagnosing
grey matter as well as white matter neurological diseases such as brain tumors or
multiple sclerosis, but also for identifying the neuronal regions involved in the
processing of specific tasks, or during rest (through fMRI). Though a few risks are
associated with MR scanning, exposure to the magnetic field itself is generally
regarded as safe andside effect free, and the use of thetechnology forneuroimaging
purposesdoesnotnormallyrequireexposuretocontrastagents.

44

ThemaindisadvantagesofMRIincludehighcostofequipment,lowtemporalresolution,
risk for subjects with implants or pacemakers, and high sensitivity towards subject
movement. The cost of acquiring as well as running MR scanners (power costs) are
relatively expensive,and theequipment isbulkyandimmobile.Lowtemporalresolution
makes it difficultto track changes inneuronaltransmissionthathappensinresponseto
stimuli ortasks. Patients withmetalimplants orpacemakersareat risk when exposed
to a highintensity magnetic field. Finally, since movement inside the scanner induces
artefacts, subject are required to be immobile for long periods of time during scans,
whichcanbechallengingforchildrenespecially.

3.3.Positronemissiontomography
Positron emissiontomography (PET) issimilarly tofMRIa scanning techniqueusedto
create functional images of the brain. Since PET requires a radioactive tracer to be
injected insubjects,itis rarely allowedin research withchildren.Itisconsideredaboth
invasive and expensive neuroimaging technology, and for these reasons I do not
consider PETas a viable technologyin facilitating ADHDdiagnosis.Consequently,no
studiesusingPETareincludedinthisthesis.

3.4.Combiningmodalities
As we have seen, different imaging technologies each have their advantages and
limitations. It is possiblethat thetechnologies on their ownarenot sufficientlyeffective
to diagnose psychiatric disorders including ADHD, and that a combination of
modalities arerequiredtoovercomelimitations.Thecombinationofdifferentmodalities
is becoming increasingly popular in research for exactly this reason, namely that
combination increases advantages and overcomes limitations of respective
technologies. For example, thecombinationofMRIandfMRIprovidesbothstructuralas
well as functional imaging of the brain, allowing for more precise pinpointing of
structures involving with specific functions. Perhaps even more interesting, combining
(f)MRIwithEEGenablesbothhighspatialaswellastemporalresolutiontobeobtained,
overcomingthemajorlimitationofeachtechnology.

45

However, the combining of modalities also introduces newchallenges andsourcesof

error. For example, the useofEEGmeasuringdevicesinsideaMRscannerintroduces
electrical noise, manifesting as artefacts on scans. There is also a slight risk of the
magneticfieldheatinguptheelectricwiresused inEEG,whichcancauseskinburnson
the subjects. The use of combined modalities is relatively new in the field of
neuroimaging, and much isstillto be learnedinthisarea,howeverthepotentialishuge
for both the possibility of diagnosis, as well as for basic neurocognitive research in
general.

4.Researchdata

This section will providean overviewofthe research performed on neuroimaging as a

diagnostic tool in discriminating between subjects with ADHD and healthy controls or
other psychiatric disorders. The research includes several neuroimaging modalities,
including EEG, ERP, MRI and fMRI. The studies were selected using the following
criteria:
Asearchof PubMedusingthe keywordsADHD, neuroimaging, diagnosis,EEG,
ERP, MRI, fMRI was conducted. Studies were limited to within ten years of
publication, human subjects and articles in English. A manual review of titles and
abstracts, based on the relevance to the research question of this thesis, further
reducedthenumberofstudies.
In a few cases, studies wereincluded from references in papers and not found directly
in the PubMed search. What emerged was a number of metaanalyses, as well as
severalsingle studies conductedafter the publicationof the reviews these studiesare
describedinthefollowing.

4.1.EEGstudies
Theassociationof brainactivitymeasurablewithEEGandADHDhasbeenthesubject
of research for decades. The most consistent finding in these studies has been
increased frontocentral theta activity less consistently increased posterior delta, as
wellas reduced posterioralphaand beta activity,hasbeen reported(Arns, Connors&
46

Kraemer,2013Barry et al.,2009Barryetal.,2010Clarkeetal.2013Loo&Makeig,
2012). Gamma activity has been the focus of only a few studies in ADHD, however,
Barry et al. (2010) have reported reduced gamma activity, correlating with inattention
symptoms,inchildrenwithADHD,makingitaninterestingareaforfuturestudies.

Since theta activity is associatedwith drowsiness, and beta activity isassociated with
attention and motor activity,anincreasedtheta/betaratio(TBR)wouldseemtosuggest
hypoarousal which could explain the symptoms of ADHDaccording toseveral models.
Sergeants (2000) cognitiveenergetic model immediately comes to mind here, but
hypoactivityin frontocentral regionsalso fitsBarkleys (1997)model ofdeficientmotor
inhibition, as well as Halperins (2006) ideaof underdevelopedcortical regions. Lubar
(1991) proposed increased TBR as a method ofdiscriminatingbetween patients with
ADHD and healthy controls, and increased TBR in ADHD has been replicated in
severalstudies,strongestin Monastraetal.(1999),wheretheauthorsclassifiedADHD
in482subjectswithasensitivityof86%andaspecificityof98%.

ItisimportanttonotethatincreasedthetaactivityisanonspecificEEGabnormalitythat
may appear in a number of disorders, such as epilepsy, polysubstance dependence,
dementia, alcoholism, and schizophrenia(Snyder&Hall,2006,p.452).Similarly,theta
activity increase and beta activity decrease may be found in several disorders that
appear as differential diagnoses of ADHD, including developmentaldelays or injuries
and dysgenesis of diverse origin. Moreover, the findings of increased theta and
reduced beta activity have not been entirely consistent, with several distinct EEG
profiles found in research. In particular, groups of children with excess rather than
reduced beta activity have been observed, most commonly associated with boysand
thecombinedADHDsubtype(Clarkeetal.,2013).

The question of arousal in ADHD has been examined using measures of skin
conductance levels (SCLs). When a person is aroused, perspiration of the skin as a
result of sympathetic nervous system activity is measurable as increased electrical
conductance. If increased TBR is indicativeof hypoarousal,thiswould be expected to
correlate with lower SCLs in subjects withADHD expressing this trait. However, Barry
47

et al. (2009) found that TBR does not correlate with SCLs, but instead alpha activity
does (negatively). This is in accordance with research on normal children where the
closingoftheeyesreducesSCLsandincreasesalphaactivity,andreopeningtheeyes
results intheopposite.Barryetal.(2009)proposesthatincreasedTBRisnotindicative
of hypoarousal, but rather hypoactivation.Wherearousalisdefinedasenergeticstate,
activationisdefinedaschangeinarousalfromrestingbaselinetotaskhandling,aswell
asthe requirement ofactivation ofrelevantbrainregions.Assuch,thisfindingsupports
Menons (2011) model of dysfunctional network engagement. Clarkeet al. (2013) has
confirmed the findings of Barry et al. (2009). The authors identified a group of ADHD
children with a typical excess theta profile, as wellas a group withanatypicalexcess
beta profile, and found similar SCLs in both groups. Therefore, it still remains unclear
whatexactlytheTBRismeasuring.

Another importantquestion iswhetherpsychiatric comorbiditiesimpactTBRinADHD,

andthishas been examined inat least onestudy. A study byRabiner(2001inSnyder
& Hall, 2006) compared TBR in subjects with ADHD and subjects with oppositional
defiant disorder (ODD) or affectivedisorders(but without ADHD), andfoundthat 78%
of ADHD subjects demonstrated increased TBR, whereas 97% ofsubjectswith other
disordersdidnotdemonstratethistrait.However,thisisincontrasttofindingsbyLooet
al. (2013), who found that psychiatric comorbidities has a significant impact on TBR
(more on this later). Taken together, the impact of comorbidities on TBR in ADHD
subjectsisstillunclearandneedstobeexaminedfurther.

In 2013 the American Food & Drug Administration (FDA) approved an EEGbased
methoddevelopedbythecompanyNEBAHealthforaidinginthediagnosisofADHDin
children and adolescents aged 617 years, when used as a supplement to standard
clinical evaluation (FDA,2013). ThemethodisbasedonthemeasurementofTBR,and
NEBA Health has reported an accuracy of 88% in diagnosing ADHD when the EEG
measurementis combinedwithstandarddiagnosisperformedbyaclinician,compared
to an accuracy of 61% when only standard clinical diagnosis is performed (NEBA,
2013).

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With regard to EEG alpha activity, there are important reasons why this is relevantto
ADHD.Alphaoscillationsarerhythmicchangesinneuronalactivityreflectingloworhigh
excitability that may stem from the fluctuations of inhibitory neurons. Klimesch et al.
(2007) hypothesizes that synchronized alpha activity (large amplitude in scalp EEG)
reflects a state of inhibition (low excitability), whereas desynchronized alpha activity
(smallamplitudeinscalpEEG)reflectsastateofhighexcitability.Alphasynchronization
isobserved insubjectsatrestand witheyes closed, whereasalphadesynchronization
(suppression of alpha activity) is seen when subjects open their eyes, and when they
engage incognitive tasks.Duringinformation processing,largepopulationsofneurons
no longer oscillate in synchrony, a phenomenon known as eventrelated
desynchronization (ERD). On the other hand, eventrelated synchronization (ERS) of
alpha activity reflects inhibition involving topdown control processes. To sum up, a
decrease in alpha band activity is functionally related to active cognitive processing,
and thus ERD reflects active information processing in the sense of excitatory brain
processes, whereas eventrelated synchronization (ERS) reflects inhibitory brain
processes (Klimesch et al., 2007). Of relevance to ADHD, increased alpha band
activity (ERS) is involved with the active inhibition of taskirrelevant stimuli, whereas
decreasedalphaactivity(ERD) isbelieved toreflectareleaseofinhibition,allowingfor
the enhancedprocessingof attendedstimuli.Assuch,alphaactivitycanbeunderstood
as asortof gatingor filteringof stimuli tobeencoded (Lenartowicz et al.,2014,p.
1179). Therefore, abnormalalpha activity during trials may reflect animpairmentin the
ability to filter taskrelevant stimuli,leading tohigher distractibility and poorer cognitive
controlinADHDsubjects.

In orderto examine theclinicalutility ofEEG biomarkers for diagnosingADHD, Iwillin

the following review research data, starting with metaanalyses conducted on the
subject, after which ananalysisofseveralsinglestudieswillbeincluded.Singlestudies
are includediftheywereperformedafterthepublicationofthelatestmetaanalysis,orif
theyexaminediagnostictechniquesnotcoveredinthose.

49

4.1.1.Metaanalyses
As a demonstration of the utility of their fourstep approach mentioned in the
introduction, Boutros et al. (2005) selected the biological finding of increased EEG
theta activity in ADHD.Their metaanalysisincluded 12 studies, and found a weighted
mean effect size of 0.68. The metaanalysis focused on increased thetaband activity
rather than TBR, and confirmed the authors prediction of clinical groups exhibiting
significantly higher levels of theta activitycompared to controls.The authorsconcluded
that the finding of increased theta is apromising candidateas a diagnostic marker of
ADHD, and shouldbe furtherdeveloped as a diagnostic test.They criticize thelack of
reliability of studies as a seriousdeficiencythat needs to be remedied, as wellasthe
lack ofblinding procedures, which possibly introducedbias intheresults.However,the
most significant source of error in this metaanalysis is in my opinion the lack of
specificity of inclusion criteria. Specifically, no criteria for age and EEG recording
conditions (e.g., electrode placement,Eyes Open/Closed)wereusedintheinclusionof
studies, and this lack of standardization undermines the validity, as well as the
generalizability, of the findings. The importance of inclusion criteria will be discussed
furtherinthediscussionsectionofthisthesis.

Snyder and Hall (2006) examined the association between increased TBR and a
diagnosis of ADHD in nine studies, including 1498 subjects. Age, gender, subtype,
medicationuseandexistingcomorbiditieswerenotdefinedintheinclusioncriteria.The
overall effect size found was 3.08, from which the authors statistically extrapolated a
sensitivity and specificity of94%.ThemetaanalysisconcludedthatincreasedTBRisa
common trait in patients with ADHD versus healthy controls, but the authors note that
thistraitis found inseveral othermentaldisorders,andthatstandardizationoftheEEG
methodusedinthesestudiesisnecessary.
Similarly tothe analysisbyBoutroset al. (2005),study inclusion criteria are lacking as
EEGrecording conditionswere not defined. It isalso importantto notethattheauthors
have financial interest in diagnosing ADHD using TBR as a biomarker (Snyder isthe
VicePresidentofResearchandDevelopmentforNEBAHealth).

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Loo and Barkley (2005) examined the clinical utility of TBR as a biomarker ofADHD
and concluded that increased TBR is not presently a valid and reliable tool for
diagnosing ADHD, and that more research on the subject isnecessary beforeclinical
utility can be achieved. Their review was followed by an update by Loo and Makeig
(2012) which reached the same conclusion. The reviews did not specify inclusion
criteria(e.g.,EEGrecordingcriteria)forselectedstudies,underminingthevalidityofthe
conclusions. The authors suggest that ADHD discrimination using EEG can be
improved by applying machine learning techniques in the analysis of the signal, in
particular independent source analysis (ICA). ICA provides a method for separating
brain from nonbrain signals in EEG data, for imaging its cortical sources, and for
examining, with relatively high precision, the dynamics of single sources or source
networks even, in single trials or other continuous time periods without requiring
responseaveraging (Loo &Makeig,2012). Anexampleofthisapproach istheMueller
etal.(2011)studywhichisreviewedlaterinthisthesis.

Arns, Conners and Kraemer (2013) likewise examined the association between
increased TBR and ADHD diagnosis. Included were nine studies, comprising 1253
children andadolescentswithADHDand517healthycontrols.Theeffectsize (Hedges
D)calculatedwas0.75forthe613yearolds,and0.62forthe618yearolds.However,
a negative correlation between effect size and publication year was noted, and
therefore the authors suspect that the effect size found is an overestimation.
Interestingly,the drop in effectsizeacrosstimeareexplainednotbyadecreaseinTBR
in ADHD subjects as might be expected, but by an increase in TBR in controls. The
authors suggest several reasons for this phenomenon, including a decrease in sleep
time across years (childrensleeping less),orincreasingvitamin D deficiency (children
spending less timeoutdoors).Thisis animportantfinding,andwillbediscussedfurther
laterinthisthesis.
The authors conclude that increased TBR is not a reliable measure for diagnosing
ADHD, but note that since increased TBR was found in a subgroup of patients
(2540%), it could have value as a prognostic tool in relation to treatment with
medication and neurofeedback. This metaanalysis is not only the latest, but also
comprises the most specific inclusion criteria of them all. The criteria were: (a)
51

diagnosis of ADHD or ADD according to the DSMIV or DSMIVTR (b) age range
between 6 and 18 years (c) availability of mean, SD, and sample size of theTBRat
electrode site Cz during Eyes Open (d) availability ofa healthy control group and (e)
thestudypublishedinEnglish.(Arnsetal.,2013,p.2).Thestrictinclusioncriteriaofthe
analysismakes it the mostvalidfor judging the clinicalutilityofdiscriminationofADHD
basedonTBR,inmyopinion.

4.1.2.Singlestudies
By applying a machine learning algorithm (support vector machine) to ERP data
recordedduringago/nogotask,Muelleretal.(2011)seekedtodifferentiateadultswith
ADHD from healthy controls. The machine learning algorithm was used toperforman
independent component analysis (ICA) of ERP components. ICA separates a set of
mixed eventrelated potentials into a corresponding set of statistically independent
source signals, which are likely to representdifferentfunctional processes (Mueller et
al., 2011, p.1). Subjectsconsistedof75 patients(includingallADHDsubtypes)and75
healthycontrols,matchedforage(2050years)andgender(bothmaleandfemale).
Thestudyincluded subjects withcomorbiditieswhilethosewithseriousheadinjuriesor
neurological disorders were excluded. All patients completed a 24hour washout of
medicationpriortorecording.Findingsshowed differentiationbetweentheindependent
ERPcomponents in ADHDsubjectsandcontrols,resultinginadiscriminationaccuracy
of 91%.The independent ERP componentswere through ICA locatedto regionsinthe
motor cortex, leading the authors to suggest a deficit of motor inhibition as a likely
causeofADHDsymptoms,similartothemodelproposedbyBarkley(1997).
This study qualifies forseveral ofthe WFSBPcriteria, including accuracyofdiagnosis,
as well as being reliable, reproducible, inexpensive, noninvasive and easy to use.
However, the findings still needs to be replicated by independent researchers to fully
complywith the criteria.Furthermore, thestudyused adult subjectsandsinceweknow
thatage is afactorwhen discriminatingADHDusing neuroimaging,itisnotpossibleto
concludethatthismethodcanbeutilizedindiagnosingchildren.

52

Nazhvani et al. (2013) used ERP recording to measure the Visual Evoked Potential
(VEP) in order todiscriminate betweenADHD andBipolar Disorder (BD)subjectsas
well as healthy controls.VEPis the alteration of theEEGsignal due to visual stimulus.
The usual VEP waveform is characterized by a negative deflectionat75ms (N75), a
positive deflection at 100ms (P100) andanegative deflectionat 145ms (N145). The
trialincluded 36 subjects 12 withADHD,12withBDand12controls,age1022years.
ADHD subtype and any existing psychiatric comorbidities were undefined. Results
showed a classification rate of 94.56% between ADHD and controls, and 92.85
between ADHD and BD. The classification rate was obtainedbyextracting amplitude
and latency from the VEP patterns and applying them toa1NearestNeighbor(1NN)
classifier. As a comparison, the data was also applied to a support vector machine
(SWM)classifier, which obtainedalowerclassificationrate of82.04%betweenADHD
and BD. The authors suggest that future studies should include data from Auditory
Evoked Potential(AEP),Sensory EvokedPotential (SEP)aswellasdatafromfMRIor
PET obtained during stimulus. CombiningtheERPsignaldatawith fMRIimaging data
wouldallow localization ofthe abnormalities,something that isnotpossibleusingEEG
alone. It should be noted that 12 subjectsin eachgroupis rather low,and reduces the
statisticalpoweroftheresults.

In a recent trial, Loo et al. (2013) examined the use of TBR as a clinical marker in
ADHD.Theirsamplewasdividedintothreeagegroups,child(511years),adolescents
(1218 years) and adults (19 years and above). The childgroupincluded 303 children
with ADHDand 59typicallydevelopingcontrols,theadolescentsgroup178withADHD
and 55 controls, and the adults group 81 with ADHD and 195 controls. In sum, 562
patients with ADHDand309 healthycontrolsparticipatedinthestudy.The samplewas
further divided into ADHD subtype, as well as evaluated for psychiatriccomorbidities
and tested for cognitive performance. Based on previous studies, the authors
hypothesized increased TBR in all groups, and particularly in the combined subtype.
Furthermore, the authors expected comorbidities would not affect TBR, but cognitive
measureswerepredictedtocorrelate(negatively)withTBR.
The results showed no significant difference in TBR between patients with ADHDand
controls in any of the groups as a whole.Similarto findings by Arns et al. (2013), this
53

result wascaused by increased TBR inthe control group,which is incontrasttoearlier

studies. However, a significant difference in TBR between the combinedsubtypeand
controls werefound. Secondly, an age effect wasfound, showingdecreasing TBRwith
age, such thatTBRwas actually below controls intheadultADHDgroup, the opposite
of the expected hypothesis. Finally, the study found that certain psychiatric
comorbidities (disruptive behaviour disorder,anxiety and depression)hadasignificant
impact onTBR. Thisstudyhighlights theimportanceofage,subtypeandcomorbidities
asimportantfactorsinneuroimagingbaseddiagnosisofADHD.

Liechti etal. (2013)likewisetriedto validate TBR as a biomarker ofADHD. Theirtrial

consistedof 32children(age816years)and22adults(age3255years)withADHD,
combined subtype. Controls were matched for IQ, gender and age. Subjects with
comorbidities were included. Results showed no difference in TBR between ADHD
subjects and controls, even when controlling for factors such as EEGanalysis, resting
condition, age, severity of ADHD, and comorbidities. This is in contrast to Loo et al.
(2013)whofoundincreasedTBRinthecombinedADHDsubtype.
The authors conclude that TBR is not a valid biomarker of ADHD. However, an age
effect was found, such that children showed higher TBR than adults, and younger
children showed higherTBRthanolderchildren.Thisfindingisnotunexpected,astheta
activityisknowntobehigherinchildhood.

Mazaheri et al. (2013) examined the neurophysiological differences between 23

typically developing adolescents and 17 adolescents with ADHD, predominantly
inattentive subtype or combined subtype, respectively. Patients with predominantly
hyperactive/impulsive subtype werenotincluded inthestudy.Theagegroupwas1217
years. Resultsshowed reducedinhibition of posterioralphaactivityaftervisualcues in
the inattentive subtype,aswell as reducedinhibition of contralateral betaactivity inthe
combined subtype. Furthermore, a reduced couplingbetween frontaltheta activity and
occipital alpha activity was found in both subtypes. This suggests a lack of topdown
suppression of alpha activity as a common impairment in ADHD. Reduced alpha
suppression couldleadto reduced gatingorfiltering ofexternalinformation, leadingto
higherdistractibility.
54

The aim of the study was not the diagnosis of ADHD, but the authors note that
measurement of EEG activity might provide a neural signature for the distinction of
different subgroups of ADHD. The article further discusses whether inattentive and
combined subtype arefacets ofthesamedisorderorentirelydifferentdisorders,as the
neural signatures ofthetwosubtypesdonotoverlap,andconcludesthatmoreresearch
isneededtoilluminatethis.

Lenartowicz et al.(2014)examined performance onaspatial working memory(SWM)

task in52ADHDsubjectsand47typicallydevelopingchildren(aged714years)during
EEG recording. The trial includedallADHD subtypes and subjectswith comorbidities,
all werefree ofmedication at thetimeoftesting.TheSternbergSWMtaskemployedin
the trial has the advantage of being separable into three analysis phases of WM
processing: alerting, encoding and maintenance. Results showed attenuatedoccipital
alpha band eventrelated desynchronization (ERD) during the encoding phase, and
increased frontocentral theta power during the maintenance phase, in the ADHD
group. According tothe authors,these findingssuggestsproblemsduringtheencoding
phase,leadingtocompensatoryeffortsduringthemaintenancephase,andindicatethat
WM performance deficits in ADHDare atleastinpartresultingfrompoorvigilanceand
atypical encoding (Lenartowicz et al., 2014, p. 1179). The EEG measures predicted
ADHDdiagnosiswith70%accuracy,notquitesufficienttosatisfyWFSBPcriteria.

4.2.MRIstudies
Structural neuroimaging findings in ADHD include reduced grey matter particularly in
frontal regions, butalso parietal,temporal andoccipitalcortices, as wellassubcortical
regions such as the hippocampus, amygdala, basal ganglia and in the cerebellum
(Matthews et al., 2014). Volumetric reductions in white matter tracts, in particular
frontostriatal and frontocerebellarcircuits,havealsobeenreported(Castellanos,Kelly
&Milham,2009).

Functional neuroimaging findings in ADHDinclude abnormalitiesin attention networks

(dorsolateral PFC, parietal cortex, cerebellum) and inhibitory networks (inferior frontal
55

cortex and ACC), supporting models of deficits in topdown inhibition. Findings

supporting bottomup models of dysfunctional reward processing include reduced
ventral striatal activity in response to reward, leading researchers to hypothesize
increased rewardseeking behavior in ADHD as a means of compensation for this
neuralhypoactivity(Matthewsetal.,2014).

An interesting focus of fMRI studies in ADHD has been the tasknegative network
versus the taskpositivenetwork.Thetasknegativenetwork,alsoknownasthedefault
mode network, is the physiological baseline brain function when the brain is at rest
and not processing any tasks. I quote at rest becausethebrain isreally rather busy,
with lots of activity going on even when no specific tasks are being handled.
Castellanos et al. (2009) describes this as the restless brain. In contrast, the
taskpositive network, also known as the executive network, isanticorrelated with the
default mode and active during tasks. The tasknegative network includes the medial
and lateral parietal cortex as well as the medial prefrontal cortex and the
precuneus/posterior cingulate cortex. The taskpositivenetworkincludethedorsolateral
PFC, thesupplementarymotorareasand regionsof the parietalcortex(Castellanoset
al.,2009).ThesenetworksaresimilartowhatMenon(2011)describesastheDMNand
CEN.

Research has shownthatfailuretosuppressactivityintheDMNduringattentionaltasks

correlates with longer reaction times (RT), and decreased cuerelated activation in
three prefrontal regions (right middle frontal gyrus, right inferior frontal gyrus and right
dorsal ACC) predicted slower RT and decreased defaultmodenetworksuppression
(Weissman et al.,2006in Castellanoset al., 2009, p.3).Thissuggeststhat prefrontal
regions areinvolved inthe regulationoftheDMN,andsubsequentlySonugaBarkeand
Castellanos (2007) have presented the defaultmode hypothesis of ADHD, which
describes howaberrant interactions betweenfrontal anddefault mode network circuits
maycontributetodysfunctioninADHD,aswellasaccountfortheincreasedintrasubject
variability often observed. Increased intrasubject variability in ADHD has been
demonstratedin cognitive tests,includingsustained attention, attentionalcontrol,motor

56

sequencing and control, inhibitory control, time perception, and choice RT tasks
(Castellanosetal.,2009,p.3).

Consistent with the defaultmode hypothesis, during a Go/Nogo task higher DMN
activitypredictedhigherRTvariability,andhigherpresupplementarymotorareaactivity
predicted lower RT variability. Similarly, during an oddball task lower ACC activity
predictedhigher RTvariability inADHD subjects(Castellanosetal.,2009).Asaresult,
Castellanos et al. (2009) has suggested a focus on RT variability, both in
neuropsychological assessment and neuroimaging, as a means of endophenotypic
classification in ADHD. Lastly, besides findings supporting aberrant network
interaction, abnormalities intrinsic to the DMN, including volume reductions of the
posterior cingulate cortex and precuneus (Castellanos et al., 2009), have also been
reported.

4.2.1.Machinelearningstudies
By utilizing a machine learning approach, Eloyan et al. (2012) attempted to predict
ADHD status and subtype based on (f)MRI data from the ADHD 200 dataset, a
compilation of over 1000structuralandfunctionalscansofADHDpatientsandcontrols.
Demographics included age 726 yearsold, predominantlyrighthandedmales,with a
lower average IQ for ADHD subjects. Several machine learning prediction algorithms
were tested, and the top algorithm produced a specificity of 94% and a sensitivity of
21%. According to the authors, the most promising imaging biomarker found was a
motornetworkparcellationin the ADHDgroups. Networkparcellationisatermusedto
describe compartmentalization of neural regions that normally should be
interconnected. Motor network parcellation thus describes reduced connectivity
(coupling)withinthemotornetwork,whichisthoughttoreflectanimmaturityoftheneural
systems involved with the inhibition of motor activity, also known as motor overflow.
According to the authors, this motor network likely involves the same topdownneural
systems involved with behavioral inhibition, and this lack of inhibitory control in turn
gives rise to thesymptomsof ADHD.Ifcorrect,thiswouldprovideaneurophysiological
basis for Barkleys (1997) modelof behavioral inhibition.However, witha sensitivityof

57

only 21% this finding is at this point questionable. The authors conclude that their
prediction model does not at this time translate into a clinically useful prediction tool,
andthatmoreresearchinthefieldisneeded.

Limet al. (2013) appliedGaussian process classification (GPC),amultivariatepattern

recognition approach, to grey matter volumetric MRI data, in order to differentiate
adolescents with ADHD from healthy controls as well as individuals with Autism
Spectrum Disorder (ASD). The study included 29 adolescentsdiagnosed withADHD
(combined subtype), 29 controls and 19 diagnosed with ASD. All participants were
boys, matched for age (1018 years), right handed and mostly medication naive.
Participants with comorbidities, learning disorders or IQ <70 were excluded from the
study.The GPCalgorithmproducedasensitivityofclassificationfortheADHDgroupof
75.9%, and a specificity of classification for the control group of 82.8%,achieving an
overall accuracy (average of sensitivity + specificity) of classification of 79.3%. The
classificationsensitivity of theADHDgroupversustheASDgroupreachedasensitivity
of 79.3% and a specificity of 75%, achieving an overall classification accuracy of
77.1%.These results areveryclose to thecriteriaproposedbytheWFSBPtaskforce.
Theregions involvedin the pattern predictionof ADHDwerethebilateralventrolateral,
premotor and ventral temporal cortices, limbic regions including hippocampus,
amygdala,hypothalamus,ventralstriatum/putamen,insula,posteriorcingulate andbrain
stem (Lim et al.,2013,p. 5).This findingwouldseemto supportHalperinandSchulzs
(2006)hypothesisofADHDbeinganeurodevelopmentaldisorderofsubcorticalorigin.

Hart et al. (2013) hypothesized that multivariate analysis can provide objective
diagnostic neuroimaging biomarkers for ADHD. According to the authors, univariate
analysis is well suited at groupleveldescriptions,butinsufficient for makingindividual
predictions of ADHD status. Based on the common finding of consistent deficits in
motorresponseinhibitionin ADHD, the authorsused GPC ontaskbasedfMRIdatato
classify ADHD from controls. The participants were 30 boys diagnosed with ADHD
(combined subtype) and 30 controls, all aged 1017 and righthanded. Most were
medication naive, andallhada48hourwashoutperiodbeforescans.Exclusioncriteria
were IQ <70, learning disordersaswell as otherpsychiatric disorders,exceptconduct
58

disorder (CD) and ODD in the ADHD group. The task performed during fMRI scans
was a tracking Stop task, which measuring the participants ability to suppress an
already triggered motor response. The GPC based prediction pattern reached a
sensitivity of90%in classifying the ADHDgroup and a specificityof63%inclassifying
controls, achieving anoverall classificationaccuracyof77%.Whileanaccuracyof77%
seems very closeto the criteria setforthbytheWFSBPtask force, the skewing of the
results towards highersensitivityandlowerspecificitymakesitlessusefulclinically.The
regions most involved with the prediction of ADHD status were earlier developing
mostly ventromedial frontolimbic areas such as ventromedial frontal cortex, ACC,
insula, amygdala, hippocampus, and inferior cerebellum (Hart et al., 2013, p. 3090).
Theauthorsfindtheresultspromising,andsuggestthatitmightbepossibleinthefuture
to diagnose ADHDbased on machine learning pattern recognition. Theinvolvementof
both frontaland limbic structures inthisstudysupportstheSonugaBarkes(2003)dual
pathwaymodel.

In a followup study, Hart et al. (2014) performed multivariate analysis of fMRI data
during a finetemporal discrimination task, on 20 adolescent boys with ADHD
(combined subtype) and 20 matched controls. Similarly to the authors prior study, all
were aged 1017, righthanded and medication naive. Participants were excluded if
they had any psychiatric comorbidities, except forCD/ODD in theADHD group. Also,
anyone with an IO score <70 were excluded. The GPC based pattern recognition
reachedasensitivity of80%inclassifyingpatientswithADHD,andaspecificityof70%
in classifying controls, achieving an overall classification accuracy of 75%.Though the
overall classification accuracy is lower than the results from their prior study, the
sensitivity and specificity scores are more even, making it a clinically more useful
method. The regions involvedwith the predictionof ADHD status includedtheinferior
anddorsolateral prefrontal, insula,and parietalcortices, andthebasal ganglia,anterior
cingulate, and cerebellum(Hart etal.,2014,p.569).Thefrontostriatalcircuitsfoundto
be involved in this study quite clearly supports Barkleys (2006) model of a deficit in
behavioralinhibition.

59

Peng et al. (2013) compared the efficiency of a socalled extreme learning machine
(ELM) algorithm versus support vector machine (SVM) algorithm to accurately predict
ADHD diagnosis on structural MRI data of 55 ADHD subjects and 55 controls. The
subjects were selected from the ADHD200 dataset, and included age range 914
years,righthandedness,and an IQ score >80 and ahistoryofmedicationuse(48hour
washout). Subjects with other psychiatric disorders, head trauma or neurological
disease wereexcluded. TheELMalgorithmisbasedonananalysisofthefollowingfive
structuralcortical features:thickness,surface area,foldingindex,curvatureandvolume.
Ofthe five features, surfaceareaand volume werefoundto bethe mostdiscriminative
fortheprediction ofADHD status. Thestructureswiththemostpronounceddifferences
between ADHD and healthy controls were the frontal, temporal, occipital and insular
cortices. The accuracy reached was 90% for the ELM algorithm and 8586% for the
SVM. The ELM algorithm was also more than 1000 timesfasterthanSVM,making it
much more efficient. The authors are planning future studies using a combination of
fMRI, PET and DTI, tofurtherimproveclassification accuracy.The findingsof reduced
cortical surface area and volume quite clearly supports Halperin and Schulzs (2006)
neurodevelopmentalmodel.

4.2.2.Restingstatefunctionalconnectivitystudies
Usingresting statefMRI,Mattfeldetal.(2014)examinedthefunctionalbraindifferences
between persistent and remitted ADHD, as well as controls, in adulthood. The study
included13participantswithpersistentADHD,22participantswithremittedADHDand
17 healthy controls.Allparticipants inthe ADHD groups were diagnosed in childhood.
All three groups were matched for demographic variables, including age, sex and
socioeconomicstatus. BothADHD groups hadasimilarhistoryofmedicationuse,and
fivepersistent as wellsasfour remitted subjectswere being treated withmedicationat
the time of the study, but all underwent a 24hour washout period. Subjects with
comorbidities were included in the study, but the rate of comorbidities did not differ
between persistentandremitted ADHDgroups.BothADHDgroupshadlowerIQsthan
controls.

60

The authors found absent coupling between the posterior cingulatecortex andmedial
PFC in the group of patients of which ADHDhad persisted into adulthood,compared
with both remitted patients and controls. These structures are anchors of the default
mode network (DMN) which isnormally activeduringnontaskconditions.Furthermore,
the authors found reduced negative connectivity (decoupling) between the medial and
dorsolateral PFC, in both the persistent and remitted group. The PFC is heavily
involved in working memory and executive function,andshouldbe disengaged during
resting state conditions. This finding indicates that even in individuals with ADHD
remitted in adulthood, problems with executive functions still persist.Furthermore, this
finding of reduced decoupling in the PFC could possibly point to an endophenotypic
marker for ADHD. The findings of abnormal coupling and decoupling in this study
supports Menons (2011) model of dysfunctional engagement and disengagement of
neurocognitivenetworksinADHD.

Finally,McCarthy et al. (2013)examined resting statefunctional connectivity(RSFC)in

the following five neurocognitive networks: the affective network, the ventral attention
network, the dorsal attention network, the cognitive control network and the default
modenetwork.
The study included 16 adults diagnosed with ADHD (combined subtype)in childhood
and 16 healthy controls. The controls werematched forage, sex, handedness, IQand
educationallevel. IntheADHD group, twosubjectsweremedicationnaive,tensubjects
had a previous history of methylphenidate use but were drugfree for a mean of 11.6
years,and foursubjectswere still beingtreatedwithmethylphenidatebuthada48hour
washoutbeforethestudy.Subjectswithcomorbiditieswereexcludedfromthestudy.
In contrast to Mattfeld et al. (2014), the authors found increased functional coupling
(RSFC) in the DMN of the ADHD group, but the main finding of the study was a
significant lack of RSFC in the ventral attention network of ADHD participants. The
ventral attention network consists of the temporoparietal junction and ventral frontal
cortex, and is involved with the orientation of attention towards behaviorally relevant
salient stimuli. Thisinturnactivatesthedorsalattentionnetwork,consistingofstructures
such as the intraparietal sulcus and the frontal eye field, which is involved with the
controlofspatialattentionandactivationofappropriatemotorresponses.Thedisrupted
61

exchange betweenthe ventral anddorsal attentionnetworkshasbeen linked to ADHD

symptoms such as increased distractibility andperseverance. Although some findings
from thisstudy are incontrasttothefindingsofMcCarthyet al.(2013)theynevertheless
highlight the importance of taskappropriate engagement and disengagement of
neurocognitive networks, similar to what Menon (2011) suggests in his triple network
model. In particular, the finding of significant hypoconnectivity within the attention
network of ADHDsubjects clearlypointstoadeficitinaccuratelyallocatingappropriate
attentionalresources inresponse tobehaviorally relevant salient stimuli, a centralpoint
ofMenons(2011)model.

4.3.Eyemovementtracking
Although eye movement tracking is not technically a neuroimaging technology,itis an
affordable, easy touseand portable modality, andresearch employing eyemovement
tracking is often combined with neuroimaging modalities such as EEG. For these
reasons, I have chosen to include a very recent trial, in which Fried et al. (2014)
examined the oculomotor behavior and parameters associated with ADHD during a
TOVA test. The trial included 22 adults with ADHD and 22 controls, matched for age
and gender (both maleand female). Using a linear classificationapproach, the results
showed an accuracy of 70%, a sensitivity of 59%, and a specificity of 82% in
diagnosing ADHD. The study found impairment of the ability to inhibit involuntary eye
movements(microsaccades) andblinkrates inresponse tovisualstimuli intheADHD
group. Theseparameterswere normalizedwithmedication(methylphenidate),however
at the cost of increased basal arousal to above normal levels (as measured by pupil
dilation). The authors speculate that patients with ADHD are unable to maintain
sufficient levels of arousal during tasks, limiting their ability to dynamically allocate
attention resources to visual stimuli. The findings of this trial might describe on a
behavioral levelthe neurofunctional findingsofMcCarthy etal.(2013), namelyreduced
RSFC in the ventral attention network of ADHD patients. The frontal eye field
component of this network is involvedin the control ofoculomotoractivity(Middleton &
Strick, 2000), and so it is possible that hypoconnectivity in this region might render
ADHDpatientsunabletomustersufficientvisualattentionressources.Asthefrontaleye
62

field is innervated by dopaminergic projections from the basal ganglia, the authors
theory of hypoarousal as a causative factor supports Sergeants (2000)
cognitiveenergeticmodel.

Study

Met

Condition

hod

Sub

Age

Comor

typ

Group

bidity

Findings

e
Muelleretal. 75ADHD,

ERP

Task,Eyes All

Adult

Yes

Open

AbnormalERP

75CON

Nazhvaniet

12ADHD,

al.2013

12BD,12

discriminates

CON

ADHD,BMDand

VEP

WFSBP

ura

Criteria

cy

2011

ERP

Acc

91%

No

93%

No

NA

No

responseADHD
All

All

Yes

VEP

controls
Looetal.

562

Resting

IA,

2013

ADHD,

EEG

State,EO,

CT

309CON

EC

Child,Adult

Yes

IncreasedTBR
ChildCT,
decreasedTBR
adultCT

Liechtietal.

54ADHD,

2013

51CON

EEG

Resting

CT

Child,Adult

Yes

AgeeffectTBR

NA

No

IA,

Adolescent

Yes

Reduced

NA

No

70%

No

58%

No

79%

No

State,EO,
EC

Mazaheriet

17ADHD,

al.2013

23CON

EEG

Task,EO

CT

posterioralpha
ERD,Reduced
couplingfrontal
thetaposterior
alpha

Lenartowic

52ADHD,

zetal.2014

47CON

EEG

Task,EO

All

Child

Yes

Reduced
occipitalalpha
ERD,increased
frontocentral
theta

Eloyanetal. 285

(f)M

2012

RI

ADHD,

NA

All

All

Yes

Motornetwork
parcellation

491CON
Limetal.

29ADHD,

MRI

NA

CT

Adolescent

No

Greymatter

2013

19ASD,

volume

29CON

reductions
frontocentral
andlimbicareas

63

Hartetal.

20ADHD,

2014

20CON

fMRI

Task

CT

Adolescent

Yes

Finetemporal

75%

No

90%

No

NA

No

NA

No

discrimination
deficit

Pengetal.

55ADHD,

2013

55CON

MRI

NA

All

Child,

Yes

Adolescent

Surfacearea
andvolume
difference

Mattfeldet

13ADHD,

al.2014

22

fMRI

Resting
State

remitted,

All

Adult

Yes

ReducedRSFC
DMN

17CON
McCarthyet

16ADHD,

al.2013

16CON

fMRI

Resting

CT

State

Adult

No

Decreased
RSFCattention
network,
IncreasedRSFC
DMN

Table 1. Summary of included studies. IA = inattentive subtype CT = combined subtype EO = eyes

openEC=eyesclosed.

5.Discussion

In this section I will discuss and evaluate the findings of the neuroimaging studies
reviewed above, in relation to their relevance as clinical tools for aiding in ADHD
diagnosis. As stated in the introduction, the criteria used forthisevaluationwillbethe
criteria set forth by the WFSBP task force for biomarkercandidate evaluation, which
were: (1) sensitivity > 80%, (2) specificity > 80%, (3) the candidate is reliable,
reproducible, inexpensive, noninvasive,easy touse, and(4) confirmedby atleasttwo
independent studies in peerreviewed journals conducted by qualified investigators
(Thomeetal.,2012,p.379).

5.1.TBRasadiagnosticmarker
The research data on TBR show an inconsistent picture withvast differences in effect
sizes reported in the metaanalyses, in particular between the reviews of Snyder and
64

Hall(2006)and Arns etal.(2013). How can weexplain this variabilityin results across
studies? First, these differences likely reflect a lack of standardization in research
methodology. Standardization is an important issue in relation to the diagnosis of
psychiatricdisorders usingneuroimagingtechnologies,aswell as research ingeneral.
Differences in imaging devices, inclusion/exclusion criteria, collection of data
(measurement), processing of data and models of statistical analysis employed all
contribute to this issue. Imaging devices employed in research are of different make
andtypeandmeasurementprotocols(recordingconditions)vary.

One potentialissueisthestandardizationofrecordingconditions.Recordingconditions
are important because reliability requires standardization, equal conditions so that
results between studies can be compared. Furthermore, test conditions should
approximate real life conditions to maximize validity. Lets look at some of these
conditions. First, recording with standardized electrode placement is important for
reliability. Second, Eyes Open (EO) or Eyes Closed (EC) condition during EEG
recording is important for two main reasons. The first reason is that weknowthatthe
EEGactivitychanges when eyes are closed(e.g., alpha activity increases),soitwould
beexpectedtoseedifferencesintheresultsofthetrials,makingthemhardtocompare.
Theother reason is that trialconditionsshouldapproximatereallifeconditionsasmuch
aspossible, andwhen performing cognitivetasks people usuallyhave theireyesopen.
Eyes closed is associated with rest, while eyes open is associated with work. In
situationswhenADHD impairments are most pronounced, suchasinlearning,working
or even socialcontexts,peoplenormally have their eyes open, andsowe might argue
that trials should approximate this condition. Third, with regards to age, weknow that
EEGactivitychanges withage,soitisvitalthatagegroupisdefinedsothattrialresults
canbereliably compared.Finally,for the correct calculation of effect sizes,meansand
standarddeviation(SD)datafromsimilarelectrodesitesshouldbeavailable.

One other important standardization factor is the EEG recording time. Kitsune et al.
(2014) has reported that recording time matters when trying to discriminate ADHD
using EEG. The authors examinedrestingstateEEGpower atthebeginning (time1),
and after 1.5 hours (time2), in 76 adolescents/adults with ADHD, as well as 86
65

controls. Results showed elevated delta and theta power in ADHDsubjects attime1,
but notattime2,andelevatedbetapowerattime2.Thesefindingscouldexplainsome
of theinconsistencies inTBRstudies.ADHD subjectsarevulnerableto atimeontask
effect (performance decrease over time) on cognitive performance (Bioulac et al.,
2012), and this effect is expected to show intheirEEGprofile.Therefore, I finditvery
unfortunate that none of the inclusion criteria of the metaanalyses included recording
time,makingithardtospeculateontheinfluenceofthisfactoronresults.

Snyderand Hall (2006)didnotstandardize forelectrodelocationorrecordingcondition

(Eyes Open, Eyes Closed, Task, etc.) when including studies. In contrast, Arns et al.
(2013) included only studieswhere means and SDs couldbe obtainedfromelectrode
location Cz during Eyes Open condition. The difference ininclusion criteria could very
wellexplain the remarkabledifferencein effect sizesfoundin thestudies,whichvaried
between 0.62 and 3.08. Therefore, we need to examine the inclusion criteria of the
metaanalyses, as they differ significantly between studies. All metaanalyses started
withasearchoftheliterature,usingkeywords(e.g.,ADHD,EEG).TherecentArnsetal.
(2013) metaanalysis used the strictest additional inclusion criteriaof group, while the
Looet al. (2005, 2012) analysisdidnotspecifyinclusioncriteriaandalsodidnotreport
effect sizes, making it difficult to evaluate their findings. Snyder and Hall (2006) and
Boutros et al. (2005)used morelooselydefined inclusioncriteria,andmostimportantly
did not specify the conditions for the EEG measurements, as Arns et al. (2013) did.
This means that studies using conditions such as Eyes Closed during EEG, or not
providingmeasurementattheCzelectrodesitewereincluded.

Furthermore, Arns etal.(2013)pointed outproblems withthe statisticalcalculations of

effect size (ES) in the Snyder and Hall (2006) review: Note that the ES reported by
Snyderand Hall is Glasss D, whichis calculatedusingtheSDofthecontrolgrouponly
and does not use the pooled SD as is the case with Hedges D, thereby perhaps
explaining this difference. Furthermore, both metaanalyses calculated theESs from F
statisticsandpvalueswhennomeansandSDswereavailable,whichisknownto result
in a less accurate ES (Arns et al., 2013, p. 2). This highlights the potential issues
stemming from differencesin statisticalanalyses, as differentresearchersusedifferent
66

statistical calculations, making it difficult to directly compare results. Assuch, thiscan

beadescribedasaproblemofresearchstandardization.

The Arns et al. (2013) analysis included more recent studies than the earlier
metaanalyses, butalsoexcludedstudiesthat Boutrosetal.(2005)andSnyderandHall
(2006) included, on the basisof inconsistency inrecording conditions and lack ofage
group definition. These factors makes the Arns et al. (2013) metaanalysis the most
valid of the analysesin my opinion, and Ithereforeregardthe effect sizesfoundin this
study (0.620.75, age dependent) as the most realistic. However, as noted earlier, a
negative correlation between ES and publication year was found in the post hoc
analysis, such that earlier studies on TBR reported higher ES than later studies. The
decline in ES for TBR across time was mainly due to an increase in TBR in control
groups, rather than a decrease in TBR in ADHD groups.SincetheESforADHDwere
consistent across studies, this finding isnot likelyexplained by differences ininclusion
criteria forADHD patients, orheterogeneityintheADHDgroups(i.e.,subtypes).Which
other factors could explain the finding? The authorssuggestseveral possible reasons
for this drop in ES across years. First, as discussed above, differences in EEG
recordingconditions,aswellasdifferencesinEEGequipment andanalysissoftwareis
a possible reason. However, since the drop in ES is linear, this explanation seems
unlikely. Second, a simultaneous drop in sleep duration among children in the same
time period could possibly influence the results, as fatigue and drowsiness are
associated with increased thetaactivity.Third,anincreaseinvitaminDdeficiency,asa
result of a decline in time children spend outdoors is suggested, as vitamin D is
involved in catecholamine synthesis. Finally, the authors suggest winners curse, a
tendency of finding large effect sizesin earlystudies that cannot later be replicated,to
be a possible explanation. Because of these factors, Arns et al. (2013) conclude that
the ESobtained in themetaanalysis is somewhatmisleading and overestimated, and
therefore TBR cannot be considered a reliable measure fordiagnosing ADHD atthis
time.

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5.2.Age,subtypeandcomorbidity
The Loo et al. (2013) study has been illuminating in several ways. In the study three
major variable effects on TBR were found: an age effect, a subtype effect and a
comorbidityeffect. The ageeffectshowed, surprisingly,adropinTBRwithage,sothat
adults(19years andabove)hadlowerTBRthancontrols.Thisisincontrasttoprevious
studies, and the authors suggest sampling as a possible explanation for this
discrepancy.The adultsinthesamplewereparentsofchildrenwithADHD,andassuch
might carry some of the same gene variants that predisposed the children to the
disorder.Additionally,apercentageoftheadultcontrolscarriedoneormorepsychiatric
diagnoses, incontrastto previousstudies whichusedcontrolsfreeofdiagnoses.Other
explanations are also possible in the adolescent group an association of inattention
symptomsandTBRwas found,butthisassociationwas absent intheadultgroup.The
adults were also generally higher functioning with mean IQ in thehighaveragerange.
This lack of association between behavioral/cognitive measures and TBR might
suggest some sort of compensatory mechanism, perhaps akin to what Halperin and
Schulz (2006) have suggested. We can perhapsspeculate that neurodevelopmentand
maturation of the PFC as a compensatory measurein the adult group haslead to the
decreasedTBRobservedinthestudy.

With regards to the subtype effect observed, it is interesting that increased TBRwas
only found in the combined subtype. It should be noted that the predominantly
hyperactive/impulsive subtype groupwas removedfromtheanalysisduetolowsample
size, which left only the predominantly inattentive and combined subtypes. Since
increased TBR was found in the combined subtype, but not in the predominantly
inattentive, the data suggests an association between hyperactivityimpulsivity and
increased TBR. It has been previously suggested that increased TBR represents
hypoarousal,butthishypothesis has since been rejected, and the data from theLooet
al. (2013) study seems to confirm that this is not the case. The significant difference
between thetwosubtypesalsoopensthediscussiontowhetherADHDsubtypesshould
be considered facets of the same disorder,or entirelyseparatedisorders, a question
also posed by Mazaheri et al. (2013) who likewise found significant differences
68

between the predominantly inattentive and combined subtype in their study.However,

the findings ofLiechti et al.(2013)contradictthis,assubtypewasfoundnottoinfluence
results.

Comorbidities such as disruptive behavior disorder, anxiety and depression

significantly impacted TBR in the Loo et al. (2013) study, mediating its expression.
Again, this was in contrast to earlier studies, and also here the authors suggest
sampling (inclusion/exclusion criteria) as a possible explanation of this differential
finding. As with the issue of ADHD subtypes, psychiatric comorbidities is another
diagnostic grey area,asitcan be challenging to distinguish onedisorderfromanother
when symptoms overlap. In sum, the study sheds light on the reasons for the many
conflicting findings in studies in the field, and questions whether ADHD, as presently
defined in the DSM, isadequately homogenoustobediagnosedas a single disorder
usingEEG.

Overallwe mustconcludethattheresearch data on TBR asadiagnosticbiomarkerfor

ADHD do not comply with WFSBP criteria.Although severalstudies have reachedan
accuracy higher than the demanded 80%, and although the method is inexpensive,
noninvasive and easy to use, findings from trials are simply not reliable enough to
qualifyTBRasadiagnosticmarker.

5.3.OtherEEGfindings
Rather than finding increased TBR, Mazaheri et al. (2013) found evidence ofreduced
suppression ofalphaand betaactivity inpatientswithADHD.Intheprimarilyinattentive
subtype, the authors found reduced alpha activity suppression in responsetoavisual
cue, which indicates problems with the processing of visual information provided by
cuesin this subtype.Thiswas alsofound, to alesserdegree,inthecombinedsubtype.
In both subtypes, absent couplingbetween frontalthetaandposterioralphaactivitywas
observed,indicatingproblemswithreducedgating(filtering)ofexternalinformation,due
to a lack of topdowncontrolin those ADHDsubtypes. Finally, areducedabilityof the
combined subtype to suppress beta activity in the contralateral side in response to
69

visual motor cues, indicates a problem with the formation of appropriate motor
response in this subtype. For diagnostic purposes (of all ADHD subtypes), could we
use the finding of absent coupling between frontal theta and posterior alpha as a
biological marker? Only more replication studies will be able to tell. In any case, the
data from this study suggestthatADHDischaracterizedbyaproblemwiththecoupling
(and perhapsuncoupling)ofneurocognitivenetworks,similartowhatMenon(2011)has
suggested. We know that the saliency network (SN) is involved in the processing of
visualcues, andin thegating of relevant,salient stimuli.Itmay bepossiblethatdeficits
in theSNimpairstheabilityofADHDpatientstofilterexternalinformation,creatinghigh
levels of noise and exhaustion of cognitive resources, as well as an inability to
correctly engage and disengage the relevant neurocognitive networks for solving the
taskathand.

Two ERP based studies produced a discrimination accuracy high enough to comply
with WFSBP criteria, namely Mueller et al. (2011) and Nazhvani et al. (2013). EEG
technology fulfills the criteria of being inexpensive, noninvasive and easy to use.
However, although both studies employed ERP recording, the research methodology
varied significantly. Mueller et al. (2011) measured the ERP response to a go/nogo
task, whereas Nazhvani et al. (2013) measured VEP. For this reason the findings
cannot be said to have been confirmed by at least two independent research teams,
andthereforedoes notfully complywithallWFSBPcriteriaat present.Furtherresearch
isnecessarytoensurethereliabilityofthesemeasuresasdiagnosticbiomarkers.

Regarding the analysis of EEG data, Ponomarev et al. (2014) found that Group
Independent ComponentsAnalysis (gICA) and CurrentSourceDensity(CSD)methods
were superior to raw EEG when discriminating ADHD. Using these data analysis
methods, the authors found reduced spectral EEG power in frontocentral regions of
ADHD subjects, and speculate this finding as a possible diagnostic biomarker for
discriminating ADHD. Interestingly, ADHD subtype was found to be unimportant in
relation to discrimination accuracy. These findings again highlights the importance of
researchmethodologyforachievingreliableresults.

70

5.4.FindingsfromMRIstudies
With regards to MR studies, the picture is perhaps even more complex, as both
structuralandfunctionalMRIstudiesshowquiteaheterogeneousselectionoffindingsin
ADHD.Because the natureofMRimagingresearchmakesitvery timeconsuming,itis
not feasible for researchers to manually examine the structureor function of theentire
brain, andinstead regionsof interest(ROI)arechosen and examined. TheseROIsare
usually chosen on the background of previousknowledge ofregions associatedwith a
given disorder. However, by incorporating machine learning techniques, it becomes
possible to examine much larger areas of the brain. In laymans terms, the computer
basically goes fishing for any difference in structure or function between diagnosed
subjects and controls. By averagingfindings across many scans, it becomes possible
to statisticallyanalysethe probabilities ofspecific deviations ineach region. If findings
can be replicated by other teams, they paint an illuminating picture of the specific
disorders neurophysiologicalsignature. Thesesignatures can then possiblybeutilized
in thediagnosis ofindividuals,at least in theory. Inpracticehowever,things are notso
simple.Neuroimaging iscurrently employedtoidentifyaveragestructuralandfunctional
differences between groups of individuals carrying a specific diagnosis and healthy
controls, and the diagnosis of individuals onthe backgroundof averagegroupdata is
presently difficult. On the group level, the observation of statistically significant
differencesispossible,butonthelevelof theindividuallargeheterogeneityexistamong
patients carrying the same diagnosis and even among healthy controls. Therefore,
imaging methods have difficulty in producing adequate sensitivity and specificity to
reliablydiagnosesingle individuals accordingtothe diagnostic categories of theDSM
(Gillihan&Parens,2011Farah&Gillihan,2012).

Nevertheless,afewMRI studiesreviewedinthisthesiscomesveryclosetofulfillingthe
WFSBP task force criteria for diagnosis, namely Lim et al. (2013) and Peng et al.
(2013).Lim etal.(2013) reachedanaccuracyof 79%, and Pengetal.(2013)reached
an accuracy of 90%. Bothofthese studiesemployed structuralMRI andboth reported
reduced grey matter in ADHD subjects, particularly in frontocentral regions.
Furthermore, both teams ofresearchers employed machinelearningalgorithmson the
71

data. Overall the researchmethodology wasvery similar,and machinelearning based

analysis of grey matter differences as a diagnostic marker therefore has been
confirmed by atleasttwo independentstudies inpeerreviewed journalsconductedby
qualified investigators (Thome et al., 2012, p. 379). As to thecriteriaof whether MRI
basedtechnologies for ADHD diagnosis fulfills the criteriaofbeinginexpensiveaswell
as easy to use, this is ultimately a political question, but to my knowledge it is not
feasible atpresenttoemployMRscanningineverycaseseekingpsychiatricdiagnosis,
asthere simplyarenot enough scanners orpersonnelavailable to handle this.Forthis
reason alone, I am inclined tosuggestfocusing on EEG basedtechnologies (coupled
perhaps with eye movement tracking) for the purpose of ADHD diagnosis. EEG
equipment is inexpensive and portable enough to beinstalledin psychiatricreception
centers,somethingthatisnotpossibleforMRscanners.

5.5.Structuralvsfunctionalimaging
While structuralMRI seems superior to functionalMRIintermsofADHDdiscrimination,
ERP(EEG),afunctionalneuroimagingtechnique,lookspromisingintheabovestudies.
This begsthe question: whyisfunctionalEEGeffectivewhenfunctionalMRIisnot?One
reason could be that because of the inconsistency observed in the behavioral
symptomsof ADHDsubjects,ADHD discriminationrequiresahighdegreeoftemporal
resolution to track variance. As Kofler et al. (2013) described it, ADHD subjects are
consistently inconsistent in performance. If this is the case, the superior temporal
resolution of EEG over fMRI might be the reason for higher discrimination accuracy.
FMRI might simplybe tooslowto pick uptheminutechangesinperformanceofADHD
subjects. Psychostimulants decrease performance variability in ADHD, and thiscould
be explained by a higher ratio of tonic versus phasic firing of catecholamine
neurotransmitters. When tonic firing is low, and phasic firing is high, performance is
inconsistent. Whereas fMRI on its own does not impress as a standalone diagnostic
tool,combiningfMRIwithEEGmightbeacompletelydifferentmatter.

72

5.6.Frontocentralthetaandoccipitalalphaabnormalities
At present we have findings across neuroimaging modalities that seem hard to
reconcile, nevertheless I will attempt to do this here. A trend that seems to emerge
across studies is structural and functional abnormalities in the frontocentral region of
ADHDsubjects:

Lim et al. (2013) and Peng et al. (2013) both found reduced grey matter in
frontocentralareasonstructuralMRIscans.
Elyoan et al. (2012) found hypoconnectivity in the motor cortex, a frontocentral
region.
Hart et al. (2013 2014) found deficitsin motor inhibition (frontocentralactivity)
onfunctionalMRI.
McCarthy et al. (2014) found reduced RSFC in the ventral attention network, a
frontocentralregion.
Mattfeldet al. (2014) found reduced RSFCin the DMN,andincreasedRSFCin
thePFConfunctionalMRI,bothfrontocentralregions.
Mueller et al. (2011) found abnormalities of the ERP signal, localized to motor
cortex.
McLoughlin et al. (2014) found frontocentral EEG power was linked with RT
variability.
Lenartowicz et al. (2014)foundincreased frontocentraltheta powerwas linked
withpoorerWMperformance.
Zhao etal.(2014) found increasedfrontocentralthetaactivityduringa WMtask,
localizedtothemiddlefrontalgyrus.
Mazaheri et al. (2013) found reduced frontocentral theta and occipital alpha
powercoupling.
Ponomarev et al. (2014) found reduced spectral EEG power in frontocentral
regions.

These findings together point to the possibility that abnormalities of frontocentral

regions in fMRIstudies arelinkedtoabnormalitiesoffrontocentralthetaactivityinEEG
73

studies, reflecting the same underlying neuronal impairment. This has also been
suggestedbyPincham (2014).OnlythroughthecombineduseoffMRIandEEGwillwe
beabletoconfirmthisconnection.

Besides abnormalfrontocentralEEGtheta activity duringthemaintenance phase of a

WM task, Lenartowicz et al.(2014) further found that this was preceded by attenuated
alpha ERD during the encoding phase. Mazaheri et al. (2013) and Missonier et al.
(2013) likewise found reduced alpha ERD in ADHD subjects. EEG alpha activity is
strongest over the occipital lobe, and therefore Pincham(2014)suggests focusingon
this area in future ADHDresearch, as abnormaloccipitalalphaactivitymightprecede
frontocentral abnormalities. Could we perhaps be so lucky that reduced alpha
desynchronization onthe occipitallobe isa biomarkerofADHD?Inanycase,itseems
that the association of theta and alpha activity is more important than theassociation
between theta and beta activity that muchof the research inADHD has beenfocused
on.

5.7.Summary
In summary, four studies (Mueller et al., 2011 Nazhvani et al.,2013Limetal., 2013
Peng etal., 2013) came close tofulfilling WFSBPcriteria. Twoofthesestudies(Limet
al., 2013 Peng et al., 2013) employedMRI, which atpresent would requireincreased
investment inorderto utilizethistechnologyon alargescale.Thetworemaining studies
(Mueller et al., 2011 Nazhvani et al., 2013) employed ERP recording, although with
different recording protocols and method of analysis. Since the ERP studies showed
even larger accuracy than the MRI studies, and because EEG is a more inexpensive
and portable technology compared to MRI, it is my opinion that EEG based studies
holds the most promise for improving the reliability of ADHD diagnosis. Combining
EEG with eye movementtracking, another inexpensive andportable technology, could
furtherimproveaccuracyofdiagnosis.

The three studies producing a discrimination accuracy over 90%(Muelleret al,2011

Nazhvani et al., 2013 Penget al., 2013) included all ADHD subtypes,andeven some
74

psychiatric comorbidities, in their design. This would seem to suggest that the
heterogeneity of different subtypes andcomorbidities isirrelevant whendiscriminating
ADHD. Could it be that even though some behavioral symptoms vary between the
phenotypes, some common neurophysiological abnormality underlies attention
problems in general? All studies included in the present review found structural or
functional frontocentral abnormalities, and many found occipital EEG alpha activity
abnormalities. Nazhvani et al. (2013) did not localize the ERP abnormality found, but
since VEP involves the visual pathway, both frontocentraland occipital regionswould
beexpectedtobeinvolved.

Looking at the models of ADHD, all models involve abnormalities of frontocentral

regions,making it difficult tosaywhich model fit thedatamost. Thedatareviewedhas
not consistently supported hypoarousal (Sergeant,2000)or faulty reward mechanisms
(SonugaBarke, 2003) asetiological factors, butbehavioralinhibitiondeficits(Barkley,
1997), delayed neurodevelopment (Halperin & Schulz, 2006) and dysfunctions of
neurocognitive networks (Menon, 2011) are all relevant as explanatory models.
Frontocentral EEG theta abnormalities and attenuated occipital EEG alpha activity
suggests deficitsof behavioral inhibition (Barkley, 1997).Reducedgreymatter volume
onstructuralscans suggest delayed neurodevelopment (Halperin &Schulz, 2006), and
abnormalities in the DMN and attentional networks suggest dysfunctional network
interaction(Menon, 2011).AsthemodelsdescribethesymptomsofADHDondifferent
analyticallevels, they are notmutually exclusive, and therefore an integrationofmodels
mightbecomefeasibleinthefuture.

6.Perspectiveandfuturesuggestions

For the purpose of developing clinically useful diagnostic tools, for reasons already
explained, I suggest focusing on EEG based technologies, perhaps coupled witheye
movement tracking. However, for the purpose ofgaining understandingof ADHD, it is
important that basic research is carried on, employing a combination of multiple
modalities, includingbothstructuralandfunctionalscansaswellaselectrophysiological
75

recordings, in order to attain the highest possible spatial and temporal resolution of
data.Only by aggregatingdata from multiple sourceswillwebeabletofullyunderstand
thenatureofADHDandotherpsychiatricdisorders.

Especially promising for discrimination purposes seems ERP, and therefore further
research inthisfield should beencouraged.WeneedtoverifythefindingsofMuelleret
al. (2011) and Nazhvani et al.(2013) in orderto develop robustand clinically effective
diagnostic tools. The research data shows that methods of data analysis is hugely
important, andthatIndependent Component Analysis(ICA),orCurrent SourceDensity
(CSD)aresuperiortorawEEGdataprocessing,andthesetechniquesshouldoptimally
be refined and standardized. Furthermore, as suggested by Nazhvani et al. (2013),
combining the recording of VEP with AEP and SEP would likely improve diagnostic
accuracy.

A central issue in the context of discovering objective diagnostic biomarkers is that

psychiatric diagnoses existing today are not mirrored in nature, but instead are
constructions created to provide a common foundation for research and treatment.
Mental disorders are not categorical, but rather dimensional, and expressed over a
wide spectrum with great variation in presentation and degree of severity. This
heterogeneity makes it extremely challenging todistinguish one disorderfromanother,
or even to distinguish patients from healthy individuals. No objective biomarkers such
asthose found inmedicinepresently existtoguidethisdiscriminationprocess(Gillihan
& Parens, 2011). It is therefore likely that the existing diagnostic criteria as defined
today in the DSM must either be heavily revised or that entirely new criteria must be
developed to reflect the neurophysiological signatures emerging from neuroimaging
studies(Farah&Gillihan,2012).

Karalunas (2014) suggests that instead of working forward from DSM diagnoses and
searching for biomarkers thatfit each category,itmay bemore productive to startwith
biomarkers and work backwards to create different diagnostic categories. For
example, we might identify children with increased RT variability (regardless of

76

diagnosis), and determine whether they share otherneurological,cognitive, geneticor

behavioralcharacteristics.
This approach is similar to what the NIMH is suggesting with their RDoC framework
project. The goal of RDoC is to foster research to validate dimensions defined by
neurobiologyand behavioral measures that cutacrosscurrentdisordercategories,and
that can inform futurerevisions of our diagnostic systems (Cuthbert,2014,p. 29).The
RDoC framework can be described as a matrix (figure 9), whose rows represent
domains(majordimensionsof mental function)andwhosecolumnsrepresentunitsof
analysis. There are five domains, including Negative Valence Systems, Positive
Valence Systems, Cognitive Systems, Systems for Social Processes, and
Arousal/Regulatory Systems. Each domain is further subdivided into several
constructs, for example the Cognitive Systems domain includes the constructs
attention, perception, working memory and cognitive control. Units of analysis include
genes,molecules, cells,circuits,physiology,behaviorandselfreports,anddescribethe
mental function domainson different analyticallevels,cuttingacrossexistingdiagnostic
categories(Cuthbert,2014).

Looking at theRDoC matrix, it would betemptingto attempttoplotinanADHDprofile,

however this is exactlywhattheNIMHwantstoavoidwiththisproject.Insteadofstarting
with a DSM category and attemptingto map a profile, eachpatientwouldbe mapped
according tothe symptoms(constructs) theyexhibitatdifferentanalyticallevels(unitsof
analysis). Over time, itis likely thatpatternswould emerge, grouping patients into new
categories,basedontheirRDoCmatrixprofile.Perhaps theseprofileswouldbesimilar
to the current existing subtypes (presentations) of ADHD, but most likely entirely new
categories would emerge. The latter is particularly likely when considering currently
defined comorbidities, such thatinstead ofhavingapatientwith inattentive ADHD and
anxiety, as well as another with combined ADHD and ODD, RDoC matrix profiles
encompassing all exhibited constructs, at all measurable analytical levels, could be
developed. In my opinion, this is the way forward for research trying to combine
biomarkerfindingswithdiagnosticsystems.

77

Figure9.TheRDoCmatrix(Cuthbert,2014).

DARPA, the research agency for the American Department of Defense is working
closely together with University of Southern California (USC) on a project called
Detection and Computational Analysis of Psychological Signals (DCAPS). DCAPS
utilizes a technology called Multisense which automatically tracks and analyzes in
realtime facial expressions, body posture, acoustic features, linguistic patterns and
higherlevel behavior descriptors (e.g., attention and fidgeting) (USC, 2011). This
project is on the cutting edge of technologies such as machine learning, natural
languageprocessing andcomputervision,andgivesaglimpseofwhatiscominginthe
near future. Already this technology is utilized in a virtual therapist called SimSensei,
whotreatsAmericanwarveteransforPTSD.

Aswe havealready seen, machinelearningis a powerfultoolforidentifyingpatternsof

psychopathology, and combining systems such as Multisense with data from multiple
sources suchasinterviews, cognitive tests,eye movement andneuroimagingwilllikely
leadtoaveryhighdegreeofdiagnosticaccuracyinthefuture.

78

Returning to the fourstep approach by Boutros et al. (2005) described in the

introduction, we are somewhere between Step 1 and Step 2. Biological anomalies
havebeen observed inADHD(Step 1),but havenot yetbeenreplicatedbyasufficient
number ofindependentresearchgroups,andthereforemorestudiesareneededforthe
confirmation of findings. The demonstration of difference between ADHD groups and
differential diagnoses (Step 2) has begun in afewstudies comparing ADHD with BD
andASD, but much work isstillneeded inthisarea. Thediagnosticaccuracyreported
in studies vary, and the influence of subtypes andcomorbidities on diagnosishas not
yet been adequately established therefore we must conclude that Step 3 (and
subsequentlyStep4)hasnotyetbeenachieved.

In summary,several neuroimaging technologies show promisingevidenceof providing

objective diagnostic markers fortheclinicaldiagnosis ofADHD.Ofthesetechnologies,
I regardEEGandeyemovementtrackingthemostfeasible,bothintermsofeconomics
and usability. As pointed out in the introduction, the multivariate analysis of several
different endophenotypic biomarkers will most likely provide the highest accuracy of
diagnosis. It is important to note that neuroimaging technologies are not meant to
replace the clinician, but rather to aid him in diagnosis a common sense approach
based on the symptoms that patients exhibit is important. Byaggregating information
from amultitudeof different sources, theclinicianwillhave thebestpossibleconditions
forprovidingpatientswith accurate diagnosis as wellas effectivetreatment,andinthis
regardthefuturelooksbright.

References

1. American Psychiatric Association. (1994). Attention Deficit/Hyperactivity

Disorder. In Diagnostic and statistical manual of mental disorders (DSMIV).
Washington,DC:Author.

79

2. American Psychiatric Association. (2013). Attention Deficit/Hyperactivity

Disorder. In Diagnostic and statistical manual of mental disorders (DSMV).
Washington,DC:Author.
3. Arns, M., Conners, C. K., & Kraemer, H. C. (2013). A Decade of EEG
Theta/Beta Ratio Research in ADHD A MetaAnalysis. Journal of Attention
Disorders,17(5),374383.
4. Arnsten, A. F. T. (2011). Catecholamine Influences on Dorsolateral Prefrontal
CorticalNetworks.BiologicalPsychiatry,69(12),e89e99.
5. Baddeley,A.(1992).Workingmemory.Science,255(5044),556559.
6. Baddeley, A. D.,&Hitch,G.(1974).WorkingMemory.InGordon H. Bower(Ed.),
PsychologyofLearningandMotivation,8,4789.
7. Bansal, R.,Staib,L. H., Laine, A. F.,Hao,X., Xu, D.,Liu, J., Peterson,B. S.
(2012). Anatomical brain images alone can accurately diagnose chronic
neuropsychiatricillnesses.PloSOne,7(12),e50698.
8. Barkley, R. A. (1997). Behavioral inhibition, sustained attention, and executive
functions:constructingaunifyingtheoryofADHD.PsycholBull,121(1),6594.
9. Barry,R.J.,Clarke,A.R.,Hajos,M.,McCarthy,R.,Selikowitz,M., &Dupuy,F.E.
(2010).

Restingstate

EEG

gamma

activity

in

children

with

AttentionDeficit/Hyperactivity Disorder. Clinical Neurophysiology, 121(11),

18711877.
10. Barry, R. J., Clarke, A. R., Johnstone, S. J., McCarthy, R., & Selikowitz, M.
(2009).

Electroencephalogram

Ratio

and

Arousal

in

AttentionDeficit/Hyperactivity Disorder: Evidence of Independent Processes.

BiologicalPsychiatry,66(4),398401.
11. Biederman, J. (2005). AttentionDeficit/Hyperactivity Disorder: A Selective
Overview.BiologicalPsychiatry,57(11),12151220.
12. Bioulac,S., Lallemand,S., Rizzo,A.,Philip,P.,Fabrigoule,C.,&Bouvard,M.P.
(2012). Impact of time on task on ADHD patients performances in a virtual
classroom. European Journal of PaediatricNeurology: EJPN: Official Journal
oftheEuropeanPaediatricNeurologySociety,16(5),514521.

80

13. Bledsoe, J.C., SemrudClikeman,M.,&Pliszka,S.R.(2013).Anteriorcingulate

cortexand symptom severityinattentiondeficit/hyperactivitydisorder.Journalof
AbnormalPsychology,122(2),558565.
14. Botteron, K.,Carter,C.,Castellanos,F.X.,Dickstein,D.P.,Drevets,W.,Kim,K.
L., Sheline, Y. (2012). Consensus Report of the APA Work Group on
Neuroimaging Markers of Psychiatric Disorders. Arlington, VA: American
PsychiatricAssociation.
15. Boutros, N. N. (2011). Standard electroencephalography in clinical psychiatry
apracticalhandbook.Chichester,WestSussexHoboken,NJ:WileyBlackwell.
16. Buxton, R. B. (2009). Introduction to functional magnetic resonance imaging
principlesandtechniques.Cambridge:CambridgeUniversityPress.
17. Brne og Ungdomspsykiatrisk Selskab (2008). Referenceprogram for
udredning og behandling af brn og unge med ADHD. Retrieved from
http://www.bupnet.dk/media/ADHDReferenceprogram080508_jsb[1].pdf
18. Castellanos, F. X.,Kelly, A. M.C., & Milham, M.P.(2009).The Restless Brain:
AttentionDeficit/Hyperactivity Disorder, Resting State Functional Connectivity
and Intrasubject Variability. Canadian Journal of Psychiatry. Revue
CanadiennedePsychiatrie,54(10),665672.
19. Castellanos, F. X., & Proal, E. (2012). LargeScale Brain Systems in ADHD:
Beyond the PrefrontalStriatal Model. Trends in Cognitive Sciences, 16(1),
1726.
20. Clarke, A. R., Barry, R. J., Dupuy, F. E., McCarthy, R., Selikowitz, M., &
Johnstone, S. J. (2013). Excess beta activity in the EEG of children with
attentiondeficit/hyperactivity disorder: A disorder of arousal? International
JournalofPsychophysiology,89(3),314319.
21. Cuthbert, B. N. (2014). The RDoC framework: facilitating transition from
ICD/DSM to dimensional approaches that integrate neuroscience and
psychopathology.WorldPsychiatry,13(1),2835.
22. Del Campo, N., Chamberlain, S. R., Sahakian, B. J., & Robbins, T. W. (2011).
The Roles of Dopamine and Noradrenaline in the Pathophysiology and
Treatment of AttentionDeficit/Hyperactivity Disorder. Biological Psychiatry,
69(12),e145e157.
81

23. Eloyan, A., Muschelli, J., Nebel, M. B., Liu, H., Han, F., Zhao, T., Caffo, B.
(2012). Automated diagnoses of attention deficit hyperactive disorder using
magneticresonanceimaging.FrontiersinSystemsNeuroscience,6,61.
24. Farah, M. J., & Gillihan, S. J. (2012). The Puzzle of Neuroimaging and
Psychiatric Diagnosis: Technology and Nosology in an Evolving Discipline.
AJOBNeuroscience,3(4),3141.
25. FDA. (2013). Press AnnouncementsFDApermitsmarketingoffirstbrainwave
test to help assess children and teens for ADHD. Retrieved from
http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm360811.htm
26. Fell, J., Fernndez, G., Klaver, P., Elger, C. E., & Fries, P. (2003). Is
synchronized neuronal gamma activity relevant for selective attention? Brain
ResearchReviews,42(3),265272.
27. Fried, M., Tsitsiashvili, E., Bonneh, Y. S., Sterkin, A., WygnanskiJaffe, T.,
Epstein, T., & Polat, U. (2014). ADHD subjects fail tosuppress eye blinks and
microsaccades while anticipating visual stimuli but recover with medication.
VisionResearch,101,6272.
28. Gillihan, S. J., & Parens, E. (2011). ShouldWeExpect Neural Signatures for
DSMDiagnoses?TheJournalofClinicalPsychiatry,72(10),138389.
29. Giorgio, A.,& DeStefano, N. (2013). Clinicaluse ofbrain volumetry. Journalof
MagneticResonanceImaging,37(1),114.
30. Gottesman,I.I.,&Gould,T.D.(2003).Theendophenotypeconceptinpsychiatry:
etymologyandstrategicintentions.TheAmericanJournalofPsychiatry,160(4),
636645.
31. Halperin, J. M., & Healey, D. M. (2011). The Influences of Environmental
Enrichment, Cognitive Enhancement, and Physical Exercise on Brain
Development: Can we Alter the Developmental Trajectory of ADHD?
NeuroscienceandBiobehavioralReviews,35(3),621634.
32. Halperin, J. M.,& Schulz,K. P. (2006).Revisitingtheroleoftheprefrontalcortex
in the pathophysiology of attentiondeficit/hyperactivity disorder. Psychol Bull,
132(4),56081.
33. Hart,H., Chantiluke, K.,Cubillo,A.I.,Smith,A.B.,Simmons,A.,Brammer,M.J.,
Rubia, K. (2013). Pattern classification of response inhibition in ADHD:
82

Toward the development of neurobiological markers for ADHD. Human Brain

Mapping35,30833094.
34. Hart, H., Marquand, A. F., Smith, A., Cubillo,A., Simmons, A.,Brammer, M., &
Rubia,

K.

(2014).

Predictive

neurofunctional

markers

of

attentiondeficit/hyperactivitydisorderbasedonpatternclassificationoftemporal
processing. Journal of the American Academy of Child and Adolescent
Psychiatry,53(5),569578.e1.
35. Insel,

T.

(2013).

Transforming

Diagnosis.

Retrieved

from

http://www.nimh.nih.gov/about/director/2013/transformingdiagnosis.shtml
36. Jensen, P. S.,Arnold, L.E., Swanson,J.M.,Vitiello,B.,Abikoff,H.B.,Greenhill,
L. L., Hur, K. (2007). 3year followup of the NIMH MTA study. J Am Acad
ChildAdolescPsychiatry,46(8),9891002.
37. Karalunas, S. L., Geurts, H. M., Konrad, K., Bender, S., & Nigg, J. T. (2014).
Annual Research Review: Reaction time variability in ADHD and autism
spectrum disorders: measurement and mechanisms of a proposed
transdiagnostic phenotype. JournalofChildPsychologyandPsychiatry,55(6),
685710.
38. Kitsune,G.L., Cheung, C. H. M., Brandeis,D., Banaschewski,T.,Asherson,P.,
McLoughlin, G.,&Kuntsi,J.(2014).AMatterofTime:TheInfluenceofRecording
Context on EEG Spectral Power in Adolescents and Young Adultswith ADHD.
BrainTopography,111.
39. Kofler, M.J.,Rapport,M.D.,Sarver,D.E.,Raiker,J.S.,Orban,S.A.,Friedman,
L. M., & Kolomeyer, E. G. (2013). Reaction time variability in ADHD: A
metaanalytic review of 319 studies. Clinical Psychology Review, 33(6),
795811.
40. Koziol, L. F., &Stevens,M.C.(2012).NeuropsychologicalAssessmentandThe
ParadoxofADHD.AppliedNeuropsychology:Child,1(2),7989.
41. Lenartowicz, A., Delorme, A., Walshaw, P. D., Cho, A. L., Bilder, R. M.,
McGough, J. J., Loo, S. K. (2014). Electroencephalography Correlates of
Spatial Working Memory Deficits in AttentionDeficit/Hyperactivity Disorder:
Vigilance, Encoding, and Maintenance. The Journal of Neuroscience, 34(4),
11711182.
83

42. Liechti, M. D., Valko, L., Mller, U. C.,Dhnert, M., Drechsler, R.,Steinhausen,
H.C.,& Brandeis, D. (2013).Diagnostic valueof restingelectroencephalogram
in attentiondeficit/hyperactivity disorder across the lifespan. Brain Topography,
26(1),135151.
43. Lim, L., Marquand, A., Cubillo, A.A., Smith, A.B., Chantiluke, K.,Simmons,A.,
Rubia, K. (2013). DisorderSpecificPredictive Classification ofAdolescents
with Attention Deficit Hyperactivity Disorder (ADHD) Relative to Autism Using
StructuralMagneticResonanceImaging.PLoSONE,8(5),e63660.
44. Loo, S. K., & Barkley, R. A. (2005). Clinical utility of EEG in attention deficit
hyperactivitydisorder.AppliedNeuropsychology,12(2),6476.
45. Loo, S. K., Cho, A., Hale, T. S., McGough, J., McCracken, J., & Smalley, S. L.
(2013). Characterization ofthetheta tobetaratio in ADHD: identifying potential
sourcesofheterogeneity.JournalofAttentionDisorders,17(5),384392.
46. Loo, S. K., & Makeig, S. (2012). Clinical Utility of EEG in
AttentionDeficit/Hyperactivity

Disorder:

Research

Update.

Neurotherapeutics,9(3),569587.
47. LopezLarson, M. P.,King, J.B., Terry,J.,McGlade, E. C.,&YurgelunTodd,D.
(2012). Reduced insular volume in attention deficit hyperactivity disorder.
PsychiatryResearch,204(1),3239.
48. Lubar, J. F. (1991). Discourse on the development of EEG diagnostics and
biofeedback for attentiondeficit/hyperactivity disorders. Biofeedback and
SelfRegulation,16(3),201225.
49. Luck, S. J. (2005). An Introduction to the EventRelatedPotentialTechnique.
Cambridge,MA:TheMITPress.
50. Mattfeld, A. T., Gabrieli, J. D. E., Biederman,J., Spencer, T., Brown, A., Kotte,
A., WhitfieldGabrieli, S. (2014). Brain differences between persistent and
remitted attention deficit hyperactivity disorder. Brain: A Journal of Neurology,
137(9),24232428.
51. Matthews, M., Nigg, J. T., & Fair, D. A. (2014). Attention Deficit Hyperactivity
Disorder.CurrentTopicsinBehavioralNeurosciences,16,235266.
52. Mazaheri, A., Fassbender,C., CoffeyCorina, S.,Hartanto,T. A., Schweitzer, J.
B., & Mangun, G. R. (2013). Differential Oscillatory Electroencephalogram
84

Between AttentionDeficit/Hyperactivity Disorder Subtypes and Typically

DevelopingAdolescents.BiologicalPsychiatry,76(5),422429.
53. McCarthy,H.,Skokauskas,N., Mulligan,A.,Donohoe,G.,Mullins,D., Kelly,J.,
Frodl, T. (2013). Attention network hypoconnectivity with default and affective
network hyperconnectivity in adultsdiagnosedwith attentiondeficit/hyperactivity
disorderinchildhood.JAMAPsychiatry,70(12),13291337.
54. McLoughlin, G.,Palmer,J. A.,Rijsdijk,F.,&Makeig,S.(2014).GeneticOverlap
between Evoked Frontocentral ThetaBand Phase Variability, Reaction Time
Variability, and AttentionDeficit/Hyperactivity Disorder Symptoms in a Twin
Study.BiologicalPsychiatry,75(3),238247.
55. Menon, V. (2011). Largescale brain networks and psychopathology:a unifying
triplenetworkmodel.TrendsinCognitiveSciences,15(10),483506.
56. Middleton, F. A., & Strick, P. L. (2000). Basal ganglia and cerebellar loops:
motorandcognitivecircuits.BrainResearchReviews,31(23),236250.
57. Missonnier, P., Hasler, R., Perroud,N., Herrmann,F. R.,Millet, P.,Richiardi,J.,
Baud, P. (2013). EEG anomalies in adult ADHD subjects performing a
workingmemorytask.Neuroscience,241,135146.
58. Monastra, V.J.,Lubar, J.F.,Linden,M.,VanDeusen,P.,Green,G.,Wing,W.,
Nick,T.(1999). Assessing attentiondeficithyperactivitydisorderviaquantitative
electroencephalography: An initial validation study. Neuropsychology, 13(3),
424433.
59. Mueller, A., Candrian, G., Grane, V. A., Kropotov, J. D., Ponomarev, V. A., &
Baschera, G.M. (2011). Discriminating between ADHD adults and controls
using independent ERP components and a supportvectormachine:avalidation
study.NonlinearBiomedicalPhysics,5,5.
60. Nazhvani, A. D., Boostani, R., Afrasiabi, S., & Sadatnezhad, K. (2013).
ClassificationofADHDandBMDpatientsusingvisualevokedpotential.Clinical
NeurologyandNeurosurgery,115(11),23292335.
61. NEBAHealth.(2013).Retrievedfromhttp://www.nebahealth.com/research.html
62. NLM. (2013). Controversy over DSM5: new mental health guide National
Library

of

Medicine.

PubMed

Health.

Retrieved

from

85

http://www.ncbi.nlm.nih.gov/pubmedhealth/behindtheheadlines/news/20130815
controversyoverdsm5newmentalhealthguide/
63. Parens, E., & Johnston, J. (2009). Facts, values, and AttentionDeficit
Hyperactivity Disorder (ADHD): an update on the controversies. Child and
AdolescentPsychiatryandMentalHealth,3,1.
64. Peng, X., Lin, P., Zhang, T., & Wang, J. (2013). Extreme Learning
MachineBased Classification ofADHD Using Brain StructuralMRI Data.PLoS
ONE,8(11),e79476.
65. Pincham,H.L. (2014).The Neural Correlates ofWorkingMemoryImpairmentin
AttentionDeficit/Hyperactivity Disorder. Journal of Neuroscience, 34(17),
57355737.
66. Polanczyk, G.,de Lima,M.S, Horta,B.L.,Biederman,J.,&Rohde,L.A.(2007).
TheWorldwide Prevalence ofADHD:ASystematicReviewand Metaregression
Analysis.AmericanJournalofPsychiatry,164(6),942948.
67. Politiken. (2013). Ny choktal: Nu fr 38.000 ADHDmedicin Politiken.dk.
Retrieved

from

http://politiken.dk/indland/ECE1944560/nychoktalnufaar38000adhdmedicin/
68. Ponomarev, V.A.,Mueller,A.,Candrian,G.,GrinYatsenko,V.A., &Kropotov,J.
D. (2014). Group Independent ComponentAnalysis (gICA)and CurrentSource
Density (CSD) in the studyof EEGin ADHDadults.Clinical Neurophysiology,
125(1),8397.
69. Seeman, P., & Madras, B. (2002). Methylphenidate elevatesrestingdopamine
which lowers the impulsetriggered release of dopamine: a hypothesis.
BehaviouralBrainResearch,130(12),7983.
70. Sergeant, J. (2000). The cognitiveenergetic model: an empirical approach to
attentiondeficit hyperactivity disorder. Neuroscience and Biobehavioral
Reviews,24(1),712.
71. Shaw, P., Eckstrand,K., Sharp, W., Blumenthal,J.,Lerch, J.P., Greenstein,D.,
Rapoport,J.L.(2007).Attentiondeficit/hyperactivitydisorderischaracterized
byadelayincorticalmaturation.ProcNatlAcadSciUSA,104(49),1964954.
72. Snyder, S. M., & Hall, J. R.(2006). A metaanalysisof quantitativeEEGpower
associated with attentiondeficit hyperactivity disorder. Journal of Clinical
86

Neurophysiology:

Official

Publication

of

the

American

ElectroencephalographicSociety,23(5),440455.
73. SonugaBarke,E.J. (2003). Thedualpathway model of AD/HD:an elaboration
of neurodevelopmental characteristics. Neuroscience & Biobehavioral
Reviews,27(7),593604.
74. SonugaBarke, E. J. S., & Castellanos, F. X. (2007). Spontaneous attentional
fluctuations in impaired states and pathological conditions: a neurobiological
hypothesis.NeuroscienceandBiobehavioralReviews,31(7),977986.
75. Statens Serum Institut. (2012). Salget af ADHD medicin fra 2002 2011.
Retrieved

from

http://www.ssi.dk/Sundhedsdataogit/Laegemidler/Lagemiddelforbrugsanalyser/2
012/ADHD.aspx
76. Sundhedsstyrelsen. (2014). National klinisk retningslinje for ADHD hos brn
og

unge.

Retrieved

from

https://sundhedsstyrelsen.dk/da/nyheder/2014/nationalkliniskretningslinjeforad
hdhosboernogunge#
77. Tamm,L.,Narad,M. E.,Antonini, T. N.,OBrien,K.M., Hawk, L.W.,&Epstein,
J. N. (2012). Reaction TimeVariability inADHD: AReview.Neurotherapeutics,
9(3),500508.
78. Thome, J., Ehlis, A.C., Fallgatter, A. J., Krauel, K.,Lange, K.W.,Riederer, P.,
Gerlach, M. (2012). Biomarkers for attentiondeficit/hyperactivity disorder
(ADHD). A consensus report of the WFSBP task force on biological markers
and the World Federation of ADHD. The World Journal of Biological
Psychiatry: The Official Journal of the World Federation of Societies of
BiologicalPsychiatry,13(5),379400.
79. USC.(2011).SimSensei.Retrievedfromhttp://ict.usc.edu/prototypes/simsensei/
80. Weiler, M. D., Bellinger, D. K., Simmons, E. K., Rappaport, L.K., Urion,D.K.,
Mitchell, W. J., Waber,D.(2000). Reliabilityandvalidity ofaDSMIVbased
ADHD screener. Child Neuropsychology:A Journalon Normal andAbnormal
DevelopmentinChildhoodandAdolescence,6(1),323.

87

81. Zhao,Y., Tang, D.,Hu,L.,Zhang, L.,Hitchman,G.,Wang,L., &Chen,A.(2014).

Concurrent working memory task decreases the Stroop interference effect as
indexedbythedecreasedthetaoscillations.Neuroscience,262,92106.

88