REVIEW

Siri D. S. Noordermeer1 & Marjolein Luman1& Jaap Oosterlaan1

Received: 28 August 2015 /Accepted: 18 December 2015 /Published online: 5 February 2016# The Author(s) 2016. This article is published with open access at Springerlink.com

Abstract Oppositional defiant disorder (ODD) and conductdisorder (CD) are common behavioural disorders in childhoodand adolescence and are associated with brain abnormalities.This systematic review and meta-analysis investigates struc-tural (sMRI) and functional MRI (fMRI) findings in individ-uals with ODD/CD with and without attention-deficit hyper-activity disorder (ADHD). Online databases were searched forcontrolled studies, resulting in 12 sMRI and 17 fMRI studies.In line with current models on ODD/CD, studies were classi-fied in hot and cool executive functioning (EF). Both themeta-analytic and narrative reviews showed evidence ofsmaller brain structures and lower brain activity in individualswith ODD/CD in mainly hot EF-related areas: bilateral amyg-dala, bilateral insula, right striatum, left medial/superior fron-tal gyrus, and left precuneus. Evidence was present in bothstructural and functional studies, and irrespective of the pres-ence of ADHD comorbidity. There is strong evidence thatabnormalities in the amygdala are specific for ODD/CD ascompared to ADHD, and correlational studies further supportthe association between abnormalities in the amygdala andODD/CD symptoms. Besides the left precuneus, there wasno evidence for abnormalities in typical cool EF related struc-tures, such as the cerebellum and dorsolateral prefrontal cor-tex. Resulting areas are associated with emotion-processing,error-monitoring, problem-solving and self-control; areas as-sociated with neurocognitive and behavioural deficits impli-cated in ODD/CD. Our findings confirm the involvement of

hot, and to a smaller extent cool, EF associated brain areas inODD/CD, and support an integrated model for ODD/CD (e.g.Blair, Development and Psychopathology, 17(3), 865-891,2005).

Keywords ODD .CD .ADHD .StructuralMRI . FunctionalMRI . ALEmeta-analysis

Introduction

In recent years, magnetic resonance imaging (MRI) studieshave provided insight into the underlying brain mechanismsof disruptive behaviour disorders, including oppositional de-fiant disorder (ODD) and conduct disorder (CD). This reviewwill integrate and discuss studies using structural (sMRI) andfunctional MRI (fMRI) in these disorders. ODD and CD aredevelopmental disorders that are among the most commonlydiagnosed mental health conditions in childhood (Hamiltonand Armando 2008; Loeber et al. 2009). Community samplesshow a prevalence rate for ODD ranging between 2 and 14 %and for CD ranging between 2 and 16 % (Boylan et al. 2007;Loeber et al. 2000). Both disorders are more prevalent in boysthan in girls with ratio’s ranging from 3:1 to 9:1 (Loeber et al.2000). ODD is defined by a frequent and persistent pattern ofirritable and angry mood, vindictiveness and developmentallyinappropriate, negativistic, defiant, and disobedient behaviourtoward authority figures (American Psychiatric Association2013). CD is characterised by a persistent pattern of multipleantisocial behaviours during childhood and adolescence, in-cluding fighting, bullying, stealing, vandalism, and lying forpersonal gain (American Psychiatric Association 2013).Depending on whether the individual was younger or olderthan 10 years at the time of symptom onset, there is a

* Siri D. S. Noordermeers.d.s.noordermeer@vu.nl

1 Faculty of Behavioural and Movement Sciences, ClinicalNeuropsychology Section, VU University Amsterdam, Van derBoechorststraat 1, 1081 BTAmsterdam, The Netherlands

Neuropsychol Rev (2016) 26:44–72DOI 10.1007/s11065-015-9315-8

A Systematic Review and Meta-analysis of Neuroimagingin Oppositional Defiant Disorder (ODD) and Conduct Disorder(CD) Taking Attention-Deficit Hyperactivity Disorder (ADHD)Into Account

differentiation between childhood-onset CD and adolescent-onset CD (American Psychiatric Association 2013).

Although both disorders have some distinct characteristics,the general consensus is that ODD and CD are highly corre-lated expressions of psychopathology. Till the emergence ofthe DSM-5, ODD has been coined as a milder version of CDas emphasised by the hierarchical rule stipulated in the DSM-IV stating that a diagnosis of ODD is precluded when CD ispresent, due to very high levels of ODD features in individualswith CD and the precursory role of ODD for CD. This pre-cursory role of ODD for the later development of CD is sup-ported by a quadrupled risk for the development of CD inindividuals with ODD (Burke et al. 2002; Loeber et al.2009; Rowe et al. 2010). In addition to the high levels ofODD features in CD, comorbidity rates of ODD are as highas 45 % in children with CD, and in clinical samples theserates increase to up to 96 % (Loeber et al. 2009; Rowe et al.2002). ODD and CD share risk factors in both the psychoso-cial domain, such as poverty and social disadvantage, and thefamily domain, such as a history of criminality in biologicalparents (Rowe et al. 2002; Burke et al. 2002). An extensivereview on the heritability of ODD and CD shows heritabilityrates of 61 and 74 %, respectively, with 50 % of the reportedgenes being associated with both disorders (Coolidge et al.2000; Lahey and Waldman 2012). The presence of eitherODD or CD predicts poor future outcomes, including com-promised psychiatric, family and social functioning, as well asan increased risk for adverse life events: e.g., peer rejection,criminal behaviour and incarceration at a young age (Burke etal. 2002; Hamilton and Armando 2008; Loeber et al. 2000).When ODD or CD persists, individuals are at a heightenedrisk for anxiety disorders and depression. Furthermore, persis-tence of childhood ODD or CD into adulthood results in adiagnosis of antisocial personality disorder (APD), which isin turn related to high rates of domestic violence, unemploy-ment and homelessness (Loeber et al. 2008; Kimonis andFrick 2010). APD can only be diagnosed when there is ahistory of some symptoms of CD and the transition fromCD to APD occurs in around 54 % of individuals with CD(Fairchild et al. 2013b; American Psychiatric Association2013). Treatment of ODD and CD is generally not specificto either disorder, and a combination of interventions that aimat multiple domains tends to bemore successful than treating asingular domain. In the current review, ODD and CD will betreated as representing one dimension of psychopathology,because of the similarities in many domains includingaetiology, phenotypical manifestation, correlated features, aswell as treatment.We will refer to this dimension as ODD/CD.

Several explanatory models of ODD/CD focus specificallyon neurocognitive impairments, which are thought to be relat-ed to abnormalities in underlying brain mechanisms.Neurocognitive impairments that are associated with ODD/CD include lower IQ, deficiencies in inhibitory control,

abnormalities in emotional processing and social cognition,and abnormalities in reinforcement processing. Most of theexplanatory models emphasise a deficit in so-called executivefunctioning (EF). EF is the sum of neurocognitive processesthat maintain an appropriate problem-solving set to attain agoal (Pennington and Ozonoff 1996; Willcutt et al. 2005). Awell-known distinction in EF is that between hot and cool EF.Hot EF is characterised by motivational and affective aspectsof cognitive processing, such as reinforcement learning, affec-tive decision-making and emotional processing (Anderson etal. 2008; Blair and Lee 2013; Kerr and Zelazo 2004; Zelazoand Carlson 2012). Brain areas that are reported to be impor-tant for hot EF include the amygdala, anterior cingulate cortex,insula and orbitofrontal cortex (Crowe and Blair 2008;Prencipe et al. 2011; Rubia 2011). In contrast, cool EF refersto goal-directed and problem-solving behaviours, as well asself-regulation, not involving motivational or affective as-pects. Cool EF encompasses functions using diverse abilitiessuch as inhibition, working memory, planning, flexibility, andthe ability to creatively generate solutions for problems(Sarkar et al. 2013; Diamond 2013). Brain areas reported tobe central to cool EF include the dorsolateral prefrontal cortexand the cerebellum (Prencipe et al. 2011; Rubia 2011; Yangand Raine 2009; Sterzer and Stadler 2009). This distinctionbetween hot and cool EF provides a framework to study un-derlying brain mechanisms of observed behavioural andneurocognitive abnormalities in ODD/CD. This knowledgecan help test theoretical models on ODD/CD through clarify-ing involvement of brain areas central to those models. Thisimportant information on theoretical model building can inturn help to further advance the field, by yielding supportingor opposing evidence for the involvement of brain areas.

An altered reinforcement system, and thus a hot EF problem,was proposed in early models on ODD/CD by Quay (1965,1993) and by Newman and Kosson (1986). Indeed, a recentextensive review in antisocial individuals showed altered sen-sitivity to reward and punishment and processing of these con-tingencies (Byrd et al. 2014). Specifically, antisocial individualsshow an increased affinity for immediate reward over delayedreward, an insensitivity to punishment, and increased reward-seeking (Byrd et al. 2014). This altered reinforcement sensitiv-ity has been related to problems in social cognition in individ-uals with ODD/CD. For example, these individuals tend toshow a preference for more aggressive reactions in social situ-ations, which might be due to their unsparing surge for rewardand decreased punishment sensitivity (Burke et al. 2002;Loeber et al. 2008; Quay and Hogan 1999; Rubia 2011). Inaddition, abnormalities in emotional processing have been re-ported repeatedly in studies with ODD/CD samples (Byrd et al.2014), including reduced levels of empathy and deficits in therecognition of emotional expressions (Blair 2013). Both abnor-malities in reinforcement sensitivity and emotional processingin ODD/CD have been related to abnormalities in hot EF brain

Neuropsychol Rev (2016) 26:44–72 45

areas, such as the amygdala and the striatum (Crowe and Blair2008; Prencipe et al. 2011).

Another important explanatory model, that is more fittingwith a cool EF deficit, was proposed by Moffitt (1993), whodistinguished between adolescent-limited ODD/CD, and themore severe, life-course persistent ODD/CD (Moffitt 1993).According to that model, adolescent-limited ODD/CD ismerely a stage in development during which adaptive socialbehaviour is tested and learned, while life-course persistentODD/CD is thought to arise of an interplay between a difficultand under-controlled temperament and adverse environmentalfactors. This under-controlled temperament is thought to bepromoted by a deficit in cool EF, including difficulties ininhibition and self-control (Burke et al. 2002; Loeber et al.2008; Moffitt 1993). Evidence from neurocognitive studiesgenerally points toward a range of abnormalities in cool EFin ODD/CD, such as low IQ, inefficiencies in problem solv-ing, and less than optimal inhibitory control (Oosterlaan et al.1998; Burke et al. 2002; Loeber et al. 2008; Quay and Hogan1999, but see Van Goozen et al. 2004), and have been relatedto abnormalities in the dorsolateral prefrontal cortex and cer-ebellum (Yang and Raine 2009; Prencipe et al. 2011).

Finally, one of the most influential explanatory models atpresent is proposed by Blair, who suggests that individualswith ODD/CD demonstrate impairments in two separate cir-cuits associated with hot and cool EF (Blair 2005). Accordingto Blair (2005), the first compromised circuit is involved inemotional processing and regulation and is responsible for anincrease in antisocial behaviour. The key component of brainareas underlying this mainly hot EF circuit is supposedly theamygdala. The second compromised circuit is involved inresponse inhibition and is responsible for loss of temper andexaggerated aggressive responses in individuals with ODD/CD. The key component of brain areas underlying this mainlycool EF circuit is supposedly the ventrolateral frontal cortex.

Support for the explanatory models on ODD/CD is wellestablished in behavioural studies. However, knowledgeabout these models in terms of structural and functional neu-roimaging is incomplete. While a review of the current struc-tural and functional neuroimaging literature would be an idealway to provide neurobiological evidence to confirm or reject amodel, such a review has not been conducted so far. Thecurrent review aims to fill this gap with the goal to enhanceinsight into the underlying mechanisms of ODD/CD and ad-ditionally test the plausibility of hot and cool EF models inODD/CD in terms of neural mechanisms.

A highly comorbid condition of ODD/CD is attention-deficit hyperactivity disorder (ADHD), one of the most com-monly diagnosed disruptive behaviour disorders in children.The percentage of individuals diagnosed with ODD/CD thatadditionally qualify for a comorbid ADHD diagnosis rangesup to 35 %, and up to 50 % of children with disruptive behav-iours show symptoms of both ADHD and ODD/CD (Loeber

et al. 2000; Anderson and Kiehl 2013; Connor et al. 2010;Waschbusch 2002). In children and adolescents with ODD/CD and comorbid ADHD, the prognosis, including the risk todevelop anxiety and depressive disorders and antisocial per-sonality disorder, is considerably worse than when only ODD/CD or only ADHD is present (Dolan and Lennox 2013;Loeber et al. 2000). In addition, this comorbid group showsan earlier age of symptom onset, exhibits more physical ag-gression and delinquency, shows significantly higher ODD,CD and ADHD symptom severity, and shows more functionalimpairments than a group with any of these diagnoses in sin-gularity (Anderson and Kiehl 2012; Loeber et al. 2000;Waschbusch 2002). This highlights the importance of clarify-ing the specificity of abnormalities associated with ODD/CDand contrasting ODD/CD-only with ODD/CD+ADHD, whenstudying these disorders.

Although previous reviews have addressed structural andfunctional brain abnormalities in ODD/CD (Matthys et al.2013; Rubia 2011), these reviews were neither systematic re-views, nor focussed exclusively on diagnostic groups ofODD/CD, nor were set out to investigate the relative contri-bution of ADHD. To address structural and functional brainanatomical aspects of ODD/CD, the current comprehensivereview includes a complete systematic narrative review aswell as meta-analyses using ALE (Eickhoff et al. 2009,2012; Laird et al. 2005) of the available structural and func-tional imaging studies. The quantitative approach increasesthe precision and the power of reported results compared toa purely qualitative review, and indicates which brain areas aremost robustly implicated in ODD/CD. However, since anALE meta-analysis does not allow inclusion of studiesreporting on non-significant group differences, the narrativereview provides the necessary balance in interpreting the find-ings. The narrative review complied with the standards of asystematic review, performing a literature search based on adetailed plan and search strategy, and had the goal of reducingbias by identifying, appraising and synthesising all relevantstudies on this topic. In addition, we investigated the specific-ity of brain correlates. Firstly, we investigated specificity bydiscussing results from studies using ODD/CD-only samplesseparately from results from studies using ODD/CD+ADHDsamples. Secondly, we compared results of samples includingindividuals with ODD/CD (with and without comorbidADHD) to samples including individuals with ADHD-only.In addition, we reported associations between abnormalities ininvestigated structures and ODD/CD related symptoms.Knowledge about the specificity of reported abnormalitiesmay help to clarify the heterogeneity in studies on ODD/CD.

This review is divided in two sections. The first sectiondeals with structural findings, integrating findings for all re-ported brain areas; the second section deals with functionalfindings, and is divided in a part describing hot EF and asubsequent part describing cool EF, based on the assessed

46 Neuropsychol Rev (2016) 26:44–72

tasks and contrasts. Each section starts with a quantitativemeta-analysis, for which an activation likelihood estimation(ALE) meta-analysis was performed. ALE is a technique thatis used to identify significant anatomical locations for whicheffects are consistent, and that is robust to publication bias (fora detailed description of ALE see: Eickhoff et al. 2009; Lairdet al. 2005; Eickhoff et al. 2012). This quantitative meta-analysis is followed by a narrative review. Then, both thesections on structural and functional findings are integratedto provide a complete overview of all involved brain areasand to assess the evidence for abnormalities in terms of hotand cool EF related brain areas. We expected to find abnor-malities in brain structure and function of individuals withODD/CD subserving both hot EF (i.e., the amygdala, anteriorcingulate cortex, insula, and orbitofrontal cortex (Rubia 2011;Prencipe et al. 2011; Crowe and Blair 2008)) and cool EF (i.e.the dorsolateral prefrontal cortex and cerebellum (Rubia 2011;Prencipe et al. 2011; Yang and Raine 2009; Sterzer and Stadler2009)), which would be in line with an integrated model suchas the model proposed by Blair.

Methods

Study Selection

This review included all empirical studies that met the follow-ing inclusion criteria: (1) the study reported on functional orstructural magnetic resonance imaging results, comparing (a)individuals with ODD/CD with or without comorbid ADHDto control subjects, and if included, to individuals withADHD-only, or (b) individuals with ODD/CD withoutADHD to ODD/CD individuals with ADHD. The controlgroup of each study was carefully checked on reported psy-chiatric disorders, and when a study reported on the presenceof any psychiatric disorder in participants of the control group,that study was excluded from the current study. This resultedin the exclusion of two studies. (2) Diagnosis of the partici-pants had to be based onDSM-III, DSM-IVor DSM-5 criteria.(3) The study had to be published in a peer-reviewed Englishlanguage journal. No limits were set on the ages of partici-pants. All relevant studies published up till June 2015 wereincorporated.

The databases PubMed, EMBASE, PsycInfo and Web ofScience were searched, using the search terms ODD, CD,disruptive behavioural disorder, disruptive behaviour,externalising behavioural disorder, externalising behaviour,MRI, neuroimaging, and equivalent MeSH terms.Furthermore, reference lists of selected studies and reviewswere checked for additional relevant studies. A total of 576studies were initially retrieved and screened, after which atotal of 67 studies remained that fulfilled inclusion criteriabased on screening of the title and abstract. These 67 studies

were further assessed for eligibility using the full text of thestudy, resulting in 29 studies that met inclusion criteria andwere incorporated in the present review; see Fig. 1 for the flowdiagram of included studies. The 29 studies selected for re-view included a total of 1278 individuals, including 713 pa-tients and 565 controls.

In this review, we distinguished the following samples: (1)ODD/CD-only, including only individuals with ODD/CDwithout comorbid ADHD, (2) ODD/CD-mixed, includingboth individuals with ODD/CD-only and individuals withODD/CD+ADHD, and (3) ODD/CD+ADHD, including onlyindividuals classifying for both ODD/CD and ADHD. Weincluded a total of 10 ODD/CD-only studies (7 structural, 3functional), 14 ODD/CD-mixed studies (9 structural, 5 func-tional), and 5 ODD/CD+ADHD studies (1 structural, 4 func-tional). By differentiating between these three samples, it waspossible to discern whether an abnormality was related toODD/CD and not confounded by comorbid ADHD, whichwould be suggested when an abnormality is found in anODD/CD-only sample. Alternatively, when an abnormalityis found in an ODD/CD-mixed or ODD/CD+ADHD sample,it may be possible that the abnormality is also related to co-morbid ADHD. Therefore, results are discussed separately forODD/CD-only samples versus controls and for ODD/CD-mixed and ODD/CD+ADHD samples versus controls.When included in a study, results from additional comparisonswith an ADHD-only sample were provided.

The section on structural neuroimaging findings reports allbrain areas, not distinguishing between hot and cool EF. Thesection on functional neuroimaging findings is divided in twoparts: the first part is focused on hot EF and the second part isfocused on cool EF. Classification of studies as hot or coolwas done in line with the literature. Two authors independent-ly inspected the task characteristics and the reported contrastsfor each study and judged these as assessing either hot or coolEF. In case of disagreement, the third author was consulted,resulting in full agreement on all studies. One study (Rubia etal. 2009b) targeted both hot and cool EF and we thereforediscussed this study in both parts of the fMRI results. Afterpresentation of the meta-analytic and narrative results of thestructural and functional studies, findings are integrated forstructural and functional studies in order to provide an over-view of all relevant literature and resulting conclusions interms of hot and cool EF related brain areas.

Meta-analysis: Activation Likelihood Estimation

For the quantitative meta-analysis, an activation likelihoodestimation (ALE) meta-analysis was performed using theBrainmap GingerALE software package (Eickhoff et al.2009, 2012; Laird et al. 2005). For the ALE meta-analysis tobe reliable, the minimum number of studies to be included isfive (www.brainmap.org). The algorithm used by GingerALE

Neuropsychol Rev (2016) 26:44–72 47

applies a random-effects approach to identify anatomical lo-cations for which effects are observed most consistently, andwhich renders it robust for the possible effects of publicationbias (Fox et al. 1998). Analyses were performed separately forthe structural and the functional studies, and for the functionalstudies these were performed separately for studies on hot andon cool EF. Studies eligible for inclusion in the meta-analysiswere additionally required to report x/y/z coordinates for clus-ters showing group differences in volume (structural MRI) oractivity (functional MRI) in either Montreal NeurologicalInstitute (MNI) or Talairach space.

All coordinates originally reported in MNI space were nor-malised to Talairach space using Lancaster’s Transform; co-ordinates which were already in Talairach space were convert-ed back to MNI coordinates and subsequently normalised toTalairach space using Lancaster’s Transform, to account fordivergent analyses procedures and minimise differences incoordinates between studies (Lancaster et al. 2007; Laird etal. 2010). The 2.3.1 version of GingerALE (Eickhoff et al.2009) was applied in the current study and used the coordi-nates of the reported voxels of each study, referring to theareas that showed a group difference, as a probability distri-bution to create an ALE distribution map (Turkeltaub et al.2002; Eickhoff et al. 2009, 2012). Results across studies wereaggregated by GingerALE, and modelled activation maps

were generated by calculating the probability that a particularvoxel was activated as the union of probabilities for that voxelacross studies. The contribution of each study to the meta-analytic result was weighted using the study’s sample size,by widening the Gaussian distribution for a voxel with smallersamples to compensate for spatial uncertainty. Meta-analyticmaps were generated by combining all the modelled activa-tions maps, and were subsequently corrected for multiplecomparisons using Family Wise Error correction. This en-sured that differences between studies in terms of the numberof areas showing significant group differences (e.g., due toapplying a lower statistical threshold), did not influence thecombined ALE map (Turkeltaub et al. 2012). This combinedALEmap was then compared to a map from a null distributionwith the same number of foci, but now randomly placedthroughout the grey matter of the brain. After this, the finalALE map was thresholded at p< .05 using a False DiscoveryRate (FDR) correction for multiple comparisons, and a mini-mum cluster size of 100 mm3 (see www.brainmap.org/ale/).

Both studies using a region of interest (ROI) approach, thusa hypothesis driven pre-selection of specific brain areas, andstudies using a whole brain analyses (WBA) approach, thusstudying the entire brain, were included in this review. To testthe possibility that studies using an ROI approach might biasmeta-analytic results due to less stringent statistical criteria,

Fig. 1 PRISMA flow diagramshowing the process of studyselection

48 Neuropsychol Rev (2016) 26:44–72

the resulting map of all studies (using both WBA and ROIapproach) was compared to the resulting map from studieswith a WBA approach. When differences between the mapswere present, results from the map including only the WBAstudies were reported. The ALE map was overlaid onto aTalairach anatomical template for visualisation purposes, andthe areas reported in our Results section refer to the locationsof the extrema.

Results

Results of the reviewed studies are discussed in two mainsections with the first section summarising the structural neu-roimaging findings and the second section summarising thefunctional neuroimaging findings. Both sections start with ageneral overview of all included studies, after which the re-sults from the meta-analysis are reported, followed by theresults from the narrative review. The narrative parts containa summary of the main findings for ODD/CD-only groupsfirst since those are not biased by comorbid ADHD, followedby the main findings in ODD/CD-mixed and ODD/CD+ADHD groups, and ends with the correlational findings andthe specificity of findings regarding ODD/CD.

After presentation of the meta-analytic and narrative resultsof the structural and functional studies, structural and func-tional findings are integrated in order to provide an overviewof all relevant literature and resulting conclusions in terms ofhot and cool EF related brain areas. Since an ALE meta-analysis cannot include studies that reported on non-significant group differences, but rather identifies anatomicallocations for which effects are observed most consistently,findings from the ALE meta-analysis are combined with theresults of the narrative review to provide a comprehensive andbalanced overview of available evidence.

Structural Neuroimaging Findings

General Overview Table 1 shows a total of 12 studies thatinvestigated structural differences in individuals with ODD/CD-only (three studies), ODD/CD-mixed (five studies), orODD/CD+ADHD (four studies) compared to controls. All12 studies usedWBA to investigate regional brain differences,while three studies additionally used an ROI approach(Fairchild et al. 2011, 2013a; Sterzer et al. 2007). Two of thesestudies also reported on results of contrasts between ODD/CD(with and without comorbid ADHD) and ADHD-only. In ad-dition, seven studies investigated the association betweenbrain region volumes and symptom counts of ODD/CD(Sterzer et al. 2007; Huebner et al. 2008; Fahim et al. 2011;Fairchild et al. 2011, 2013a; Stevens and Haney-Caron 2012;Michalska et al. 2015).

All studies investigated children/adolescents. For informa-tion regarding group and study characteristics of the includedstudies, see Table 1. Reported differences in brain structuresare bilateral, unless reported to be either left or right sided.Results are reported from WBA approaches, unless specifiedto be the result of ROI based analyses, see Table 1.

Structural ALE Meta-analysis Eight structural studies, allusing aWBA approach, reported coordinates and were includ-ed in the meta-analysis (studies marked with a in Table 1). Dueto the limited number of studies in ODD/CD-only (three stud-ies) it was not possible to perform an ALE meta-analysis onstudies comparing ODD/CD-only groups and controls (mini-mum number of studies required is five). Hence, the ALEmeta-analysis was performed on all ODD/CD samples, there-with including both individuals with and without comorbidADHD. Total sample sizes for all included studies rangedbetween 24 and 90 individuals, adding up to a total of 415individuals, of which 267 were patients and 148 were controls(age range 8–21 years). Five studies used a full male sample,two studies used a sample consisting of 71 % males and onestudy used a full female sample. These studies provided a totalof 58 foci of grey matter volume abnormalities in individualswith ODD/CD with and without comorbid ADHD.

The ALE analysis revealed four significant clusters of al-tered grey matter volumes that differed between patients andcontrols (see Fig. 2 for visualisation). The largest cluster(760 mm3) was located in the left amygdala, with three fociinside this cluster. A second cluster (456 mm3) was found inthe left insula, containing three foci. A third cluster (352 mm3)was located in the left medial/superior frontal gyrus, contain-ing two foci. The fourth cluster (216 mm3) was located in theright insula, containing two foci.

Narrative Review Table 1 provides an overview of investi-gated samples and approach (WBA or ROI) and summarizesthe findings of the 12 studies reporting on sMRI. Total samplesizes for all included studies ranged between 20 and 111 indi-viduals, adding up to a total of 643 individuals, including 334patients and 309 controls (age range 6–21 years). The samplesconsisted predominantly of males, with five studies using afull male sample, six studies using a sample largely consistingof males (ranging from 48 to 90%), and one study using a fullfemale sample.

ODD/CD-only versus controls (3 studies). For total greymatter volume, one of three studies reported a reduction in theODD/CD-only group. In terms of regional grey matter vol-umes, abnormalities in the insula (left and bilateral), amygdala(left and bilateral), the cingulate cortex (left and paracentral),the inferior frontal gyrus (left and right), and the leftdorsomedial prefrontal cortex were repetitively reported (twoout of three studies).

Neuropsychol Rev (2016) 26:44–72 49

Tab

le1

Summaryof

studycharacteristicsandresults

forstructuralim

aging

Study

Total

sample

size

(%male/

female)

Num

berof

subjects(specified

pergroup)

Age

(years,

rangeor

M(SD))

Analysismethod

Resultsof

comparisons

betweenODD/CD-onlyandcontrolg

roup,

betweenODD/CD+ADHDandcontrolg

roup,and

betweenODD/CD-

mixed

andcontrolg

roup.

(brain

regionsreported

show

reducedvolumes

inthepatient

group,

unless

otherw

isereported)

ODD/

CD

-only

ODD/

CD+

ADHD

ODD/CD-

mixed

ADHD-

only

Controls

Amygdala

Insula

Prefrontal

cortex

Other

1.Fahim

etal.2011a

,d47

c

(100

%male)

22N/A

N/A

N/A

25Patients:8.4

(0.10)

Controls:8.4

(0.07)

Wholebrain(V

BM,

corticalthickness)

Correlationalanalyses

nsBilateral

Left dorsom

edial

ODD/CD-onlyversus

controls:

VBM:L

eftm

edialfrontalcortex

/claustrum,right

inferior

frontal

cortex/in

ferior

parietalcortex

Corticalthickness:leftinsula,left

cingulate,leftanterior

cingulate,

leftmedialfrontal,leftrectal/

orbitofrontal,leftuncus,left

precuneus,rightm

iddlefrontal,

rightsuperiortemporal,right

posteriorcingulate

ODD/CD-onlyversus

controls:

VBM:N

egativecorrelation

betweenrightsuperiortemporal

cortex,leftsuperiorfrontal

gyrus,righto

ccipitalcortexand

leftprecuneusvolumeand

ODD/CDsymptom

severity

2.Fairchild

etal.2011a

,d90

(100

%male)

63N/A

N/A

N/A

2716–21

ROI;am

ygdala,insula,

anterior

cingulate

cortex,orbitofrontal

cortex

(VBM)

Wholebrain

(VBM)

Correlationalanalyses

Bilateral

(ROI)

Left(ROI)

Left dorsom

edial

ODD/CD-onlyversus

controls:

Bilateralcaudate,leftfusiform

gyrus,leftinferior

and

superior

occipitalcortex

ODD/CD-onlyversus

controls:

Negativecorrelationbetween

rightinsulaandCDsymptom

s

3.Stevensand

Haney-Caron

2012

a,d

72(71%

male)

24N/A

N/A

2424

12–18

Wholebrain(V

BM)

Correlationalanalyses

Left

nsns

ODD/CD-onlyversus

controls:

Leftinferiorfrontal,right

inferior/m

iddlefrontal,right

parahippocam

pal/fusiform

,paracentralcingulate

ODD/CD-onlyversus

controls:

Positiv

ecorrelationbetween

bilateralamygdala,bilateral

temporalcortexandright

lateralo

rbito

frontalv

olum

eandODD/CDsymptom

severity

4.Bussing

etal.2002

31 (74% male)

N/A

12N/A

N/A

198–12

Wholebrain(V

BM)

nsns

nsODD/CD+ADHDversus

controls:

Leftand

totalp

osterior

superior

verm

is,leftand

totalp

osterior

inferior

verm

is

5.Kruesi

etal.2004

20b,c

(90% male)

N/A

10N/A

N/A

10Patients:16.1

(3.6)

Controls:

15.9

(3.2)

Wholebrain(V

BM)

nsns

nsODD/CD+ADHDversus

controls:

Right

temporallobe

6.Sterzer

etal.2007a

,d24 (100

%male)

N/A

N/A

12 (5ODD/

CD-

only)

N/A

12Patients:12.8

(0.49)

Controls:12.5

(0.45)

ROI:am

ygdala,anterior

insula,anteriorcingulate

cortex,orbitofrontal

cortex

(VBM)

Left (ROI)

Bilateral

(ROI)

nsns ODD/CD-m

ixed

versus

controls:

Negativecorrelationbetweenleft

amygdalaandbilateralinsula

50 Neuropsychol Rev (2016) 26:44–72

Tab

le1

(contin

ued)

Study

Total

sample

size

(%male/

female)

Num

berof

subjects(specified

pergroup)

Age

(years,

rangeor

M(SD))

Analysismethod

Resultsof

comparisons

betweenODD/CD-onlyandcontrolg

roup,

betweenODD/CD+ADHDandcontrolg

roup,and

betweenODD/CD-

mixed

andcontrolg

roup.

(brain

regionsreported

show

reducedvolumes

inthepatient

group,

unless

otherw

isereported)

ODD/

CD

-only

ODD/

CD+

ADHD

ODD/CD-

mixed

ADHD-

only

Controls

Amygdala

Insula

Prefrontal

cortex

Other

Wholebrain(V

BM)

Correlationalanalyses

volumeandODD/CDsymptom

severity

(ROI)

7.McA

lonan

etal.2007a

,d59

a,c

(100

%male)

N/A

28N/A

N/A

316–13

Wholebrain(V

BM)

nsns

nsODD/CD+ADHDversus

controls:

Midlinecerebellum,right

globus

pallidus,rightm

iddlefrontal

gyrus,rightsuperiorfrontal

gyrus,rightp

recuneus,left

inferior

parietalgyrus,left

superior

occipitalg

yrus

8.Huebner

etal.2008a

,d46

c

(100

%male)

N/A

N/A

23 (6ODD/

CD-

only)

N/A

2312–17

Wholebrain(V

BM)

Correlationalanalyses

Left

nsns

ODD/CD-m

ixed

versus

controls:

Greymatter,bilateralinferior

temporallobes,left

hippocam

pus,leftorbitofrontal

gyrus

Increasedbilateralcerebellar

volumein

ODD/CD-m

ixed

group

ODD/CD-m

ixed

versus

controls:

Negativecorrelationbetween

bilateralamygdalavolumeand

ODD/CDsymptom

severity

9.Sasayama

etal.2010a

,d35 (71% male)

N/A

10N/A

817

6–16

Wholebrain(V

BM)

Left

nsns

ODD/CD+ADHDversus

controls:

Bilateraltem

porallobes,bilateral

occipitallobes

10.F

airchild

etal.2013a

,d42

b,e (100

%female)

N/A

N/A

22 (203O

DD/

CD-

only)

N/A

2014–20

ROI;am

ygdala,anterior

insula,striatum,anterior

cingulatecortex,

orbitofrontalcortex

(VBM)

Wholebrain

(VBM)

Correlationalanalyses

nsBilateral

(ROI)

Right dorsolateral

ODD/CD-m

ixed

versus

controls:

Right

(ventral)striatum

(ROI),

righto

rbito

frontalcortex(ROI),

leftprecentralgyrus,rightm

id-

occipitalcortex,rightinferior

frontalg

yrus,leftp

recuneus,

middletemporalg

yrus

ODD/CD-m

ixed

versus

controls:

Negativecorrelationbetween

bilateralinsulavolumeand

psychopathictraits(ROI),

negativecorrelationbetween

both

bilateralinsulaandleft

striatum

volumeandcallous-

unem

otionaltraits

(ROI),

positivecorrelationbetween

bilateralm

iddle/superior

orbitofrontalcortexand

callous-unemotionaltraits

(ROI).

11.H

ummer

etal.2015

66c

1419

33N/A

3313–17

Wholebrain

(VBM)

nsns

nsns

Neuropsychol Rev (2016) 26:44–72 51

Tab

le1

(contin

ued)

Study

Total

sample

size

(%male/

female)

Num

berof

subjects(specified

pergroup)

Age

(years,

rangeor

M(SD))

Analysismethod

Resultsof

comparisons

betweenODD/CD-onlyandcontrolg

roup,

betweenODD/CD+ADHDandcontrolg

roup,and

betweenODD/CD-

mixed

andcontrolg

roup.

(brain

regionsreported

show

reducedvolumes

inthepatient

group,

unless

otherw

isereported)

ODD/

CD

-only

ODD/

CD+

ADHD

ODD/CD-

mixed

ADHD-

only

Controls

Amygdala

Insula

Prefrontal

cortex

Other

(73% male)

(14ODD/

CD-

only)

12.M

ichalska

etal.2015

111b

(48% male)

N/A

43N/A

N/A

689–11

Wholebrain

(VBM)

Correlationalanalyses

nsns

nsns ODD/CD+ADHDversus

controls:

Negativecorrelationbetweenleft

superior

temporalsulcus

volumeandCDsymptom

s

Groupsdidnotdifferinterm

sof

gender,IQ,orsocioeconom

icstatus,unlessstated

otherw

ise.ADHDAttentionDeficitHyperactiv

ityDisorder;CDConductDisorder;N/A

notapplicable;nsno

significant

results

arereported

forthisregion;O

DDOppositionalDefiant

Disorder;ROIregion

ofinterest;V

BM

voxel-basedmorphom

etry

aIncluded

nodataon

medication-useor

didnotadjustfor

effectsof

medication-use

bGroupsdiffered

onIQ

,orincluded

nodataon

IQcParticipantswith

held

stim

ulantm

edicationfor>24

hpriorto

scanning

dResultsincluded

inALEanalysis

eGroupsdiffered

onsocio-econom

icstatus

52 Neuropsychol Rev (2016) 26:44–72

ODD/CD-mixed and ODD/CD+ADHD (9 studies). Two ofthe four studies investigating total grey matter in ODD/CD-mixed and ODD/CD+ADHD samples reported smaller vol-umes in the diagnostic groups, compared to controls. In ac-cordance with results from the studies in the ODD/CD-onlygroup, three of the nine studies in ODD/CD-mixed and ODD/CD+ADHD groups provided support for abnormalities in theleft amygdala. Additionally, abnormal volumes were reportedin the ODD/CD-mixed and ODD/CD+ADHD groups forstructures that were not found for ODD/CD-only groups,which might indicate that these abnormalities reflect the pres-ence of comorbid ADHD rather than ODD/CD. These struc-tures with smaller volumes were the temporal lobe (four out ofnine studies: one left, one right, two bilateral) and the cerebel-lum (three out of nine studies: one left, two bilateral).

Correlational findings and specificity. A total of sevenstudies investigated relations between grey matter abnormali-ties and ODD/CD symptoms. Three out of seven studies re-ported associations for the amygdala, insula and temporal cor-tex. The three studies that reported associations between theamygdala and ODD/CD symptoms, showed either a positiveassociation (thus a larger volume related to more ODD/CDsymptoms) for the amygdala in an ODD/CD-only sample, ornegative associations (thus a smaller volume related to moreODD/CD symptoms) for the bilateral or left amygdala inODD/CD-mixed samples. For the insula, all three studies re-ported negative associations, one between the right insula andODD/CD symptoms in an ODD/CD-only sample and twobetween the insula and ODD/CD symptoms in ODD/CD-mixed samples. For the three studies that found associationsbetween the superior temporal cortex and ODD/CD symp-toms, one study reported a positive association for the superior

temporal cortex in an ODD/CD-only sample, while the othertwo studies reported a negative association for the right supe-rior temporal cortex in an ODD/CD-only sample and for theleft superior temporal cortex in an ODD/CD+ADHD sample.

In terms of specificity of abnormalities for ODD/CD ascompared to ADHD, one study reported grey matter reduc-tions in the amygdala and frontal gyrus to be specific forODD/CD-only, since these were not present in the ADHD-only group. In addition, another study looked at disorder spec-ificity by covarying for ODD/CD in an ODD/CD-mixedgroup and reported that the grey matter reductions in theamygdala turned non-significant, suggesting that these greymatter reductions were specific for ODD/CD.

Structural Summary Combining the results from the meta-analysis and the narrative review, structural neuroimagingstudies most consistently implicated abnormalities of the leftamygdala, insula and left frontal gyrus in ODD/CD.

Functional Neuroimaging Findings

General Overview Tables 2 and 3 shows a total of 17 studiesthat investigated brain activity correlates in individuals withODD/CD-only (seven studies), ODD/CD-mixed (nine studies),or ODD/CD+ADHD (one study) compared with typically de-veloping individuals. Of the 17 included studies, 14 conducted aWBA approach to investigate regional brain differences, ofwhich 5 also conducted ROI analyses (S.F. White et al. 2013;Finger et al. 2011; Herpertz et al. 2008; Passamonti et al. 2010;Cohn et al. 2014). In three studies only ROI analyses werereported (Gatzke-Kopp et al. 2009; Marsh et al. 2008; Sterzeret al. 2005). Seven studies investigated the association between

Fig. 2 Results of the structuralALE meta-analysis showing theclusters in left amygdala, insula,and left medial/superior frontalgyrus (pcorrected < 0.05)superimposed on a structural scanin Talairach space. Top row: cor-onal view, bottom row: axial view.L Left, R Right

Neuropsychol Rev (2016) 26:44–72 53

Tab

le2

Summaryof

studycharacteristicsandresults

forfunctio

nalimaging–Hot

EF

Study

Totalsam

ple

(%male/female)

Num

berof

subjects(specified

pergroup)

Age

(years,

rangeor

M(SD))

Analysismethod

Task

andconditions

Resultsof

comparisons

betweenODD/

CD-onlyandcontrolg

roup,between

ODD/CD+ADHDandcontrolg

roup,

andbetweenODD/CD-m

ixed

and

controlg

roup.(brainregionsreported

show

reducedvolumes

inthepatient

group,unless

otherw

isereported)

ODD/

CD-

only

ODD/

CD+

ADHD

ODD/CD

-mixed

ADHD-

only

Controls

13.R

ubia

etal.

2009ba

,b

48c,d (100

%male)

14N/A

N/A

1816

9–16

Wholebrain

Contin

uous

Perform

ance

Task

-Rew

ard

-Non-rew

ard

ODD/CD-onlyversus

controls:

Behavioural:N

osignificantg

roup

differences,allg

roupsshow

edequally

enhanced

performance

asa

resultof

reward(versusnon-reward

trials)

Rew

ard>non-reward:

reducedactiv

ityin

rightlateralandmedial

orbitofrontalcortex

14.K

alnin

etal.2011

44c,d,e

(59%

male)

22N/A

N/A

N/A

2213–17

Wholebrain

EmotionalS

troop

task

-Violent

words

-Non-violent

words

ODD/CD-onlyversus

controls:

Behavioural:N

osignificantg

roup

differences

Nosignificantg

roup

differences

15.M

arsh

etal.2013a

35c,d,f

(66%

male)

14N/A

N/A

N/A

2110–17

Wholebrain

Correlatio

nal

analyses

Viewingof

pictures

with

threepain

intensities

(severe/

mo-derate/none)

during

two

conditions:pain

appliedto

subject

him/herselfor

tosomeone

else

ODD/CD-onlyversus

controls:

Behavioural:N

osignificantg

roup

differences

Group

differences

forthemaineffectof

pain

view

ing:

reducedactiv

ityin

left

medialfrontalgyrus,rostralanterior

cingulatecortex,right

putamen

Other’spain

<ow

npain:reduced

activ

ityin

leftam

ygdala/uncus,left

superior

frontalg

yrus,right

insula

ODD/CD-onlyversus

controls:

Negativecorrelationbetweenleft

amygdalaactiv

ationandaggressive

behaviour,negativ

ecorrelation

betweenleftanterior

cingulatecortex

activ

ationandaggressive

behaviour

16.S

terzer

etal.2005

27d,f (100

%male)

N/A

N/A

13 (5ODD/

CD-only)

N/A

149–15

ROI:am

ygdala,

hippocam

pus,

orbitofrontal

cortex,anterior

cingulate

cortex

Correlatio

nal

analyses

Passiveview

ingtask

ofneutraland

negativ

epictures.

ODD/CD-m

ixed

versus

controls:

Behavioural:low

ered

arousalratings

fornegativ

epictures

andlowered

valenceandarousalratings

for

neutralp

icturesin

theCD-m

ixed

groupcomparedto

controls

Negative>neutralp

ictures:reduced

activ

ityin

leftam

ygdala(ROI),right

dorsalanterior

cingulate(ROI)

54 Neuropsychol Rev (2016) 26:44–72

Tab

le2

(contin

ued)

Study

Totalsam

ple

(%male/female)

Num

berof

subjects(specified

pergroup)

Age

(years,

rangeor

M(SD))

Analysismethod

Task

andconditions

Resultsof

comparisons

betweenODD/

CD-onlyandcontrolg

roup,between

ODD/CD+ADHDandcontrolg

roup,

andbetweenODD/CD-m

ixed

and

controlg

roup.(brainregionsreported

show

reducedvolumes

inthepatient

group,unless

otherw

isereported)

ODD/

CD-

only

ODD/

CD+

ADHD

ODD/CD

-mixed

ADHD-

only

Controls

ODD/CD-m

ixed

versus

controls:

Negativecorrelationbetweenboth

left

amygdalaandrightanteriorcingulate

cortex

activ

ationandaggressive

behaviour(negativeversus

neutral

contrast)

17.H

erpertz

etal.2008a

57e

(100

%male)

N/A

N/A

22 (6ODD/

CD-only)

1322

12–17

ROI:am

ygdala,

anterior

cingulate

cortex,

orbitofrontal/

medialfrontal

cortex,insula

Wholebrain

Passiveview

ingtask

Includingpositiv

e,negativ

e,neutral

pictures

ODD/CD-m

ixed

versus

controls:

Behavioural:C

D-m

ixed

evaluated

negativ

eandpositiv

epictures

asless

arousing,and

positiv

epictures

asless

pleasant

comparedto

controls

Negative>neutralp

ictures:increased

activ

ityin

leftam

ygdala(ROI)

18.F

inger

etal.2008a

42c,d,e(67%

male)

N/A

N/A

14 (4ODD/

CD-only)

1414

10–17

Wholebrain

Rew

ardedreversal

learning

Task

-Pu

nished

reversal

errors

-Correctrewarded

responses

ODD/CD-m

ixed

versus

controls:

Behavioural:N

osignificantg

roup

differences

Group

differences

foroverallresponse

type

(rew

ardandpunishment):

increasedactiv

ityin

leftprecuneus,

rightsuperiorfrontalg

yrus

Punishedreversal

errors

>correct

rewardedresponses:increased

activ

ityin

ventromedialp

refrontal

cortex,right

caudate

19.M

arsh

etal.2008

36e

(58%

male)

N/A

N/A

12 (5ODD/

CD-only)

1212

10–17

ROI:am

ygdala

Correlatio

nal

analyses

Implicitprocessing

task:categorise

gender

offearful,

angry,andneutral

faces

ODD/CD-m

ixed

versus

controls:

Behavioural:N

osignificantg

roup

differences

Fearful

>neutralp

ictures:reduced

activ

ityin

bilateralamygdala(ROI)

ODD/CD-m

ixed

versus

controls:

Negativecorrelationbetween

connectiv

itybetweenam

ygdalaand

rightv

entrom

edialp

refrontalcortex,

andODD/CDsymptom

severity

20.G

atzke-

Kopp

etal.2009

30d,e

(100

%male)

N/A

N/A

19 (3ODD/

CD-only)

N/A

1112–16

ROI:anterior

cingulate

cortex,

Monetaryincentive

task

-Rew

ard

ODD/CD-m

ixed

versus

controls:

Behavioural:N

osignificantg

roup

differences

Neuropsychol Rev (2016) 26:44–72 55

Tab

le2

(contin

ued)

Study

Totalsam

ple

(%male/female)

Num

berof

subjects(specified

pergroup)

Age

(years,

rangeor

M(SD))

Analysismethod

Task

andconditions

Resultsof

comparisons

betweenODD/

CD-onlyandcontrolg

roup,between

ODD/CD+ADHDandcontrolg

roup,

andbetweenODD/CD-m

ixed

and

controlg

roup.(brainregionsreported

show

reducedvolumes

inthepatient

group,unless

otherw

isereported)

ODD/

CD-

only

ODD/

CD+

ADHD

ODD/CD

-mixed

ADHD-

only

Controls

caudate,

putamen

-Non-rew

ard

Non-rew

ard>reward:

reducedactiv

ityin

bilateralanteriorcingulate(ROI)

increasedactiv

ityin

bilateralstriatum

(caudate)(ROI)

21.P

assamonti

etal.2010a

75 (100

%male)

N/A

N/A

52 (43ODD/

CD-only)

N/A

2316–21

ROI: ventromedial

prefrontal

cortex,

amygdala,

insula,

orbitofrontal

cortex

Wholebrain

Correlatio

nal

analyses

Implicitprocessing

task:categorise

gender

ofangry,

sadandneutral

faces

ODD/CD-m

ixed

versus

controls:

Behavioural:N

osignificantg

roup

differences

Angry

>neutralp

ictures:reduced

activ

ityin

bilateralamygdala(ROI),

leftinsula(ROI),right

ventromedial

prefrontalcortex

(ROI),b

ilateral

dorsolateralprefrontalcortex,

bilaterald

orsomedialp

refrontal

cortex,bilateralo

rbito

frontalcortex

(ROI),right

inferior

parietalcortex,

bilateralinferiortemporalg

yrus,left

fusiform

gyrus,rightm

iddle

temporalg

yrus,right

superior

temporalsulcus/gyrus,bilateral

thalam

us,leftp

utam

en,left

cerebellu

mSad>neutralp

ictures:reducedactiv

ityin

bilateralamygdala(ROI),

ventromedialp

refrontalcortex

(ROI),leftd

orsolateralp

refrontal

cortex,putam

en,right

cerebellu

m,

bilateralsuperiortemporalsulcus/

gyrus

ODD/CD-m

ixed

versus

controls:

Negativecorrelationbetweenright

amygdalaandCDsymptom

s(ROI),

negativ

ecorrelationbetween

ventromedialp

refrontalcortexand

CDsymptom

s(ROI),negative

correlationbetweenleftinsulaand

CDsymptom

s(ROI)

22.F

inger

etal.2011a

30f

(60%

male)

N/A

N/A

15N/A

15Patients:

14,1(1,8)

Passiveavoiding

learning

task

ODD/CD-m

ixed

versus

controls:

56 Neuropsychol Rev (2016) 26:44–72

Tab

le2

(contin

ued)

Study

Totalsam

ple

(%male/female)

Num

berof

subjects(specified

pergroup)

Age

(years,

rangeor

M(SD))

Analysismethod

Task

andconditions

Resultsof

comparisons

betweenODD/

CD-onlyandcontrolg

roup,between

ODD/CD+ADHDandcontrolg

roup,

andbetweenODD/CD-m

ixed

and

controlg

roup.(brainregionsreported

show

reducedvolumes

inthepatient

group,unless

otherw

isereported)

ODD/

CD-

only

ODD/

CD+

ADHD

ODD/CD

-mixed

ADHD-

only

Controls

(5ODD/

CD-only)

Controls:

13,2

(1,1)

ROI:am

ygdala,

orbitofrontal

cortex,striatum

Wholebrain

-Rew

ardedcorrecth

its-Pu

nished

commission

errors

Behavioural:O

DD/CD-m

ixed

made

morecommission

errorsthan

controlsduring

thelatelearning

phase(allsevenblocks

afterthefirst

block).

Overallresponse

type

(rew

ardand

punishment):reduced

activ

ityin

right

amygdala(ROI),bilateralsuperior

frontalg

yrus,leftinsula,rightm

edial

frontalg

yrus,leftm

iddlefrontal

gyrus,leftsuperior

parietallobule,

leftsuperior

temporalg

yrus,left

lingualgyrus,rightfusiform

gyrus,

leftcaudate(ROI),right

thalam

usRew

ardedcorrecth

its>punished

commission

errors:reducedactiv

ityin

righto

rbito

frontalcortex(ROI),

leftmiddlefrontalg

yrus,

parahippocam

palg

yrus

23.W

hite

etal.2013a

38c,d,f,g(Patients:

82%

maleControls:

56%

male)

N/A

N/A

20 (16ODD/C

D-on-

ly)

N/A

18Patients:

15,2(2,0)

Controls:

14,9

(2,2)

ROI:am

ygdala,

ventromedial

prefrontal

cortex,caudate

Wholebrain

Passiveavoiding

learning

task

-Rew

ard

-Pu

nishment

ODD/CD-m

ixed

versus

controls:

Behavioural:a

smallerproportio

nof

the

ODD/CD-m

ixed

groupthan

ofthe

controlsshow

edan

association

betweenexpected

valueandchoice

behaviour

Receiving

rewarding

feedback

modulated

bypredictio

nerror:

reducedactiv

ityin

leftcaudate(ROI)

Receiving

punishingfeedback

modulated

bypredictio

nerror:

increasedactiv

ityin

leftcaudate

(ROI)

24.W

hite

etal.2014a

30d,f(Patients:73

%maleControls:

66%

male)

N/A

N/A

15 (8ODD/

CD-only)

N/A

1510–17

Wholebrain

Reinforcement

learning

task

-Rew

ard(appetitive

image)

-Pu

nishment

(aversiveim

age)

ODD/CD-m

ixed

versus

controls:

Behavioural:O

DD/CD-m

ixed

were

less

likelyto

avoidphysicalthreat,

butn

otcontam

inationthreat,stim

uli

than

controls

Neuropsychol Rev (2016) 26:44–72 57

Tab

le2

(contin

ued)

Study

Totalsam

ple

(%male/female)

Num

berof

subjects(specified

pergroup)

Age

(years,

rangeor

M(SD))

Analysismethod

Task

andconditions

Resultsof

comparisons

betweenODD/

CD-onlyandcontrolg

roup,between

ODD/CD+ADHDandcontrolg

roup,

andbetweenODD/CD-m

ixed

and

controlg

roup.(brainregionsreported

show

reducedvolumes

inthepatient

group,unless

otherw

isereported)

ODD/

CD-

only

ODD/

CD+

ADHD

ODD/CD

-mixed

ADHD-

only

Controls

Receiving

rewarding

feedback

modulated

bypredictio

nerror:

reducedactiv

ityin

rightinferior

parietalcortex

Receiving

punishingfeedback

modulated

bypredictio

nerror:

increasedactiv

ityin

rightinferior

parietalcortex

25.C

ohn

etal.2014a

68 (79%

male)

N/A

N/A

45 (18ODD/C

D-on-

ly)

N/A

2317,7(1,6)

ROI:am

ygdala,

ventral

striatum

,medial

prefrontal

cortex

Wholebrain

Correlatio

nal

analyses

Monetaryincentive

delaytask

-Rew

ard

-Neutral

-Loss

ODD/CD-m

ixed

versus

controls:

Behavioural:N

osignificantg

roup

differences

Rew

ardhit>

rewardmiss(rew

ard-

feedback):reducedactiv

ityin

right

ventralstriatum

(ROI)

Loss

miss>hit(loss-feedback):

increasedactiv

ityin

rightamygdala

(ROI)

ODD/CD-m

ixed

versus

controls:

Negativecorrelationbetweenleft

amygdalaandCUtraits(ROI)

Nocorrelationbetweenpsychopathic

traitsandneuralresponses

Participantsdidnotd

ifferin

term

sof

gender,IQ,orsocioeconomicstatus,unlessstated

otherw

ise.The

italic

text

describesthecontrastforwhich

theresults

arereported.

ADHDAttentionDeficitHyperactiv

ityDisorder;CDConductDisorder;N/A

notapplicable;O

DDOppositionalDefiant

Disorder;ROIregion

ofinterest

aResultsincluded

inALE

bStudyincluded

inboth

hotand

cool

EFnarrativereview

sections

cGroupsdiffered

ongender

dGroupsdiffered

onIQ

measures

eParticipantswith

held

stim

ulantm

edicationfor>24

hpriorto

scanning

procedure,or

didnotu

semedication

fParticipantsdidnotw

ithheld

stim

ulantm

edication,butadditionalanalysisdidnotshowan

effectof

medicationuseon

outcom

emeasures

gGroupsdiffered

onsocio-econom

icstatus

58 Neuropsychol Rev (2016) 26:44–72

Tab

le3

Summaryof

Study

CharacteristicsandResultsforFunctionalImaging–CoolE

F

Study

Totalsam

ple

(%male/female)

Num

berof

subjects(specified

pergroup)

Age

(years,

rangeor

M(SD))

Analysismethod

Task

andconditions

Resultsof

comparisons

between

ODD/CD-onlyandcontrolg

roup,

betweenODD/CD+ADHDand

controlg

roup,and

betweenODD/

CD-m

ixed

andcontrolg

roup.(brain

regionsreported

show

reduced

volumes

inthepatient

group,unless

otherw

isereported)

ODD/CD-

only

ODD/CD+

ADHD

ODD/CD-

mixed

ADHD-

only

Controls

26.R

ubia

etal.2008

48–53

(100

%male)

13–14

N/A

N/A

14–20

16–20

9–17

Wholebrain

Stop

Task

-Failedstop

-Successfulstop

-Go

ODD/CD-onlyversus

controls:

Behavioural:N

osignificantg

roup

differences

Failedstops>go

trials:reduced

activ

ityin

rightp

osterior

cingulategyrus,rightp

recuneus,

leftparietalcortex

Go>successful

stop

trials:reduced

activ

ityin

anterior

cingulate

gyrus,insula,caudate,putam

en,

thalam

us,leftsuperiortemporal

cortex,premotor

cortex

27.R

ubia

etal.2009a

Sim

onTask

-Successfulcongruent

-Successfulincongruent

-Successfulo

ddball

Behavioural:,ODD/CDmademore

errorscomparedto

controls,no

differencesbetweentheADHD-

only

groupandcontrols

Successful

incongruent>

successful

oddballtrials(interference

inhibitio

n):reducedactiv

ityin

rightm

iddleandsuperior

temporallobe,rightp

recuneus

13.R

ubia

etal.2009b

aContin

uous

Performance

-Non-rew

ard

-Non-target

Behavioural:N

osignificantg

roup

differences

Non-rew

ard>non-targettrials

(sustained

attention):reduced

activ

ityin

rightinsula,right

hippocam

pus,rightanterior

cingulatecortex,cerebellum,right

thalam

us,lefto

ccipitalg

yrus,left

posteriorcingulate,leftprecuneus

28.R

ubia

etal.2010

Correlatio

nalanalyses

(2outo

f4studies)

Switching

Task

-Switch

-Repeat

Behavioural:N

osignificantg

roup

differences,buto

verall

performance

was

poorer

during

thesw

itchtrialsthan

repeattrials

Group

differences

foroveralltask

performance:reducedactiv

ityin

rightinferiorparietallobe,right

Neuropsychol Rev (2016) 26:44–72 59

Tab

le3

(contin

ued)

Study

Totalsam

ple

(%male/female)

Num

berof

subjects(specified

pergroup)

Age

(years,

rangeor

M(SD))

Analysismethod

Task

andconditions

Resultsof

comparisons

between

ODD/CD-onlyandcontrolg

roup,

betweenODD/CD+ADHDand

controlg

roup,and

betweenODD/

CD-m

ixed

andcontrolg

roup.(brain

regionsreported

show

reduced

volumes

inthepatient

group,unless

otherw

isereported)

ODD/CD-

only

ODD/CD+

ADHD

ODD/CD-

mixed

ADHD-

only

Controls

precentralgyrus,left-superior

temporal/inferiorparietalcortex,

leftprecuneus,cuneus

ODD/CD-onlyversus

controls:

Negativecorrelationbetween

dorsolateralprefrontalcortex

and

conductp

roblem

s(1

study)

29.Z

huetal.2014

21b

(100

%male)

11N/A

N/A

N/A

1010–12

Wholebrain

GoS

topTask

-Com

pletetask

ODD/CD-onlyversus

controls:

Behavioural:O

DD/CD-onlyshow

edhigher

errorrateduring

response

inhibitio

nandalonger

stop

latency

Group

differences

foroveralltask

performance:reducedactiv

ityin

rightinferiorfrontalg

yrus,

increasedactiv

ityin

dorsolateral

partsof

bilateralinferiorfrontal

frontalg

yrus,leftm

iddlefrontal

gyrus,rightsuperiorfrontalg

yrus

Participantsdidnotd

ifferin

term

sof

gender,IQ,orsocioeconomicstatus,unlessstated

otherw

ise.The

italic

text

describesthecontrastforwhich

theresults

arereported.

ADHDAttentionDeficitHyperactiv

ityDisorder;CDConductDisorder;N/A

notapplicable;O

DDOppositionalDefiant

Disorder;ROIregion

ofinterest

aStudyincluded

inboth

hotand

cool

EFnarrativereview

sections

bParticipantswith

held

stim

ulantm

edicationfor>24

hpriorto

scanning

procedure,or

didnotu

semedication

60 Neuropsychol Rev (2016) 26:44–72

activity in brain areas and ODD/CD symptom counts (A.A.Marsh et al. 2013; Sterzer et al. 2005; Passamonti et al. 2010;Cohn et al. 2014; Finger et al. 2008; Rubia et al. 2008, 2010).

We reviewed the studies using the framework of hot and coolEF in ODD/CD, which resulted in 13 studies in the hot EFsection and 5 studies in the cool EF section, of which 1 studyappeared in both sections (Rubia et al. 2009b). The 13 studies inthe hot EF section included groups with ODD/CD-only (threestudies), ODD/CD-mixed (nine studies) or ODD/CD+ADHD(one study). In all studies, these groups were compared with atypically developing group and in four studies these groupswere additionally compared with an ADHD-only group(Finger et al. 2008; Herpertz et al. 2008; Marsh et al. 2008;Rubia et al. 2009b). The five studies in the cool EF section onlyincluded individuals with ODD/CD-only that were compared toa typically developing group and in four of the studies the ODD/CD-only groupwas additionally comparedwith anADHD-onlygroup (Rubia et al. 2008, 2009a, b, 2010). Because four of thefive cool EF studies were published by the same research groupand included largely overlapping samples (Rubia et al. 2008,2009a, b, 2010), we did not perform an ALE meta-analysis oncool EF fMRI studies in ODD/CD as at least five independentsamples are required for this analysis (www.brainmap.org).

All studies investigated children/adolescents. For informa-tion regarding group characteristics of the included samples,see Tables 2 and 3. Reported differences in brain structures arebilateral, unless reported to be either left or right sided. Resultsare reported fromWBA approaches, unless specified to be theresult of ROI based analyses, see Tables 2 and 3.

Hot EF – ALE Meta-analysis Thirteen functional neuroim-aging studies of hot EF were initially included in the meta-

analysis. Due to the limited number of studies in ODD/CD-only (three studies) it was not possible to perform an ALEmeta-analysis on studies comparing ODD/CD-only groupsand controls, thus the ALE meta-analysis was performed onall ODD/CD samples, therewith including both individualswith and without comorbid ADHD.

There was a difference between the resulting maps of theALE analysis with and without the ROI-only studies.Therefore, we reported the results from the map that includedonly WBA approach-based studies given the unbiased results.Total sample sizes for all included studies ranged between 30and 75 individuals, adding up to a total of 423 subjects, of which256were patients and 167were controls (age range 9–21 years).Three studies assessed a full male sample and six studiesassessed a sample largely consisting of males (ranging from56 to 79 %). The studies reported on different tasks associatedwith hot EF functions: three studies assessed processing of con-tingencies, two studies assessed passive viewing of emotionalpictures, two studies assessed passive avoidance learning, onestudy assessed active viewing and rating of painful situations,and one study assessed implicit emotional processing.

The included studies provided a total of 68 foci of areasshowing altered activity in individuals with ODD/CD withand without comorbid ADHD. The ALE analysis revealedfive significant clusters representing areas with altered activityin patients withODD/CD-only or ODD/CD+ADHD that weremost consistently reported across the studies (see Fig. 3 forvisualisation). The largest cluster (416 mm3) was located inthe right globus pallidus, with two foci inside this cluster. Thesecond (328 mm3) and third (256 mm3) clusters were locatedin the right and left amygdala, and contained three and twofoci, respectively. The fourth cluster (208mm3) was present in

Fig. 3 Results of the functionalALE meta-analysis of hot EFshowing the clusters in rightglobus pallidus, bilateralamygdala, left caudate, and leftfusiform gyrus (pcorrected < 0.05)superimposed on a structural scanin Talairach space. Top row:coronal view, bottom row: axialview. L Left, R Right

Neuropsychol Rev (2016) 26:44–72 61

the left caudate, while the fifth cluster (200 mm3) was locatedin the left fusiform gyrus, both contained two foci.

Hot EF – Narrative Review Tables 2 and 3 provides anoverview of investigated samples and approach (WBA orROI) and summarizes the findings of the 13 included studiesreporting on hot EF. Sample sizes ranged between 27 and 75individuals, adding up to a total of 560 individuals, including334 patients and 226 controls (age range 9–21 years). Thesamples consisted predominantly of males, with five studiesusing a full male sample, and the other eight studies using asample largely consisting of males (ranging from 56 to 82 %).The studies reported on different tasks associated with hot EFfunctions: five studies assessed processing of contingencies,three studies assessed passive viewing of emotional pictures,two studies assessed passive avoidance learning, one studyassessed active viewing and rating of painful situations, onestudy assessed implicit emotional processing, and one studyassessed interference control with emotional stimuli. Of the 13studies, 10 used a WBA approach and 3 only an ROI ap-proach, resulting in different numbers of studies per investi-gated structure.

ODD/CD-only versus controls (3 studies). Two of the threestudies reported abnormalities for ODD/CD-only compared tocontrols, of which one study reported lower activity in theright striatum, left amygdala, right insula, anterior cingulatecortex, and left medial and superior frontal gyrus, and theother study reported lower activity in the right lateral andmedial orbitofrontal cortex.

ODD/CD-mixed and ODD/CD+ADHD (10 studies).Studies assessing ODD/CD-mixed and ODD/CD+ADHDgroups replicated findings of abnormal function of the stria-tum (six out of eight studies: three left, two right, one bilater-al), including the caudate and putamen, and the amygdala (sixout of nine studies: two left, two right, two bilateral).Additionally, functional abnormalities were reported inODD/CD-mixed groups for the parietal cortex (three out ofseven studies: two right, one left), which was not found forODD/CD-only groups. This might indicate that the abnormalactivity in the parietal cortex reflects the presence of comorbidADHD rather than ODD/CD.

Correlational findings and specificity. Five studies investi-gated relations between activity of specific structures andODD/CD related symptoms. All five studies reported negativeassociations (thus a smaller volume related to more ODD/CDsymptoms) between amygdala activity and ODD/CD relatedsymptoms, one for an ODD/CD-only sample (left) and fourfor ODD/CD-mixed samples (two left, one right, one bilater-al). Furthermore, two of the five studies reported negativeassociations between left and right anterior cingulate cortexactivity and ODD/CD related symptoms, of which oneassessed an ODD/CD-only sample and the other assessed anODD/CD-mixed sample, respectively.

In terms of specificity, four studies investigated disorderspecificity of the abnormalities compared to ADHD-onlygroups. Of these four studies, one study reported the loweractivity in the orbitofrontal cortex in an ODD/CD-only groupto be disorder specific, while the other study reported loweractivity in the amygdala in an ODD/CD-mixed group to bedisorder specific.

Hot EF – Summary Combining the results from the meta-analysis and the narrative review, hot EF functional neuroim-aging studies most consistently implicated abnormalities ofthe amygdala and insula. Even though the meta-analysis im-plicated the left fusiform gyrus in ODD/CD, the narrativereviews did not show support for abnormalities in this areain ODD/CD.

Cool EF – Narrative Review Tables 2 and 3 provides anoverview of investigated samples and approach (WBA orROI) and summarizes the findings of the five included studiesreporting on cool EF. Sample sizes ranged between 21 and 53individuals, with all studies assessing full male samples (agerang 9–17 years). The studies reported on different tasks as-sociated with cool EF functions: one study assessed inhibitorycontrol, one study assessed interference control, one studyassessed attention allocation, one study assessed continuousperformance, and one study assessed cognitive flexibility.

ODD/CD-only versus controls (5 studies). Four of the fivestudies reported less activation in the precuneus of ODD/CD-only groups, with two studies reporting the left precuneus, onethe bilateral precuneus, and one the right precuneus.Furthermore, two of the five studies reported lower activityof the right insula, right anterior cingulate and right posteriorcingulate cortex in ODD/CD-only.

Correlational findings and specificity. Two studies investi-gated relations between activity of specific structures andODD/CD related symptoms, of which one reported a negativeassociation between dorsolateral prefrontal cortex and ODD/CD related symptoms and the other reported no associations.In terms of specificity, four studies investigated disorder spec-ificity of the abnormalities for ODD/CD as compared toADHD-only. One of these four studies reported abnormal ac-tivity in the insula, anterior cingulate cortex, cerebellum andhippocampus to be specific for ODD/CD-only, while anotherstudy reported specificity for lower activity in the left parietal-temporal cluster and the right parietal lobe.

Cool EF – Summary The number of available studies intocool EF did not allow a meta-analysis to be conducted. Basedon the narrative review, abnormalities in the precuneus weremost consistently implicated in ODD/CD.

62 Neuropsychol Rev (2016) 26:44–72

Integration of Quantitative and Qualitative ReviewFindings

In order to determine which hot and cool EF related brainareas are implicated in ODD/CD, findings from both sMRIand fMRI meta-analyses as well as from the narrative reviewsare integrated. Since the meta-analyses provide the strongestevidence for the convergence of findings, the main findings ofthe meta-analyses are discussed first. Second, findings fromODD/CD-only studies (10) are discussed, since these are notbiased by comorbid ADHD, followed by findings from theODD/CD-mixed and ODD/CD+ADHD studies (19). Finally,all these findings are integrated, resulting in an overall con-clusion for neuroanatomical abnormalities related to ODD/CD.

Table 4 provides an overview and integration of all report-ed abnormalities. For the overall conclusion, priority was giv-en to results from the ALE meta-analyses, since these providethe most objective and strong evidence for abnormalities of acertain structure. Qualifications used in the overall conclusionencompassed ‘strong evidence’, ‘some evidence’, ‘weak evi-dence’ and ‘no evidence’. For the qualification of ‘strong ev-idence’, the structure had to be reported in both of the ALEmeta-analyses. Alternatively, the structure had to be reportedin either one of the ALEmeta-analyses, while being supportedby at least half of the studies included in the narrative reviews(structural and functional) that investigated that structure. Forthe qualifications of ‘some evidence’ and ‘weak evidence’ atleast a quarter of the studies included in the narrative review(structural and functional) that investigated that structure hadto report abnormalities, while for ‘some evidence’ the reportedabnormality needed additional support of one of the ALEmeta-analyses. Finally, when less than a quarter of the studiesthat investigated that structure reported abnormalities, it wasconcluded that there was ‘no evidence’ for involvement of thatstructure in ODD/CD.

structures: the amygdala (left and bilateral, respectively).Other hot EF related areas were only implicated in the struc-tural (insula, left frontal gyrus) or functional meta-analyses(striatum, left fusiform gyrus).

Narrative Review: ODD/CD-Only Versus Controls (10Studies) Integration of the structural and functional findingsimplicated abnormalities in several hot EF related structuresfor ODD/CD, since these structures were reported in morethan a quarter of the studies: the amygdala, right striatum,insula, and left frontal gyrus (see Table 4). For a range ofstructures there was only weak or no evidence for abnormal-ities in ODD/CD (see Table 4 for an overview).

Overall Conclusion and Specificity of Findings Integrationof the structural and functional findings across the ODD/CD-only, ODD/CD-mixed and ODD/CD+ADHD samples pro-vided strong evidence for abnormalities in structure and func-tion of two hot EF related structures: the amygdala and thestriatum (see Table 4). Additionally, there was some evidencefor structural and functional abnormalities in two other hot EFrelated structures: the insula and the left frontal gyrus (seeTable 4).

Further support for involvement of abnormalities of someof these structures in ODD/CD was established by comparingthe results from studies using ODD/CD-only samples with theresults from studies using ODD/CD-mixed and ODD/CD+ADHD samples to see if results were mainly driven byODD/CD, and reviewing the correlational and specificityfindings. The involvement of the amygdala in ODD/CD wasfurther supported by the finding that abnormalities were main-ly driven by the studies including ODD/CD-only or ODD/CD-mixed groups, and to a lesser extent by studies includingODD/CD+ADHD groups. Hence, it seems that abnormalitiesare related to ODD/CD and not to comorbid ADHD.Furthermore, there was strong evidence from studies on spec-ificity of abnormalities in the amygdala for ODD/CD as com-pared to ADHD-only, and there was strong evidence for anassociation between both amygdala structure and function andODD/CD related symptoms. Similar evidence was reportedfor the insula, where again the results were mainly driven bystudies including ODD/CD-only or ODD/CD-mixed groups,rather than by studies including ODD/CD+ADHD groups.Also, some evidence for an association between both insulastructure and function and ODD/CD related symptoms waspresent. For the striatum there was some evidence for an as-sociation between abnormalities in this area and ODD/CDrelated symptoms. For the other areas (frontal and fusiformgyrus) there was no further supporting evidence from studiesinvestigating specificity by comparing anODD/CD-only sam-ple with an ADHD-only sample, nor did correlational ap-proaches provide evidence for associations between abnor-malities in these areas and ODD/CD symptoms.

Neuropsychol Rev (2016) 26:44–72 63

Meta-analyses Meta-analytic results implicated both struc-tural and functional abnormalities for one of the hot EF related

Narrative Review: ODD/CD-Mixed and ODD/CD+ADHD (19 Studies) Overall, findings from the ODD/CD-mixed and ODD/CD+ADHD groups again showed ab-normalities in several hot EF related structures for ODD/CD:the amygdala, right striatum, insula and left frontal gyrus (seeTable 4). For the amygdala and right striatum at least half ofthe structural and functional studies investigating those struc-tures reported abnormalities, and for the insula and left frontalgyrus more than a quarter of the structural and functionalstudies investigating those structures reported abnormalities.Again, there was only weak or no evidence for involvement ofa range of structures (see Table 4 for an overview).

Tab

le4

Overviewof

AllReportedStructuresandMeta-analyticandNarrativ

eReviewFindings

ALEMeta-Analysis

Abnormalities

reported

forthestudiesincludingsamples

ofODD/CD-onlyversus

Controls

Abnormalities

reported

forthestudiesincludingsamples

ofODD/CD-

mixed

andODD/CD+ADHDversus

Controls

Conclusion

ODD/CD

versus

controls

Structural

Functio

nal

Structural

Functional

Structural+

unctional

Significant

associations

bStructural

Functio

nal

Structural+

functio

nal

Significant

associations

e

Hot

Coola

Hot

Coola

(n=8)

(n=9)

(n=3,all

WBA)

(n=3,all

WBA)

(n=5,all

WBA)

(n=11,all

WBA)

(n=5)

(n=9,all

WBA)c,d

(nvaries

7WBA;3

ROI)

d(n=0,all

WBA)

(nvaries)d

(nvaries)d

Totalg

reymatter

NA

NA

13NA

NA

1NA

3/4

3,5,8

NA

NA

3/4

NA

Someevidence

f

Amygdala

Left

Bilateral

22,3

115

ns3

23,15

36,8,9

6/9

16,17,19,21,22,25

NA

9/1

85/8

6,7,8,19,25

Strong

evidence

Striatum

gns

Bilateral

1211

521

3,26

4ns

31,7,10

6/8

18,20,21,22,23,25

NA

9/1

71/5

10

Strong

evidence

Insula

Bilateral

ns21

,211

521

3,26

512

26,10

2/6

21,22

NA

4/1

53/6

6,10,21

Someevidence

Frontalg

yrus

Left

ns21

,311

512

94

1127

,10

2/7

18,22

NA

4/1

6ns

/5So

meevidence

Fusiform

gyrus

nsLeft

22,3

nsns

2ns

ns2/7

21,22

NA

2/1

6ns

/5Weakevidence

Temporalcortex

nsns

11ns

226,27

321

,345

,8,9,10

2/7

21,22

NA

6/1

61/5

12

Weakevidence

(Pre)cuneus

nsns

11ns

413,26,27,28

511

27,10

1/7

18

NA

3/1

6ns

/5Weakevidence

Parietalcortex

nsns

11ns

226,28

3ns

17

3/7

21,22,24

NA

4/1

6ns

/5Weakevidence

Anteriorcingulate

nsns

nsns

213,26

211

521

,33/6

15,16,20

NA

5/1

61/7

16

Weakevidence

Orbito

frontalcortex

nsns

1111

3ns

2ns

28,10

2/8

21,22

NA

4/1

7ns

/7Noevidence

Prefrontalcortex

nsns

21,2

nsns

212

811

02/7

18,21

NA

3/1

62/6

19,21

Noevidence

Cerebellum

nsns

nsns

113

1ns

34,7,8

1/7

21

NA

4/1

6ns

/5Noevidence

Occipitalcortex

nsns

12ns

113

2ns

37,8,10

ns/7

NA

3/1

6ns

/5Noevidence

Cingulate

nsns

21,3

ns21

3,26

4ns

115

ns/7

NA

1/1

6ns

/5Noevidence

Hippocampus

nsns

nsns

113

1ns

181/8

22

NA

2/1

7ns

/5Noevidence

Pre-centralgyrus

nsns

nsns

128

1ns

110

ns/7

NA

1/1

6ns

/5Noevidence

Thalamus

nsns

nsns

213,26

2ns

ns1/7

21

NA

1/1

6ns

/5Noevidence

Lingualgyrus

nsns

nsns

nsns

nsns

1/7

22

NA

1/1

6ns

/5Noevidence

Uncus

nsns

11ns

ns1

nsns

ns/7

NA

1/1

6ns

/5Noevidence

Prem

otor

cortex

nsns

nsns

113

1ns

nsns

/7NA

1/1

6ns

/5Noevidence

Firstcolum

nwith

results

show

sthemeta-analyticalresults,secondcolumnshow

sresults

from

studiesusingODD/CD-onlysamples,third

columnshow

sresults

from

studiesusingODD/CD-m

ixed

and

ODD/CD+ADHDsamples,lastcolum

nshow

soverallconclusion.Fo

rthe

second

andthirdcolumns

thenumbersinthecolumns

refertothenumbersof

studiesshow

ingsignificantresultsforthisstructure,

numbers

insuperscriptreferto

thereview

edstudiesin

Table1(structuralstudies)

orTables

2and3(functionalstudies).Fo

rtheoverallconclusion

oninvolvem

entof

structures

inODD/CD,three

qualifications

wereused:strongevidence,som

eevidence,w

eakevidence,and

noevidence.T

hequalificationstrong

evidence

was

used

ifastructurewas

foundinvolved

inODD/CD(1)in

both

meta-

analyses

OR(2)eith

eroneof

themeta-analyses

ANDby

halformoreof

thestudiesinthenarrativereview

.The

qualificationsomeevidence

was

used

ifastructurewas

foundinvolved

inODD/CDineither

oneof

themeta-analyses

ANDby

aquarteror

moreof

thestudiesinthenarrativereview

.The

qualificationweakevidence

was

used

ifastructurewas

notfound

involved

inODD/CDineitheroneof

the

meta-analysis,butwas

foundinaquartero

rmoreof

thestudiesinthenarrativereview

.The

qualificationno

evidence

was

used

ifastructurewas

notfound

involved

inODD/CDineitheroneof

themeta-

analysis,andadditio

nally

was

foundby

less

than

aquarterof

thestudiesin

thenarrativereview

.ADHD

AttentionDeficitHyperactiv

ityDisorder;CD

Conduct

Disorder;NAnotapplicable;ns

not

significant;ODDOppositionalDefiant

Disorder;ROIregion

ofinterest;W

BAwholebrainanalysis

aFo

urof

thefive

studiespertainedto

largelyoverlappingsamples

bTw

ostructural,one

hotE

Fandtwocool

EFstudies

cFo

rthestudiesusingODD/CD-m

ixed

andODD/CD+ADHDsamples,onlyfour

ofthestructuralstudiesinvestigated

totalg

reymatter

dResultsaregivenaccordingto

theform

at‘num

berof

studiesreportingsignificantfindingsforthisstructure/totalnumberof

studiesreportingon

thisstructure’

eSixstructural,fivehotE

Fandtwocool

EFstudies

fThe

qualification‘som

eevidence’was

givenalthough

therewereno

meta-analyticalfindings,since

ameta-analysiswas

notp

ossiblefortotalg

reymatter

gIncludingcaudate,putamen,globuspallidus

64 Neuropsychol Rev (2016) 26:44–72

Finally, driven by results from the cool EF section usingonly ODD/CD-only samples, some evidence was found forabnormalities in a cool EF related structure in ODD/CD: theleft precuneus. However, studies that compared ODD/CD-only samples with ADHD-only samples did not provide evi-dence for these abnormalities to be specific for ODD/CD, nordid studies that assessed associations provide evidence forprecuneus volume to be related to ODD/CD symptoms.Taken together, our results show strong evidence for involve-ment of the amygdala and the striatum, some evidence forinvolvement of the insula and the frontal gyrus, and weakevidence for involvement of the precuneus in ODD/CD.

Discussion

We reviewed 29 structural and functional neuroimaging stud-ies into hot and cool EF in ODD/CD (with and withoutADHD) and performed two meta-analyses on subsets of thesestudies. We hypothesized that, compared to controls, individ-uals with ODD/CD (with and without ADHD) would showboth structural and functional brain abnormalities in areas re-lated to hot and cool EF. In addition, we investigated thespecificity of these abnormalities by discussing results sepa-rately for studies including an ODD/CD-only group and re-sults from studies including anODD/CD-mixed or ODD/CD+ADHD group, using a narrative approach. Furthermore, indi-viduals with ODD/CD were compared to individuals withADHD. The results confirmed impairments in structure andfunction in most of the hypothesised hot EF related structures(i.e. amygdala, insula, and anterior cingulate), and to a lesserextent results confirmed such impairments in cool EF relatedstructures (i.e. dorsolateral prefrontal cortex and its subcorticalconnections, including the cerebellum). Impairments weremainly present as reductions in volume or reductions in activ-ity of the structures. Some of these abnormalities were report-ed to be specific to ODD/CD when compared to ADHD-only,or showed associations with ODD/CD symptom levels.

In terms of hot EF related neuroanatomical correlates, sev-eral structures were consistently reported to be associated withODD/CD (with and without ADHD) compared to controls(see Table 4 for an overview). This pattern of findingsemerged irrespective of a structural or functional approachof the study. For two areas the combination of the narrativereview and meta-analyses of both structural and functionalMRI studies provided strong evidence of abnormalities inODD/CD. These areas were the bilateral amygdala and theright striatum, including the caudate, putamen, and globuspallidus. In addition to these two areas, some evidence wasprovided for abnormalities of the bilateral insula in ODD/CDgroups. For all three areas, the majority of studies reportedreductions in volume and activity in ODD/CD with and with-out ADHD groups compared to controls. Furthermore, for all

three areas abnormalities appeared to be mainly driven bystudies including ODD/CD-only or ODD/CD-mixed groups,and to a lesser extent by studies including ODD/CD+ADHDgroups. Hence, it seems that ODD/CD may drive these abnor-malities, rather than ADHD. For the amygdala, this claim issupported by strong evidence for the abnormalities to be spe-cific for ODD/CD when compared to ADHD-only and by asignificant association between abnormalities in the amygdalaand ODD/CD symptoms in both ODD/CD-only and ODD/CD-mixed groups. For the insula there was some evidencefor specificity for ODD/CD compared to ADHD and someevidence for an association with ODD/CD symptoms.However, for the right striatum there was neither evidencefor specificity for ODD/CD nor for an association betweenODD/CD related symptoms.

The finding of abnormalities in brain areas related to hot EFfor ODD/CD is in line with the abnormalities observed inODD/CD in terms of performance on hot EF related tasks.The amygdala, striatum, insula, and frontal gyrus are impli-cated in emotion processing (Schumann et al. 2011; Andersonand Kiehl 2012), reinforcement processing (Di Martino et al.2008; Helie et al. 2013; Jessup and O’Doherty 2011), empathy(Gu et al. 2012, 2013; Lamm and Singer 2010), and introspec-tion (Passamonti et al. 2012; Goldberg et al. 2006) in typicallydeveloping controls, respectively. There is robust support forabnormalities in emotion processing, altered reinforcementsensitivity, deficits in empathy and abnormalities in self-control in individuals with ODD/CD (Blair 2013; Byrd et al.2014; Burke et al. 2002).

In terms of cool EF related neuroanatomical correlates, fewsignificant findings emerged. Partly, this was due to the limit-ed number of functional neuroimaging studies into cool EF inindividuals with ODD/CD. Almost all available functionalstudies were performed within the same sample, precludinga meta-analysis of these findings and restricting our approachto a narrative review of studies. For the left frontal gyrus someevidence for abnormalities in ODD/CDwas found. For the leftprecuneus weak evidence was found, however this structurewas predominantly reported in studies using ODD/CD-onlygroups, suggesting involvement of this structure in ODD/CD.Future studies should confirm this claim. Surprisingly, therewas no evidence for involvement of abnormalities of moretypical cool EF structures, such as the dorsolateral prefrontalcortex or the cerebellum in ODD/CD. The lack of robustcerebellum-related results in ODD/CD may be due to abnor-malities in the cerebellum being more strongly related to co-morbid ADHD, than to ODD/CD itself. Some support for thisinterpretation was found, since structural and functional ab-normalities in the cerebellum were reported mainly in studiesincluding ODD/CD+ADHD and ODD/CD-mixed groups,and not so much in studies including ODD/CD-only groups.

The absence of a significant relationship between brainareas related to cool EF and ODD/CD is in line with the

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inconsistent findings on tasks assessing cool EF in this group.ODD/CD seems to be associated with specific inhibitory-related abnormalities (Willoughby et al. 2011; Giedd et al.2010; Hobson et al. 2011), rather than with more general coolEF abnormalities. This is emphasised by results from studiesin other cool EF related domains, such as cognitive flexibilityand working memory, that showed these domains to be intactin ODD/CD and to be associated with comorbid ADHD in-stead of ODD/CD (Dawel et al. 2012; Giedd et al. 2010;Hobson et al. 2011; Prencipe et al. 2011).

Although we have suggested that abnormalities in ODD/CD are mainly associated with hot EF, most of the reportedhot EF brain areas are also involved in cool EF (see Fig. 4 forvisualisation), implying an integrated model of abnormalitiesin both hot and cool EF, rather than a strict separation betweenthese two. This is in line with models that propose abnormal-ities in both hot and cool EF circuits to underlie the behav-ioural characteristics of ODD/CD, such as the model by Blair(2005). The connectivity between the structures we found tobe involved in ODD/CD (amygdala, insula, striatum, medial/frontal gyrus, precuneus) has been extensively studied, andstudies show that all these areas appear to be interconnected,albeit each to a different degree, and are found to subserveseveral different functions. For example, it is well establishedthat the amygdala, as part of the limbic system, is critical forhot EF, such as the processing of emotional information.Moreover, it also modulates behavioural responses subse-quent to emotionally salient information, with the regulatoryprocess being regarded as a cool EF related process(Schumann et al. 2011; Anderson and Kiehl 2012). The insulais also involved in emotional information processing, and isnecessary for empathic pain perception and compassion,hence referring to hot EF, but also for the integration of

emotional and cognitive processes, thus referring to cool EF(Gu et al. 2012, 2013; Lamm and Singer 2010). The striatum,specifically the dorsal part (mainly caudate and putamen), isassociated with inhibitory functions as well as with reinforce-ment learning, and thus referring to both cool and hot EFrelated processes, respectively (Di Martino et al. 2008; Helieet al. 2013; Jessup and O’Doherty 2011). The medial/superiorfrontal gyrus is associated with response inhibition and othercool EF functions, but also with introspection, which can beseen as a more hot EF related process (Passamonti et al. 2012;Goldberg et al. 2006). The precuneus, finally, is an area that isinvolved in reflective, self-related processing and awareness,incorporating both hot and cool EF processes (S. Zhang and Li2012). Overall, it shows that our findings of abnormalities inthe five abovementioned structures may lead to impairmentsthat show striking parallels with the behavioural characteris-tics of individuals with ODD/CD, such as their difficulties inlearning socially acceptable behaviour, and their tendency tocontribute hostile intentions to peers in socially ambiguoussituations (Byrd et al. 2014; Blair 2013; Burke et al. 2002).This supports an integrated model of hot and cool EFabnormalities in ODD/CD, for which the model by Blair(2005) is currently the most comprehensive and encompassesa full description of both circuits.

Our results regarding abnormalities in brain structure andfunction in ODD/CD are in line with models on brain func-tioning of other externalising disorders for which ODD andCD are risk-factors, such as antisocial personality disorder(ASPD) or psychopathy (American Psychiatric Association2013). ASPD and psychopathy are characterised by symp-toms of emotional detachment and impulsive behaviour, andthe disregard for, or violation of, rights of others. The overlapin neurocognitive and behavioural abnormalities betweenASPD, psychopathy and ODD/CD, suggests that these disor-ders may share an underlying aetiology. A recently proposedneurocognitive model of psychopathy includes the paralimbicsystem as a whole, comprising both the frontal lobe and thetemporal lobe (including the amygdala). A review on psy-chopathy reported that most consistently implicated areaswere the amygdala, anterior and posterior cingulate cortices,orbitofrontal cortex and adjacent (para)limbic structures (Yangand Raine 2009). Furthermore, these brain areas are also im-plicated in ASPD (Kiehl 2006; Blair 2010). Since we foundsome of these areas to be involved in ODD/CD, a sharedaetiology with ASPD and psychopathy seems plausible.

Research Agenda

The goal of the current review was to aggregate and integratefindings from structural and functional studies on brain ana-tomical aspects of ODD/CD, to provide a complete overviewof brain abnormalities associated with ODD/CD. During thisprocess we encountered several issues in the field. Firstly, in

Fig. 4 Overview of the connectivity of areas involved in ODD/CD de-scribed in this review, based on connectivity studies in typically develop-ing individuals (see main text). Green arrows indicate excitatory connec-tivity, red arrows indicate inhibitory connectivity, and arrows in bothgreen and red indicate both excitatory and inhibitor connectivity. Redboxed areas exhibit mainly hot EF, blue boxed areas exhibit mainly coolEF, and areas boxed in both red and blue exhibit a combination of hot andcool EF

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our meta-analysis of hot EF functional studies, different re-sults were obtained when the analyses were conducted withand without inclusion of ROI-based studies, suggesting thatROI-based studies may bias conclusions. We therefore re-stricted our hot EF meta-analysis to WBA approach-basedstudies, given their unbiased results. Future studies investigat-ing brain abnormalities associated with ODD/CD should notonly include ROI analyses, but would benefit from reporting(additional) whole brain analyses, rendering the results eligi-ble to be included in a meta-analysis. In addition, because ofthe limited amount of studies into cool EF and the overlap insubjects in these studies, we were not able to perform a meta-analysis on these data; further research is needed in order to beable to draw firm conclusions on the possible involvement ofcool EF abnormalities in ODD/CD, particularly since evi-dence from behavioural studies into cool EF impairments inODD/CD is inconclusive.

Secondly, in terms of sample characteristics, an importantfuture direction is to study the role of callous-unemotional(CU) traits or psychopathic traits in individuals with ODD/CD. It has been reported that children with CD and high levelsof CU traits show greater abnormalities in reward sensitivity,lower responsivity to treatment by parenting strategies, andare more resistant to psychosocial intervention than those withCD and few CU traits (Byrd et al. 2014). Another importantissue in terms of the investigated samples is that most of thestudies focussed on males, limiting generalization of currentfindings. This is emphasised by the differing pathways ofbrain development in boys and girls (Haney-Caron et al.2014), and the fact that boys and girls seem to differ in theneural characteristics of ODD/CD (Hyatt et al. 2012). Forexample, when comparing male and female samples withODD/CD-mixed, gender differences emerged for the insula(Fairchild et al. 2013a). Moreover, since substantial develop-mental changes take place during the transition from child-hood to adulthood (Giedd et al. 2009), studies should takedevelopmental patterns into account. This can be achievedby adhering to smaller age ranges when including participants,but also by matching on age or using large samples that allowdevelopmental patterns to be studied. In the majority of theincluded studies, participant ages ranged between 10 and17 years, which cover a substantial time of brain development.Furthermore, since ODD and CD are childhood disorders andare referred to as APD when persisting into adulthood, ourfindings may not be generalizable to older individuals.

Thirdly, at a statistical level, future studies should be moreconsistent in statistical corrections and thresholding. A signif-icant proportion of the studies did not correct for multiplecomparisons or Type 1 errors, nor applied clusterthresholding. Of these, most studies using a WBA approachdid report Family Wise Error or False Discovery Ratecorrected results, except for three structural and four function-al studies (Bussing et al. 2002; Kruesi et al. 2004; Fairchild et

al. 2013a; Marsh et al. 2013; Passamonti et al. 2010; White etal. 2013, 2014). However, most of these studies did set aminimum number of >10 contiguous voxels and lowered thestatistical threshold to p< .005 (Marsh et al. 2013; White et al.2013, 2014) or p< .001 (Passamonti et al. 2012; Fairchild etal. 2013a), leaving only two studies that reported at an uncor-rected statistical threshold of p< .05. This implies that theresults of both the meta-analyses and narrative reviews arein general reliable, but should be interpreted with some cau-tion, since especially in WBA-based studies, these statisticalmethods are of importance (Chumbley and Friston 2009;Chumbley et al. 2010; Nichols and Hayasaka 2003).

Fourthly, future studies should look at other imaging tech-niques, such as DTI, to improve our knowledge on structuraland functional brain abnormalities associated with ODD/CD.Up to date, eight studies have used DTI to study abnormalitiesin pathways in ODD/CD. Although there is relatively consis-tent evidence for involvement of the uncinate fasciculus(Wang et al. 2012; Finger et al. 2012; Haney-Caron et al.2014; Passamonti et al. 2012; Sarkar et al. 2013; Zhang etal. 2014a), studies largely differed in terms of the white matterstructures implicated in ODD/CD. Furthermore, while somestudies report heightened DTI measures in ODD/CD(Passamonti et al. 2012; Sarkar et al. 2013; Zhang et al.2014a, 2014b), other studies report lowered DTI measures inODD/CD (Haney-Caron et al. 2014; Wang et al. 2012), or nodifferences at all (Finger et al. 2012). In addition to integratingfindings of DTI studies, future studies could look at otherimaging techniques, such as resting-state fMRI and combinedsMRI-fMRI studies.

Finally, to advance our understanding of ODD and CD andthe specificity of neural abnormalities future studies shouldassess well-defined and sufficiently sized samples. For exam-ple, the ideal study should at least compare ODD/CD-only,ADHD-only, comorbid ODD/CD+ADHD, and typically de-veloping control groups with sufficient sample size, to inves-tigate the possible confounding effect of comorbid ADHD.Furthermore, since there appears to be a difference in under-lying mechanisms for childhood-onset and adolescent-limitedODD/CD (Moffitt 1993), future studies should differentiatebetween these types of ODD/CD. Moreover, studies shouldinclude separate groups of individuals with pure ODD andpure CD, to investigate whether these disorders are indeedtwo ends of a spectrum or rather two separate disorders, sincethis is not completely evident from studies performed so far(Matthys et al. 2013; Rowe et al. 2010). A strict separation ofthe two disorders was not possible at the time of the currentreview, given that until the release of the DSM-5, a diagnosisof ODDwas precluded when CDwas present. Therefore moststudies into CD did not investigate or report on ODD, possiblylimiting the generalization of our findings to ODD-only andCD-only samples. In terms of ADHD comorbidity, most stud-ies that reported on ODD/CD did not investigate (or report on)

Neuropsychol Rev (2016) 26:44–72 67

possible comorbidity with ADHD, hence, studies investigat-ing ODD/CD-only samples are sparse. For this reason, wecould not perform a meta-analysis on studies that comparedgroups with ODD/CD-only to groups with ADHD-only. Also,it would be of great interest to investigate whether ADHDcomorbidity adds abnormalities associated with ADHD tothose already present due to ODD/CD, or that ODD/CD withcomorbid ADHD is a genuinely separate disorder.Furthermore, in the current review we did not examine theimpact of other common comorbidities such as anxiety ordepression. This is especially important because these comor-bidities are associated with abnormalities in some of the samebrain areas that appear to be implicated in ODD/CD (Sterzer etal. 2005). Especially the amygdala is related to both anxietyand depressive disorder, albeit in an opposite direction, show-ing higher volumes, instead of the lower volumes, to be asso-ciated with ODD/CD (Machado-de-Sousa et al. 2014; Younget al. 2014). Furthermore, not all studies investigated (or re-ported on) (past) medication use, even though in almost allstudies, MRI scanning was done in individuals free of medi-cation at the time of testing (Rubia et al. 2013). Current andpast mediation use should be incorporated in future studies,since this may have long-term effects on brain structure andfunction (Hart et al. 2013; Rubia et al. 2014).

Conclusion

We reviewed 29 studies on structural and functional neuroim-aging in samples with ODD/CD with and without comorbidADHD, and performed meta-analyses on a subset of eightstructural studies and nine hot EF functional studies. Despitesome limitations and heterogeneity amongst studies, resultsindicated that individuals with ODD/CD primarily show ab-normalities in the bilateral amygdala, bilateral insula, rightstriatum and left medial/superior frontal gyrus as well as theleft precuneus. Evidence of involvement of these areas waspresent in both structural and functional studies, and irrespec-tive of whether the study included individuals with ODD/CD-only or with ODD/CD with comorbid ADHD. Our resultsshow strong evidence of specificity for abnormalities in theamygdala for ODD/CD as compared to ADHD, and correla-tional studies further support the association between abnor-malities in the amygdala and ODD/CD symptoms. Besidesthe left precuneus that was revealed by the narrative reviewof cool EF, there was no evidence for abnormalities in typicalcool EF related structures, such as the cerebellum and dorso-lateral prefrontal cortex. Our findings confirm the involve-ment of hot, and to a smaller extent cool EF associated brainareas in ODD/CD, and support an integrated model of bothhot and cool deficits for ODD/CD (e.g. Blair 2005). The areasfound associated with ODD/CD are involved in emotion-pro-cessing, error monitoring, self-control, and empathic and

social behaviour. It is precisely these functions that are im-paired in children and adolescents with ODD/CD, and thatresult in difficulties learning socially accepted behavioursand reactions, attributing hostile intentions to others, and pre-ferring aggressive solutions to social dilemmas.

Open Access This article is distributed under the terms of the CreativeCommons At t r ibut ion 4 .0 In te rna t ional License (h t tp : / /creativecommons.org/licenses/by/4.0/), which permits unrestricted use,distribution, and reproduction in any medium, provided you give appro-priate credit to the original author(s) and the source, provide a link to theCreative Commons license, and indicate if changes were made.

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