White matter microstructural abnormalities in the frontal lobe of adults with antisocial personality

14 Pages·2012·0.87 MB·English

by  Frederick Sundram

cortex 48 (2012) 216e229
Availableonlineatwww.sciencedirect.com
Journalhomepage:www.elsevier.com/locate/cortex
Special issue: Research report
White matter microstructural abnormalities in the frontal lobe
of adults with antisocial personality disorder
Frederick Sundrama,b,1,*, Quinton Deeleya,1, Sagari Sarkara, Eileen Dalya,
Richard Lathama, Michael Craiga, Malgorzata Raczeka, Tom Fahya, Marco Picchionia,
the UK AIMS Networkd, Gareth J. Barkerc,2 and Declan G.M. Murphya
aKing’sCollegeLondon,InstituteofPsychiatry,DepartmentofForensicandNeurodevelopmentalScience,London,UK
bDepartmentofPsychiatry,RoyalCollegeofSurgeonsinIreland,Dublin,Ireland
cKing’sCollegeLondon,InstituteofPsychiatry,DepartmentofNeuroimaging,CentreforNeuroimagingSciences,London,UK
dTheMRCAIMSConsortiumisaUKcollaborationofresearchcentresintheUKincludingtheInstituteofPsychiatry,London,
TheAutismResearchCentre,UniversityofCambridge,andtheAutismResearchGroup,UniversityofOxford.
TheConsortiummembersareinalphabeticalorder:BaileyAJ,Baron-CohenS,BoltonPF,BullmoreET,CarringtonS,ChakrabartiB,
DalyEM,DeoniSC,EckerC,HappeF,HentyJ,JezzardP,JohnstonP,JonesDK,LaiM-C,LombardoMV,MaddenA,MullinsD,
MurphyCM,MurphyDGM,PascoG,SadekS,SpainD,StewardR,SucklingJ,WheelwrightS,WilliamsSC
a r t i c l e i n f o a b s t r a c t
Articlehistory: Antisocialpersonalitydisorder(ASPD)andpsychopathyinvolvesignificantinterpersonal
Received11February2011 and behavioural impairments. However, little is known about their underlying neurobi-
Reviewed11April2011 ologyandinparticular,abnormalitiesinwhitematter(WM)microstructure.Apreliminary
Revised20April2011 diffusion tensor magnetic resonance imaging (DT-MRI) study of adult psychopaths
Accepted4June2011 employingtractographyrevealedabnormalitiesintherightuncinatefasciculus(UF)(Craig
Publishedonline20June2011 etal.,2009),indicatingfronto-limbicdisconnectivity.However,itisnotclearwhetherWM
abnormalitiesarerestrictedtothistractorareormorewidespread,includingothertracts
Keywords: whichareinvolvedinconnectivitywiththefrontallobe.
Antisocialpersonalitydisorder Weperformedwholebrainvoxel-basedanalysesonWMfractionalanisotropy(FA)and
ASPD meandiffusivity (MD)mapsacquiredwithDT-MRItocompare15adultswithASPDand
Psychopathy healthyage,handednessandIQ-matchedcontrols.Also,withinASPDsubjectswerelated
Neuroimaging differencesinFAandMDtomeasuresofpsychopathy.
Diffusiontensorimaging Significant WM FA reduction and MD increases were found respectively in ASPD
subjects relative to controls. FA was bilaterally reduced in the genu of corpus callosum
whileintherightfrontallobeFAreductionwasfoundintheUF,inferiorfronto-occipital
fasciculus (IFOF), anterior corona radiata and anterior limb and genu of the internal
capsule.Thesedifferencesnegativelycorrelatedwithmeasuresofpsychopathy.Alsointhe
rightfrontallobe,increasedMDwasfoundintheIFOFandUF,andthecorpuscallosum
andanteriorcoronaradiata.TherewasasignificantpositivecorrelationbetweenMDand
psychopathyscores.
* Correspondingauthor.King’sCollegeLondon,InstituteofPsychiatry,DepartmentofForensicandNeurodevelopmentalScience,POBox
50,DeCrespignyPark,SE58AFLondon,UK.
E-mailaddress:[email protected](F.Sundram).
1Jointfirstauthors,theseauthorshavecontributedequallytotheproductionofthismanuscript.
2Jointlastauthor,theseniorauthorhavecontributedequallytotheproductionofthismanuscript.
0010-9452/$eseefrontmatterª2011ElsevierSrl.Allrightsreserved.
doi:10.1016/j.cortex.2011.06.005
cortex 48 (2012) 216e229 217
Conclusions:ThepresentstudyconfirmsapreviousreportofreducedFAintheUF.Addi-
tionally,wereportforthefirsttime,FAdeficitsintractsinvolvedininterhemisphericas
well as frontal lobe connectivity in conjunction with MD increases in the frontal lobe.
Hence, we provide evidence of significant WM microstructural abnormalities in frontal
brainregionsinASPDandpsychopathy.
ª2011ElsevierSrl.Allrightsreserved.
1. Introduction tobeaparticularlyseveresubtypeofASPD(DolanandDoyle,
2007).PsychopathyandASPDarehoweverdistinguishedfrom
1.1. Thefrontallobetheoryofantisocialpersonality behaviourssecondarytofrontallobelesionsbyhighlevelsof
disorder(ASPD)andpsychopathy bothreactive(elicitedbyfrustration)andinstrumental(goal-
directed)violence(Blair,2001;GlennandRaine,2009).Never-
Theimportanceofthefrontallobesto socialbehaviour was theless, overlaps between traits of both psychopathy and
firstrecognisedinthe19thcenturyfollowingthecaseofPhi- ASPD,andfrontallobesyndrome,haveledtothesuggestion
neasGage,inwhomfrontallobedamageresultedinprofound that both PDs may result from frontal lobe abnormality
personality change associated with markedly inappropriate (Damasio, 2000). Neuroimaging studies of both people with
social behaviour [Harlow, 1993 (1869)]. A ‘frontal lobe’ ASPD, and of individuals with psychopathy, have provided
syndrome was subsequently delineated based on clinical evidenceofabnormalitiesoffrontallobestructureandfunc-
observations of the behaviour of patients with frontal lobe tionrelativetocontrolpopulations,togetherwithdeficitsin
damage (Lishman, 1998) where symptoms included apathy, temporal,limbic,andotherbrainregions(seeTable1).
emotionallability,alackofsocialawareness,unconcernfor For example, neuroimaging studies of adult psychopaths
socialrules,impulsivity,andreactiveaggression. examining the frontal cortex have reported reduced grey
It is currently recognised that there is much overlap mattervolumeinconjunctionwithreductioninthesuperior
between frontal lobe syndrome and ‘functional’ or ‘non- temporalgyrus(Mulleretal.,2008),andintheprefrontalcortex
organic’ personality disorders (PDs), particularly ASPD and (PFC) of ‘unsuccessful’ (caught) psychopaths, versus healthy
psychopathy(Damasio, 2000).The definition ofpsychopathy controls (Yang et al., 2005). Furthermore, higher total and
haschangedlittlesinceHerveyCleckleypublishedTheMaskof subfactor PCL-R scores (arrogant/deceptive, affective, and
Sanity in 1941 where he described the psychopath as impulsive/unstable)wereassociatedwithreducedprefrontal
acharming,callous,superficialindividual,lackingconscience greymattervolume(ibid).Similarly,prefrontalandtemporal
andgenuineemotion(Cleckley,1941).ThePsychopathyChecklist corticalgreymatterthinningwasfoundinpsychopathicindi-
(PCL,Hare,1980)andthelaterPsychopathyChecklisteRevised viduals,withrighthemispherereductionsrelatedtoelevated
(PCL-R,Hare,1991)weredesignedtooperationaliseCleckley’s PCL-RFactor1‘Affective’facetscores(Yangetal.,2009b).
conceptofpsychopathyasabasisfordiagnosingthedisorder. Other studies have identified associations between
ThePCL-Rconsistsof20itemscharacterisedbroadlybytwo psychopathic traits and specific subregions of the PFC. In
dimensions: Factor 1 items are primarily interpersonal or particular, the association found in brain injured patients
emotionaltraitssuchasremorselessness,deception,shallow between ventromedial PFC (vmPFC) damage and reactive
affectandcallousness,whereasFactor2itemsassessbehav- aggression (BlairandCipolotti,2000;Grafmanetal.,1996)is
iouralsymptomssuchasviolence,criminality,anddysfunc- mirroredbyvmPFCstructuralandfunctionalimpairmentsin
tionallifestyle.Foradiagnosisofpsychopathy,attributesfrom psychopaths(Tiihonenetal.,2008).Functionalneuroimaging
bothofthesefactorsneedtobepresent.WhilePCL-Rscores studies of people with psychopathy have also provided
(cid:1)30havetraditionallybeenusedtoclassifyanindividualas evidenceofabnormal frontallobeperfusionandabnormali-
having psychopathy (Hare, 2003), more recent studies have ties of task-related activation in prefrontal and other brain
arguedforascoreof(cid:1)25assufficientfordiagnosis(Edensand regionsonreversallearningparadigms(Table1).Individuals
Petrila,2006;Edensetal.,2010;Rutherfordetal.,1999). with ASPD have shown similar structural and functional
While the related construct of ASPD in DSM-IV-TR (Diag- prefrontal abnormalities to psychopaths e for instance
nosticandStatisticalManualFourthEditioneTextRevision, reducedprefrontalgreymattervolumehasbeenfoundinboth
AmericanPsychiatricAssociation,2000)includesseveraltraits antisocial adults (Raine et al., 2000) and conduct disordered
present in psychopathy (e.g., lack of guilt/remorse, and children (Huebner et al., 2008), compared with healthy
impulsivity),diagnosticcriteriacanbemetbasedentirelyon controls.Also,corticalthinningofthemedialfrontallobehas
antisocial behaviours (e.g., violation of social norms, irre- beenfoundinASPD(Narayanetal.,2007).
sponsibility, and criminality). Hence, the emotional deficits Nevertheless, structural and functional abnormalities in
fundamentaltopsychopathyarenotnecessaryforadiagnosis peoplewithpsychopathyandASPDarenotrestrictedtothe
ofASPD,evenifthesearepresentinsomecases.Estimatesof frontallobe.Forexample,abnormalamygdalastructureand
theprevalenceofthetwodisordersalsodiffer,suggestingthat functionhaveeachbeenfoundtocorrelatewiththeemotion
these are non-equivalent diagnoses. While most adult processingdeficitsobservedinASPDandpsychopathicindi-
psychopathicoffendersmeetcriteriaforASPD,onlyapproxi- viduals (Gordon et al., 2004; Kiehl et al., 2001; Yang et al.,
matelyonethirdofthosewithASPDarepsychopathic(Hart 2009a), as well as in regions (such as fusiformeextrastriate
and Hare, 1997). Psychopathy has therefore been postulated cortices) known to be modulated by the amygdala (Deeley
218 cortex 48 (2012) 216e229
Table1eSummaryofvolumetry,functionalandDT-MRIfindingsimplicatingfronto-limbicandotherbrainregion
abnormalitiesinantisocialpopulations.
Author Method Population Comparisongroup Finding Region
(Barkataki MRI ASPD Violentandnon-violent Reducedvolume Wholebrain,bilateral
etal.,2006) schizophrenia temporallobe
Increasedvolume Putamen
(Laaksoetal., MRI ASPDwithalcoholism Healthycontrols Reducedvolume Righthippocampus,
2000) posteriorhippocampi
(Laaksoetal., MRI ASPDwithalcoholism Psychiatricpatients Volumeinversely Bilateralposterior
2001) relatedtoPCLscore hippocampus
(Narayanetal., MRI ASPD Violentandnon-violent Corticalthinning MedialPFC
2007) schizophrenicsand
healthycontrols
(deOliveira- MRI ASPDwith Healthycontrols Reducedvolume Frontopolarcortex,
Souzaetal., psychopathy Volumesinversely orbitofrontalcortex,
2008) relatedtopsychopathy anteriortemporalcortex,
score superiortemporal
sulcus,insula
(Raineetal., MRI CommunityASPD Alcoholdependentsand Reducedvolume Prefrontalgreymatter
2000) healthycontrols
(Raineetal., MRI CommunityASPD Healthycontrols Increasedlength Corpuscallosum
2003) withhighpsychopathy Increasedvolume
scores Reducedthickness
(Tiihonenetal., MRI ASPDwithalcohol Healthycontrols IncreasedWMvolume Bilateraloccipitallobe,
2008) dependence bilateralparietallobe,
leftcerebellum
Increasedgreymatter Rightcerebellum
volume
(Volkowetal., PET Violentoffenders Healthycontrols Reducedglucose PFC,medialtemporal
1995) metabolism cortex
(Raineetal., PET Murderers Healthycontrols Reducedglucose PFC,corpuscallosum,
1997) metabolism superiorparietalgyrus,
leftangulargyrus
(Boccardietal., MRI Psychopathicviolent Healthycontrols Bilateraldepression Hippocampuse
2010) offenders longitudinalaxis
ReducedCA1segment Hippocampuseanterior
Abnormalenlargement Hippocampuse
lateralborders
(Craigetal., DT-MRI Psychopaths Healthycontrols ReducedFA RightUF
2009)
(Glennetal., MRI Communitysamplee Communitysamplee Increasedvolumewith Striatum
2010) highpsychopathy lowpsychopathy greaterpsychopathy
scorers scorers score
(Mulleretal., MRI Criminalpsychopaths Healthycontrols Reducedvolume Rightsuperiortemporal
2008) gyrus
(Shamay-Tsoory CT/MRI ASPDmaleswith Orbitofrontalcortex Impairedaffectiveempathy Orbitofrontalcortex
etal.,2010) psychopathictraits verusnon-frontal performanceinboth
lesionedmales orbitofrontalcortexlesioned
andhealthycontrols andpsychopathygroup
(Yangetal., MRI Unsuccessful Successfulcommunity Reducedvolume Prefrontalgreymatter
2005) community psychopathsand
psychopaths healthycontrols
(Yangetal., MRI Community Healthycontrols Reducedvolume Bilateralamygdala
2009a) psychopaths Surfacedeformations Amygdalanuclei:
basolateral,central,
cortical,lateral
(Yangetal., MRI Community Healthycontrols Corticalthinning Rightfrontalcortex,
2009b) psychopaths righttemporalcortex
Thinningassociatedwith Rightfrontalcortex,
greaterPCLfactor2score righttemporalcortex
cortex 48 (2012) 216e229 219
Table1e(continued)
Author Method Population Comparisongroup Finding Region
(Deeleyetal., fMRI Psychopaths Healthycontrols ReducedBOLDactivationto Fusiformgyrus,
2006) fearfulandhappyfacesin extrastriatecortex
emotionprocessingtask
Decreased,ratherthan Fusiformgyrus
increased,BOLDactivation
tofearfulfaces
(Soderstrom SPECT Violentoffenders Negativecorrelationbetween Frontalandtemporal
etal.,2002) withvarying interpersonalpsychopathy regions,headofcaudate,
psychopathyscores factorandperfusion lefthippocampus
(DeBrito MRI Communitysampleof Increasedgreymatter Medialorbitofrontal
etal.,2009) boysehighversuslow concentration cortex,anteriorcingulate
callous-unemotional cortex
traitscorers Increasedgreymatter Bilateraltemporallobe
concentrationandvolume
(Kruesietal., MRI Conductdisordered Healthycontrols Reducedgreymattervolume Righttemporallobe
2004) adolescents
(Huebner MRI Conductdisordered Healthycontrols Reducedgreymattervolume Bilateraltemporallobe
etal.,2008) adolescentmales Lefthippocampus,left
comorbidwithADHD amygdala
(Sterzeretal., MRI Conductdisordered Healthycontrols Reducedgreymattervolume Bilateralanteriorinsular
2007) adolescentmales cortex
Leftamygdala
(Bernsetal., DT-MRI Healthyadolescentse Highscorespositively FrontalWMtracts
2009) highversuslowon correlatedwithFAand
risktakingmeasure negativelywithtransverse
diffusivity
(Marshetal., fMRI Antisocialchildrenwith ChildrenwithADHD; ReducedBOLDactivationto Amygdala
2008) callous-unemotional healthycontrols fearfulfacesonemotional
traits processingtask
Reducedfunctional Betweenamygdalaand
connectivity vmPFC
(Fingeretal., fMRI Antisocialchildrenwith ChildrenwithADHD; AbnormalBOLDsignalto vmPFC
2008) callous-unemotional healthycontrols punishederrorsonreversal
traits learningtask
(Jonesetal., fMRI Antisocialboyswith Healthycontrols ReducedBOLDactivationto Rightamygdala
2009) callous-unemotional fearfulfacesonemotional
traits processingtask
(Stadleretal., fMRI Conductdisordered Healthycontrols ReducedBOLDactivationto Rightanteriorcingulate
2007) adolescentmales negativeaffectivepicturesin cortex
emotionalprocessingtask
etal.,2006).Reducedvolumeoftemporalregionsisalsoseen resonanceimaging(DT-MRI)(Basseretal.,1994b;Thiebautde
inASPD(Barkatakietal.,2006).Takentogether,thesestudies Schotten et al., 2012; Catani et al., 2012) wherethe ‘connec-
ofantisocialadultsandconductdisorderedchildren(withand tivity’ofneuralsystemsisassessedusingproxymeasuresof
withoutpsychopathictraits)illustratereducedvolumeofthe microstructuralintegrity.
temporal lobe and its constituent structures, and deficits in
amygdalastructureandfunction. 1.2. Disconnectivitybetweenfrontalandotherregionsin
Apartfromthesefronto-temporalstructures,otherregions psychopathy
potentially relevant to psychopathy have been less exten-
sivelyinvestigated.Forinstance,therehavebeenonlylimited DT-MRIisparticularlyusedintheassessmentoftissue(suchas
magnetic resonance imaging (MRI) studies assessing the WM networks) where water preferentially diffuses along
corpus callosum, a major white matter (WM) bundle sup- aparticularaxisalignedwiththetissue’sinternalstructureand
porting interhemispheric functional integration, where is predicated on the principle that microarchitectural struc-
abnormalitieshaveincludedincreasesinvolumeandlength tures,forinstance,cellmembranes,myelinsheaths,aswellas
but reduction in thickness (Raine et al., 2003). Also, while intracellularmicro-organelles,actasbarrierstothediffusion
reductionsinfunctionalconnectivitybetweenprefrontaland andfreemovementofwater,andthuslimitthespatialmotion
limbic regions may contribute to antisocial traits (Table 1), ofthesemolecules(MalhiandLagopoulos,2008).Theassess-
their underlying microstructural basis remains unknown. mentofthedirectionaldependenceofwatermoleculediffu-
Overall, the wider network of abnormalities in psychopathy sion in WM is usually quantified through calculation of
hasbeenrelativelyunderstudiedalthoughsuchinvestigation fractional anisotropy (FA). FA is a measure of the degree of
has been made possible using diffusion tensor magnetic anisotropy or directionality where values range from
220 cortex 48 (2012) 216e229
0 (perfectly isotropic diffusion) to 1 (perfectly anisotropic Participants in both groups were medication free, spoke
diffusion)(PierpaoliandBasser,1996)esoprovidingameasure English as their first language, and were right-handed as
oftissueintegrity(HorsfieldandJones,2002;MoriandZhang, assessed by the Annett Handedness Questionnaire. The
2006). Mean diffusivity (MD) is another DT-MRI derived WechslerAdultIntelligenceScaleeRevised(Wechsler,1981)
parameter used for reporting tissue differences which is wasusedtomeasureIQ.Allparticipants(inbothgroups)were
calculated by division of the sum of the eigenvalues of the examined by formal psychiatric semi-structured interview
diffusiontensor(whichcorrespondtothemagnitudeofdiffu- using ICD-10 research criteria (World Health Organisation,
sion in three orthogonal directions) by three. There are 1993)inadditiontoassessmentofcasenotesforadiagnosis
howeveronlylimitedstudiesexaminingneuraldisconnectivity ofASPD.Assessmentforthepresenceofcomorbidpsychiatric
usingDT-MRIinpeoplewithpsychopathyand/orASPD. illness (e.g., anxiety disorders, substance misuse, schizo-
A recent study by our group using DT-MRI tractography phrenia, major depression), neurological and extracerebral
focusing on FA in the uncinate, inferior longitudinal and disorders that may affect brain function, and contraindica-
inferior fronto-occipital fasciculi reported a significant tions to MRI scanning was also performed. Though many
reductionofthismeasureinonlytheuncinatefasciculus(UF) individualswith ASPDhavea past historyofalcohol and/or
of nine psychopaths compared with age- and IQ-matched substancemisuse,weattemptedtorecruit(asfaraspossible)
controls (Craig et al., 2009). Additionally, a significant nega- subjectswithoutcomorbiditiesratherthantocontrolforthese
tive correlation was found between measures of antisocial post hoc. None of the participants fulfilled criteria for
behaviour(PCL-RFactor2scores)andtractvolumewithinthis substancemisuseordependencesyndrome6monthspriorto
WM pathway, suggesting abnormal connectivity in the recruitment, with the exception of one subject who had
amygdalaeorbitofrontal cortex limbic network. However, as harmfuluseofcocaine.
thisstudywasconfinedtoalimitednumberofWMtracts,it 45 participants were initially recruited into the study (20
was not possible to assess WM networks on a whole brain ASPDvs25controls).However,fivewithASPDand10controls
level. Consequently, the presence of deficits affecting WM respectivelywereunsuitableforfurtherassessmentfollowing
connectivitywithotherbrainregionsisyettobeestablished exclusion for comorbid psychiatric disorder and contraindi-
ineitherASPDorpsychopathy.Further,ourpreviousstudydid cationstoMRIprocedures.PCL-Rscoreswereobtainedfrom
notexamineotherindicesofWMmicrostructure,suchasMD. casenotesderivedfromassessmentsbasedattheirspecialist
Insummary,thereisincreasingevidencethatpeoplewith forensic unit by forensic psychologists fully trained in the
ASPDandpsychopathymayhavesignificantdifferencesinthe administrationofthePCL-R,orbyaresearcher(QD)wherethe
structure and function of frontal, limbic and other brain PCL-R had not beenadministered butwhere subjectsother-
regions. However, few studies have examined the micro- wisemetinclusioncriteria.Wethereforeincluded30normal
structural integrity or connectivity of their WM networks. intelligenceright-handed adultmalesubjects:15withASPD
Therefore, we undertook the first DT-MRI investigation on and a mean PCL-R score of 26 (SD (cid:3) 7; range 13e34) aged
awholebrainlevelofASPDandpsychopathy.Weexamined 39 (cid:3) 10 years and with full-scale IQ (FSIQ) 92 (cid:3) 13, and 15
WMnetworksandtestedthemainhypothesisthatpeoplewith healthycontrolsaged37(cid:3)11years,withFSIQ99(cid:3)12.There
ASPDandpsychopathyhavesignificantdifferences,basedon werenosignificantdifferencesinageorIQbetweenpartici-
DT-MRIderivedparametersofFAandMD,inmicrostructural pant groups. Those with ASPD had a history of violent
integrity and connectivity as compared to healthy matched offending that encompassed manslaughter, attempted
controls.Also,wetestedanadditionalhypothesisthatwithin murderandmultiplerapewithstrangulation.IntheUKitis
ASPD, severity of psychopathy (as measured by PCL-R) is accepted practice to define psychopathy as a score of 25 or
relatedtodifferencesintheseWMmeasures. aboveonthePCL-R(Cooke,1996;CookeandMichie,1999)and
10 of the 15in theASPD group scoredabovethis threshold.
However,whilewewereabletoobtaintotalPCL-Rscoresfor
2. Methods theentirepatientcohort,itwasonlypossibletoacquireFactor
1andFactor2subscoresfor12ofthe15subjectsfromcase
2.1. Subjects notes.
Study participants were recruited from three specialist 2.2. MRIacquisitionprotocol
forensicinpatientunitsinsouth-eastLondon(SouthLondon
andMaudsleyNationalHealthServiceFoundationTrust)and Datawereacquiredusinga1.5TGESignaLXsystem(General
south-westLondon(StGeorge’sHealthcareNHSTrust)aspart Electric,Milwaukee,WI,USA),withactivelyshieldedmagnetic
of our longitudinal work in assessing psychopathy, over fieldgradients(maximumamplitude40mTm(cid:4)1).Astandard
aperiodofeightyears.Healthycontrolswererecruitedfrom quadrature birdcage head coil was used for both radio-
the general population through the Institute of Psychiatry, frequency transmission and signal reception. Each DT-MRI
King’sCollegeLondonbyadvertisement.Ethicalapprovalwas volume was acquired using a multi-slice peripherally-gated
obtainedfromtheEthicsCommitteeoftheSouthLondonand echo-planar imaging (EPI) sequence, optimised for precise
Maudsley Trust and Institute of Psychiatry, and St George’s measurement of the diffusion tensor in brain parenchyma,
Healthcare Trust. Written informed consent was obtained from60contiguous2.5mmthicksliceswithfieldofview(FOV)
fromparticipantsafterfulldescriptionofthestudy.Student’s 240 (cid:5) 240 mm and matrix size 96 (cid:5) 96, zero-filled during
t tests(two-tailed) wereusedto comparethedistribution of reconstructionto128(cid:5)128,givingafinalin-planevoxelsizeof
continuousdatabetweenthetwogroups. 1.875 (cid:5) 1.875 mm2 (Jones et al., 2002; Kyriakopoulos et al.,
cortex 48 (2012) 216e229 221
2008).Imageacquisitionwassynchronisedtothecardiaccycle givemapsoftheprobabilityofatissuebeingeitherwhiteor
usingaperipheralgatingdeviceplacedonthesubject’sfore- greymatterandthresholdedtheresultingimagesatalowlevel
finger.Echotimewas107msecwhiletheeffectiverepetition (10%)toprovidea(deliberatelyslightlyoverinclusive)binary
timewas15ReRintervals.Durationofthediffusionencoding mask of WM. We then smoothed the original FA and MD
gradients was 17.3 msec giving a maximum diffusion images,beforeapplyingthesemaskstorestrictthesubsequent
weightingof1300secmm(cid:4)2.Ateachslicelocation,7images statisticaltestingtoWMonly.Asdifferentsmoothinglevels
were acquired with no diffusion gradients applied, together canresultinvaryingresults(Jonesetal.,2005),intheabsence
with 64 diffusion-weighted images in which gradient direc- of a specific hypothesis about the spatial extent of any
tionswereuniformlydistributedinspace.Totalscantimewas abnormalities,weappliedaGaussiansmoothingfilterof5mm
approximately 20 min and the relative orientations of the full-width at half maximum. Because of our overinclusive
diffusion gradient vectors were based on the electrostatic mask,thesmoothedimageswillincludesomemixedgrey/WM
repulsionalgorithm(Jonesetal.,1999,2002). voxels at the edges of the masked region; however, later
Followingcorrectionofthediffusion-weightedimagesfor analysissteps(seebelow)furtherrestrictthestatisticaltesting
image distortions introduced by the diffusion-weighting toonlycoreWMregions.
gradients, in-house software was used to 1) remove non-
brain tissue and 2) determine the diffusion tensor in each 2.4. Imageanalysisandcorrelations
voxel (Basser et al., 1994a, 1994b). Images of 1) mean T2-
weightedintensity(withnodiffusiongradientsapplied)and 2.4.1. DT-MRIgroupmapping
2)FAandMDwerecomputedforeachsubject.Fulldetailsare We examined the statistical significance of between group
givenelsewhere(Jonesetal.,2002). differences in FA and MD using a non-parametric permuta-
tion-based method. Locally developed software, XBAM
2.3. Pre-processingDT-MRIdata (version3.4)(InstituteofPsychiatry,http://www.brainmap.co.
uk/)measuresbetweengroupdifferencesinstandardspaceat
Scans were examined for image corruption or motion arte- bothvoxelandclusterlevelsbyfittingananalysisofvariance
factspriortoinclusionintheimagingpipelineandnoneofthe (ANOVA)statisticalmodel.Astherewerenodifferencesinthe
acquired scans demonstrated these abnormalities. The mean values in either age or IQ between groups, and the
subsequentpre-processingstepsandanalyticalmethodology ranges similar, these were not entered as covariates and so
have been published previously (Bloemen et al., 2010; theANOVAmodelutilisedFAorMDasthedependentvariable
Kyriakopoulos et al., 2008, 2009; Sundram et al., 2010), and whilegroupclassificationwasthekeypredictorvariable.
aresummarisedbelow. Given that brain changes are likely to extend over
After construction of maps of FA and MD, a voxel-based a number of contiguous voxels, test statistics incorporating
approach in standard space using SPM2 (Wellcome Depart- spatial information such as 3D cluster mass (the sum of
ment of Imaging Neuroscience, University College London) suprathresholdvoxelstatistics)aregenerallymorepowerful
within MATLAB 6.5.2 (The MathWorks, Natick, MA, USA), thanotherpossibleteststatistics,whichareinformedonlyby
aligned,smoothedandsegmentedtheFAandMDimages.In data at a single voxel (Bullmore et al., 1999). The voxelwise
a manner analogous to the early voxel-based morphometry statistic images were therefore thresholded at a relatively
(VBM) analysis methods developed for structural T1 and/or lenientlevelofp(cid:6).05,andvoxelsthatwerespatiallycontig-
T2-weightedMRimages,wefirstperformedatwo-stagenor- uous in three dimensions in the thresholded maps were
malisationtostandardMontrealNeurologicalInstitute(MNI) assigned to the same cluster. The sum of voxel statistics
spaceusingastudy-specific,intermediatetemplatetoreduce withineachclusterwascomputedforeachrandomisationto
potentialbiasduetodifferentdegreesofwarpingthatwould formadistributionofclustermassunderthenullhypothesis.
otherwise be required to match ASPD and control brains to Asnoparametricdistributionisknownforclustermass(sum
astandard(controlsubject-based)template. of voxel statistics within each cluster), permutation testing
The mean T2-weighted (nondiffusion-weighted, b ¼ 0) wasusedtoassessstatisticalsignificance; themassofeach
images from each subject were initially registered to the clusterintheobserveddatawascomparedtothisrandomised
standardEPItemplateprovidedbySPM2.Thederivedmapping distribution, and significant clusters were defined as those
parametersforeachsubjectwerethenappliedtothe(inher- that had a greatercluster mass than the randomised distri-
entlyco-registered)FAimages.ThenormalisedFAimagesof bution at a particular significance level. The number of
all subjects were then averaged and smoothed (8 mm full- permutationsatthevoxelandclusterlevelswas1000which
width at half maximum Gaussian filter) to create a new, definesthedistributionwellenoughtopermitinferenceabout
study-specific,intermediatetemplatetowhicheachsubject’s changesbetweengroups(Bullmoreetal.,1999).Suchanon-
FA and MD images were then re-registered. Smoothing the parametric approach also overcomes the assumption that
data in order to coerce it into the appropriate statistical parametric methods adopt that the residuals of the model
distributionisaprerequisiteforsomeanalyticalapproaches, tested will follow a Gaussian distribution (which has been
but is not necessary for our non-parametric statistical shown to not always be true for DT-MRI data, even after
approach where it serves instead to aid between-subject extensivesmoothing)(Jonesetal.,2005).
anatomical matching, reduce confounds due to individual Atthisstage,weconsideredonlythosevoxelsatwhichall
variation in WM anatomy and improve the signal-to-noise subjects contribute data which, along with the masking
ratio. We therefore segmented the registered FA images procedureabove,restrictedtheanalysistocoreWMregions,
(usingSPM’sdefaultaprioritissueprobabilityinformation)to reducing the search volume (and thus the number of
222 cortex 48 (2012) 216e229
comparisonsmade)andalsoavoidedtestingatthegrey/white
3. Results
interfaces,wherethehighgrey/whitecontrastofFAimages
exacerbatesanyedgeeffects.Attheclusterlevel,ratherthan
3.1. GroupcontrastsofFAusingDT-MRIgroup
setasingleapriorip-valuebelowwhichweregardfindingsas
mapping
significant,wecalculated,forarangeofp-values,thenumber
of clusters which would be expected by chance alone.
3.1.1. ASPDversuscontrolsWMFA(Fig.1,Table2)
Astringentclustersignificancethresholdwasthenappliedto
People with ASPD, relative to controls, had a significant
renderlessthanonefalsepositiveclusterperanalysis.AsSPM
reduction in WM FA; 1) bilaterally in the frontal lobe in the
wasusedforimageregistration,XBAMyieldedcoordinatesof
anteriorportionofthecorpuscallosum(genu);2)intheright
significant clusters in MNI space and the identification of
hemisphere,onlyinanteriorregionsofthebrainandinWM
significant clusters and WM tracts intersecting them was
tracts that included the genu of corpus callosum, anterior
basedon an atlasapproachwhereseveralWMatlases were
corona radiata and anterior limb and genu of the internal
used in conjunction to determine the projection and local-
capsule, and frontal course of the uncinate and inferior
isation of WM bundles; these atlases were based on both
fronto-occipitalfasciculus(IFOF);3)inthelefthemispherein
single and multiple subject DT-MRI datasets in MNI space
both anterior and posterior regions of the brain including
(Catani and Thiebaut de Schotten, 2008; Mori et al., 2005;
respectively the genu of corpus callosum and temporo-
ThiebautdeSchottenetal.,2011;Wakanaetal.,2004).Given
occipital course of the inferior longitudinal and IFOF, and
thattheTalairachcoordinatesystemismostcommonlyused
theretrolenticularpartoftheinternalcapsuleandposterior
for reporting findings in the neuroimaging literature, MNI
thalamicradiation.
coordinatesweresubsequentlyconvertedtoTalairachspace
via a non-linear transformation (Brett et al., 2002) (details
3.1.2. ASPDversuscontrolsWMMD(Fig.2,Table2)
at http://imaging.mrc-cbu.cam.ac.uk/imaging/MniTalairach)
People with ASPD, relative to controls, had a significant
and the localisation of WM tracts and their respective
increaseinMDonlyintherightfrontallobe.Thiswaslocal-
anatomical course within cerebral lobes was additionally
isedtoaclustercontainingthefrontalcourseoftheIFOFand
confirmedusingtheTalairachatlas(TalairachandTournoux,
UF, and the genu of corpus callosum and anterior corona
1988).WheresignificantdifferenceswerefoundoneitherFA
radiata.NoregionsofincreasedMDwerefoundinthecontrol
orMDmaps,thep-valueofeachsignificantclusterisreported
group.
in Table 2 alongside the anatomical locations of their
respectiveWMtractsinTalairachspace.
3.1.3. WithinASPD,ananalysisofFactor1,Factor2and
In the investigation of cluster level effects, there is an
totalPCL-RscoresanddifferencesinWMFAandMD
underlyingassumptionthatallregionswillequally‘smooth’
In the ASPD group, there were significant correlations
and can therefore be treated equivalently (from a statistical
betweenPCL-RscoresandbothWMFAandMD.MeanFAof
point of view). However, while we restricted our analysis to
the cluster in the frontal lobe (Cluster 2) was negatively
core WM regions where signal-to-noise ratio is relatively
correlatedwithFactor2(r¼(cid:4).771,p¼.003,n¼12)andtotal
uniform,theeffectsofphysiologicalnoise(e.g.,motionarte-
PCL-R(r¼(cid:4).685,p¼.005,n¼15)scores.Additionallyinthe
facts) may still vary across the brain. We therefore concur-
frontal lobe, there was a significant positive correlation
rentlyinspectedthevoxel-levelmaps(whichtreateachvoxel
between increased MD (Cluster 3) with Factor 2 scores
independently and therefore inherently allow for such local
(r¼.669,p¼.017,n¼12).Therewerenosignificantcorrela-
differencesinstatistics)(Kyriakopoulosetal.,2008).
tions between the cluster in the temporo-occipital cortex
(Cluster1)andtotalorsubfactorPCL-Rscores.
2.4.2. PosthocanalysisofPCL-Rscores
Where significant 3D clusters were found on DT-MRI group
mappinganalyses,wecarriedoutposthocteststodetermine
ifsignificantdifferencesinWMFAorMDwereassociatedwith 4. Discussion
behaviouralvariationwithintheentiregroupwithASPD.As
the clusters detected by XBAM may encompass multiple WeusedDT-MRIinconjunctionwithwholebrainvoxel-based
anatomical regions (i.e., were not constrained to lie only analyses of MD and FA to compare WM microstructural
within particular WM tracts), we first extracted mean FA in integrity of 15 adult males with a diagnosis of ASPD and 15
combinationwithMDforeachASPDsubject.Todothis,mask healthy controls matched for age, handedness and IQ.
imageswerecreatedfromeachoftheclustersfoundbythe ReductionsofFAwerepresentinthefrontallobeoftheASPD
group mapping analysis and applied to each subject’s nor- group, and these were significantly and inversely correlated
malisedFAandMDimagestherebyenablingmeanFAandMD withseverityofpsychopathy(Factor2,andtotalPCL-Rscores).
values to be calculated over each region for each subject. Also,increasedMDwasconcurrentlyfoundintherightfrontal
These were then correlated with PCL-R scores (Factor 1: lobe of ASPD subjects which showed a significant positive
‘emotion dysfunction’; Factor 2: ‘antisocial behaviour’ and; correlationwithmeasuresofpsychopathy(Factor2scores).
total PCL-R) using Pearson productemoment correlation Thefrontalcluster(Cluster2,Table2)thatshowedsignif-
coefficients with Statistical Package for the Social Sciences icantFAreductionandnegativecorrelationswithseverityof
(SPSS14.0forWindows,SPSSInc.,Chicago,IL,USA).Signifi- psychopathyintheASPDgroupincludedthegenuofcorpus
cant correlations are reported where a Bonferroni adjusted callosum. Furthermore, it included right hemisphere struc-
alphaof.025wasapplied. tures of the anterior corona radiata and anterior limb and
Table2eWMFAandMDdifferencesinASPDrelativetohealthycontrols(clustersignificancethresholdforFAmapsp[.0025;clustersignificancethresholdforMDmaps
p[.005).
Cluster Clustersize TalairachandTournouxcoordinates Tract(s)withincluster Region ClustermeanFA ClustermeanFA p-value
label (numberof ASPD(SD) Control(SD)
x y z
voxels)
Cluster1 504 (cid:4)36 (cid:4)42 (cid:4)6 Temporo-occipitalcourseofleft Temporallobe .433(.022) .466(.029) .001378
ILFandIFOFa
(cid:4)32 (cid:4)59 4 Leftposteriorthalamicradiation Occipitallobe
andretrolenticularpartof
internalcapsule c
o
r
Cluster2 1027 16 47 (cid:4)8 RightIFOFandgenuofcorpus Frontallobe .383(.020) .409(.033) .000469 t
e
callosum x
19 30 (cid:4)8 RightUF Frontallobe 48
(cid:4)14 36 2 Leftgenuofcorpuscallosum Frontallobe (2
18 2 6 Rightgenuofinternalcapsule Sub-lobar 01
18 32 7 Rightgenuofcorpuscallosum Frontallobe 2)
23 11 9 Rightanteriorlimbofinternal Sub-lobar 2
1
capsuleandanteriorcorona 6
e
radiataa 2
2
9
Clustersize TalairachandTournouxcoordinates Tract(s)withincluster Region ClusterMDASPDmm2 ClusterMDControlmm2 p-value
(numberof sec(cid:4)1(cid:5)10(cid:4)3(SD) sec(cid:4)1(cid:5)10(cid:4)3(SD)
voxels)
x y z
Cluster3 325 13 48 (cid:4)11 Rightanteriorcoronaradiata, Frontallobe .750(.026) .729(.031) .004513
genuofcorpuscallosum,and
IFOFandUF
a LocationofvoxelshowingmaximumFAdifference.
2
2
3
224 cortex 48 (2012) 216e229
Fig.1eReducedFAinASPDrelativetohealthycontrols[ascending2mmtransversesections].
Fig.2eIncreasedMDinASPDrelativetohealthycontrols[ascending2mmtransversesections].
cortex 48 (2012) 216e229 225
genuoftheinternalcapsuleinadditiontothefrontalcourseof andGaffan,1998).IndividualswithASPDand/orpsychopathy
theUFandIFOF.Additionally,arightfrontalcluster(Cluster3, demonstrate deficits in reversal learning, a form of condi-
Table2)whichencompassedthegenuofcorpuscallosumand tional associative learning characterised by a failure to
anterior corona radiata, as well as the frontal course of the ‘reverse’apreviouslyrewardedresponsewhenitispunished
IFOF and UF also showed a significant correlation between relative to controls (Table 1). Reversal learning deficits may
increasedMDandpsychopathyscores.AlthoughFAreduction contribute to the perseveration of antisocial behaviour and
wasalsofoundinposteriorregionsofthelefthemispherein high levels of recidivism characteristic of the disorder.
the temporo-occipital course of the inferior longitudinal Further,fibresoftheUFconnecttheorbitofrontalcortexand
fasciculus (ILF) and IFOF, in addition to the retrolenticular amygdala,whileimpairedregulationofamygdalaactivityby
section and posterior thalamic radiation of the internal the orbitofrontal cortex may contribute to the behavioural
capsule (Cluster 1, Table 2), these did not correlate signifi- disinhibition encountered both in ‘acquired sociopathy’
cantly with measures of psychopathy. Overall, our findings (Brower and Price,2001) andASPDandpsychopathy(Sarkar
suggest that people with ASPD have WM microstructural etal.,2011).AlthoughabnormalitiesintheIFOFandanterior
abnormalities involving frontal WM networks, and particu- corona radiata were also found in the frontal lobe in the
larlyoftherighthemisphere. current study, functional impairments attributable to these
InapreviousreportbyourgroupemployingDT-MRItrac- tractsareexaminedlaterinthediscussion.
tographyexaminingFAandstreamlines(aproxymeasureof Additionally,FAdeficitswerefoundinthepresentstudyin
tractvolume)oftheUF,ILFandIFOFofnineindividualswith the anterior limb of the internal capsule which contains
psychopathy,FAwasfoundtobereducedonlyintherightUF; thalamo-frontal (anterior thalamic radiation), fronto-
additionallythenumberofstreamlinesintheUFbilaterallywas thalamic and corticopontine fibres, and interconnects the
correlated negatively with Factor 2 and total PCL-R scores dorsomedial and anterior thalamic nuclei with both the
thoughFAdidnotshowanystatisticallysignificantcorrelations prefrontalandcingulatecortices.Lesionsoftheanteriorlimb
(Craigetal.,2009).ThepresentfindingofreducedFAintheright of the internal capsule have been associated with ‘acquired
frontal lobe encompassing the UF replicates our original sociopathy’(Molletal.,2003).Further,deficitsintheanterior
finding,notingthattheseninesubjectswerealsoincludedin limb of the internal capsule have been suggested to lead to
ourlargersampleof15individuals.Theincorporationofmore impairments in attention, perception and working memory
subjects in our current study may have provided additional (Buchsbaum et al., 2006; Sepulcre et al., 2008). The anterior
powertodetectfurthersignificantcorrelationswithFA. limboftheinternalcapsuletogetherwiththeanteriorcorona
ApartfromFAdeficitsintheUF,thefrontallobeofASPD radiata (which connects the striatum with the anterior
subjects in the current study also showed FA deficits in the cingulate cortex) have been postulated respectively to
corpuscallosum,internalcapsule,anteriorcoronaradiataand contribute to attention impairments of alerting and conflict
IFOF;thisislikelytoindicateinformationrelayimpairments processing(Niogietal.,2010).Disruptionintractssupporting
between prefrontal and other brain regions e e.g., inter- thefunctionalintegrationofcorticalandsubcorticalregions
hemisphericallyandwiththecingulum,pons,thalamusand involved in memory, attention, volition, learning and visual
temporo-occipitalcortices(Catanietal.,2002;Schmahmann integration may contribute to the problems of people with
and Pandya, 2008). Impaired functioning of the corpus cal- ASPDinadaptivelyrespondingtoalteredcontingenciesinthe
losuminpsychopathshaspreviouslybeenpostulatedonthe socialandphysicalenvironment (includingsocialcuessuch
basisofevidenceofprolongedinterhemispherictransfertime asfacialexpressions),expressedintraitssuchasimpulsivity
relativetocontrols(HiattandNewman,2007).Lesionstudies ordifficultyinhibitingmotivatedresponses;alowthreshold
of the corpus callosum have revealed its role in supporting for the discharge of aggression; and failure to learn from
sensory-motor functional integration, attention, language, aversiveexperiences.
interhemispheric transfer of associative learning, and WealsoreportforthefirsttimeinASPD,WMMDabnor-
emotional regulation (Bellani et al., 2009; Glickstein and malitiesofthefrontallobe.MDofthediffusiontensorreflects
Berlucchi, 2008; Zaidel and Iacoboni, 2003). Consequently, the magnitude of water molecule movement that is inde-
thepresentfindingsofreducedFAandincreasedMDinthe pendentofdirectionandcontrastswithFAthatassessesthe
corpus callosum of adults with ASPD, which also correlate directional preference of such movement (Le Bihan et al.,
with measures of psychopathy, may suggest that functions 2001). Increased MD has been reported for instance in
mediated predominantly by the left hemisphere (e.g., vascularandneurodegenerativedisordersaffectingthebrain
approach behaviour, language processing) may be relatively (Herveetal.,2005;Scolaetal.,2010),schizophrenia(Leeetal.,
unmodulated by functions mainly mediated by the right 2009;Narretal.,2009)andautism(Leeetal.,2007)indicating
hemisphere (including behavioural inhibition and emotion lessrestrictedandthus,increasedmovementofwatermole-
processing) as postulated by Hiatt and Newman (2007). This cules. Similarly in our present study, increased diffusion of
proposedmechanismmayalsohelpexplaintheassociationof water molecules in the frontal lobe of those with ASPD
reducedFAinthecorpuscallosumofdependentcocaineusers suggests a less coherent underlying WM microstructure.
with increased impulsivity (Moeller et al., 2005) and WM Taken together with FA deficits concurrently found in the
abnormalitiesinthecorpuscallosumofadolescentsengaged rightfrontallobe,suchdisorganisationofWMmicrostructure
indangerousbehaviour(Bernsetal.,2009). mayhavearisenduetoabnormaldevelopmentofglialcells,
Withregardtofrontallobetracts,abnormalitiesintheUF axonsorcellmembranes(Dongetal.,2004;Herveetal.,2005).
are associated with impairments of conditional associative Furthermore,asfrontalabnormalitiesinthecurrentstudyare
learning(GaffanandWilson,2008;Gutnikovetal.,1997;Parker lateralised and involve the right hemisphere, there may be