atypical scanpaths in schizophrenia evidence of a trait or state dependent phenomenon

8/4/2019 Atypical Scanpaths in Schizophrenia Evidence of a Trait or State Dependent Phenomenon

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Review Paper

Atypical scanpaths in schizophrenia: Evidenceof a trait- or state-dependent ph enom enon ?Sara A. Beedie, PhD ; Da vid M . St. Clair, M D , PhD; Philip J. Bens on, P hD

Beedie Benson Scho ol of Psychology, College of Life Sciences and Med icine, University of Abe rdee n, King's Co lleSt. Clair School of Medicine and Dentistry, Division of Applied Medicine, University of Aberdeen, Clinical Research CenRoyal Cornhill Hospital, Aberdeen, Scotland

The development of trait markers of schizophrenia would represent an important advance in understanding the genetic architecture othe disease. To date, no candidate markers have satisfied all of the trait marker criteria, and many are not specific to the schizophreniaspectrum. Abnormalities in visual scanpaths are frequently reported in patients with schizophrenia and are emerging as a novel candidate for a schizophrenia biomarker. Here we review the suitability of scanpath measures as a target for trait marker research in schizophrenia. Papers reporting scanpath patterns in patients with schizophrenia were identified by PubMed and Google Scholar searches anby scanning reference lists in relevant articles. Search terms included "schizophrenia," "psychosis," "scanpath," "scan path," "fixation"saccade" and "eye movement." Scanpath abnormalities afford impressive sensitivity and specificity and appear largely independent opsychotropic medications. Scanpaths may demonstrate some fluctuation with symptomatology and may be useful in illuminating illnesstate or subtypes. However, there is evidence that viewing behaviours remain atypical regardless of symptom remission and may be present in unaffected relatives of individuals with schizophrenia. This research is in its early stages, and further investigation regarding paterns ot inheritance is required. Our findings support scanpath measures as a favourable topic for further investigation as a trait marker.

IntroductionSchizophrenia is a highly heterogeneous and complex disor-der. D iagnosis of the disease is currently based on clinical cri-teria and lacks objective tests. Although there is much supportfor a genetic component in vulnerability to the illness, and anumber of chromosome loci and candidate genes have beenrecognized, much about the genetic basis of schizophrenia re-mains unknown (for a recent review, see Williams and col-leagvies'). Several genes are likely to contribute to susceptibil-ity, and patterns of inheritance are intricate and irregular.Further, the natural boundaries that may distinguish schizo-phrenia from other psychotic and affective disorders, such asbipolar disorder, are unclear.' Case-control studies of theunderlying neuropathology or genetics of schizophrenia arelimited by the inherent heterogeneity of the disease and thepossibility that clinically similar phenoty pes may also have dif-ferent etiologic causes. The development of objective criteriaand external markers would help to validate external bound-aries that represent the underlying pathology of the disease.

One approach to furthering our understanding of the getic architecture of schizophrenia involves the study of enphenotypes.' Endophenotypes are measurable characteristsuch as neuropsychologic or psychophysiologic traits, thatassociated with genetic vulnerability for the disease. Thcharacteristics are believed to reflect the action of genes aciated with the illness, regardless of whether diagnosapathology develops. The study of endophenotypes conseveral benetits to genetic research in schizophrenia. Firsthe phenotyp e is defined solely on the basis of the presencabsence of a schizophrenia diagnosis in genetic studies, fanegatives will occur where individuals carry the genetic nerability but do not display symptoms, and sensitivity be reduced.* Second, the current classification of mental illusing psychiatric diagnoses does not lend itself to the distion of diseases on the basis of their complex genetic archture.' For example, the term "schizophrenia" may compseveral different disorders, each with its own genetic and ngenetic influences. Genetic analysis is made more difficulthe likely polygenic natiore of schizophrenia.' Endo pheno t

Correspondence to: Dr. S.A. Beedie, School of Psychology, College of Life Sciences and Medicine, University of Aberdeen, William GuilBIdg., King's College, Aberdeen, Scotland, AB24 3FX; [email protected] Psychiatry Neurosci 2011 ;36(3)150-64.Submitted Nov. 27, 2009; Revised June 14, Aug. 20. 2010; Accepted Sept. 1, 2010.DOI; 10.1503/jpn.090169


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help to dissect the disease phenotype into more biologicallyhomo geneous subgro ups of individuals, facilitating considera-tion of genefic underpinnings.'" Although alternafive termssuch as "vulnerability marker," "trait marker" and "bio-marker" have previously been used interchangeably with theterm "endophenotype," recent authoritafive reviews haveclarified the disfincfions between these concepts.'^Researchers have debated and refined the endophenotypeconcept in psychiatry. It is broadly accepted that a number ofcore criteria should be met. These include associafion with thedisease under invesfigation, stability over time, relative in-dependence from clinical state, evidence that the characterisficis under genefic control and cosegregation in families withprobands and other affected family members.'"'" Such meas-ures must also show good psychometric or neurometric prop-erties. Ideally, tests should be quick and inexpensive to ad-minister to allow for high-powered studies. The originalendophenotype approach assesses "intermediate phenotypes"that are proposed to consfitute causal links between genes anddisease. However, commentators have caufioned that not allputafive endophenotypes meeting the above criteria will rep-resent traits lying on the pathway between genes and disease.For example, a trait may com prise an epiphenom enon of a riskgene or m ay be associated with different genes than those pre-disposing to the disease." Such traits may sfill confer substan-tial value in identifying more genetically homogeneousgroups. Establishing that a trait truly lies on the gene-


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pursuit, intentional and reflexive saccades and scanpath for-mation. The fro ntal eye fie ld (FEF) area receives extensive in-puts from the extrastriate visual cortex and is involved in trig-ger ing and maintenance of saccadic and pursui t eyemovements.'"- Frontal eye field activity coincides with trans-formation of cognitive d ecisions into m otor signals to fixate aparticular image location." Some FEF activity is correlatedwith the freque ncy of saccadic eye movements.'^ The decisionsand motivation for preparing and performing these saccadesare controlled by the posterior cingulate cortex (the cingulateeyefield).The parietal eye fields manage shifts in visual atten-tion'' and influence saccade target selection. Neural activityhere d ictates the latency of these reflexive, visually guided sac-cades. The supplementary eye fields receive motion and spa-tial information about image features via the dorsal visualpathway and prepare motor sequences for successive sac-cades. Saccade inhibition during fixation, short-term spatialmemory and saccade prediction are orchestrated by the dorso-lateral prefrontal cortex (DLPFC). The developm ent, mati rationand integrity of this cortical network are essential for triggering

saccades generated b y the superior colliculi and brain stem.Atypical scanpaths in individuals with schizophrenia habeen observed in response to a broad range of visual stimuand in different tasks. In general, the literature has associatea restricted style of scanning with the illness, characterizby fewer fixations and saccades, increased average fixatidurations, smaller saccades and sho rter scanpath length copared with healthy viewers.'" '" In contrast to the relativeextensive or holistic scanning strategies of healthy viewescanpaths in individuals with schizophrenia also tend to less spatially dispersed, with less attention paid to percetually and semantically informative areas.* "^="*-"*''^'^''-^Several researchers have employed scanpath techniquesexamine face processing or emotion processing in individuwith schizophrenia, and a substantial proportion of reportsscanpath behav iour in this population are therefore based findings from face stimuli presented centrally on a displaHowever, replication of similar scanning patterns with stimdevoid of social content suggests that the phenomenon is nspecific to faces or social scenes. Figure 1 illustrates fixati

Healthy viewer Viewer 1 with schizophrenia Viewer 2 with schizophrenia

Fig. 1 : Fixation heat maps for representative scanpaths of a healthy viewer and 2 Individuals with schizophrenia. Red areas denote gredensity of fixations. Image brightness and contrast have been reduced for clarity. Source: data reported in references 70-72.


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patterns in individuals with schizophrenia and an unaffectedcontrol viewer.A central role of frontal lobe patholog ies in abnorm al scan-ning is supported by neuroimaging findings,'''"" similaritiesbetween scanpaths of patients with schizophrenia and indi-vidu als with frontal lobe lesions,*"^'' correlations with ne uro-psychological performance* and an association with negativesym ptom s, which in turn are linked with prefrontal dysfunc-tion.^ Scanpath abnormalities may represent an epiphenom-enon of a more basic dysfimction in oculomotor control thatis assessed by more established putative trait markers in indi-viduals with schizophrenia. The possibility that the plethoraof eye movement abnormalities arise from a common coredeficit is worthy of further investigation. However, findingsrecently published by our group as conference abstracts sug-gest that scanpath and tracking deficits occur independentlyin patients with schizophrenia and nonclinical viewers. " Thispreliminary work has also found associations between scan-path measures and neuropsychologic performance in indi-viduals with schizophrenia that were consistent with a role ofDLPFC dysfunction in restricted scanning.'" Previous studieshave reported that although the DLPFC is implicated insmooth pursuit performance,"'* "" lesions in this area impairperformance on saccadic tasks but do not disturb smoothpursuit performance."'"Methodologically, scanpaths confer a number of advan-tages over many alternative measures. Scanpath recording isinexpensive, objective and noninvasive and is not reliant onparticipants' compliance with complex task instructions.Scanpath abnormalities have been proposed as a putativemarke r for schizophrenia,""* ' ' '"' " but whe th er scan pa thdeficits are a state- or trait-related phenomenon remains con-tentious. State markers of psychiatric disease are characteris-tics that appear and disappear with clinical episodes. Traitmarkers are phenomena that are present regardless of varia-tion in clinical state.Association of scanpath ab norm alitieswith schizophreniaReliability and e ffect sizesScanpath abnormalities have been widely replicated inschizophrenia research, and results show high levels of con-sistency across studies, especially with regards to fixationnumber, saccade amplitude and scanpath length measures.Reports of null findings are infrequent. The robustness of thescanpath phenomenon is highlighted by the variations intask, stimuli and recording m ethods. Table 1 and Table 2summarize published findings in individuals with schizo-phrenia and nonclinical comparison viewers.We calculated effect sizes for all studies in Table 1 andTable 2 reporting group means and standard deviations forany of the fixation or saccade tneasures of interest (fre-quency and duration of fixations and saccades, amplitude ofsaccades and total scanpath length) for individuals withschizophrenia and nonclinical comparison groups. The28 stud ies m eeting the se criteria and includ ed in the effect

size calculations are denoted by asterisks in Table 1. Whendata for more than 1 condition were repo rted, such as datafor individual stimuli, schizophrenia subgroups or test ses-sions, individual effect sizes were calculated for each condi-tion, resulting in 202 individual effect sizes. A summary ofeffect sizes for individual measures is presented in Table 3.Medium to large effect sizes were found for each of the5 scanpath measu res, with a mean Hedges ' unbiased po pu-lation estimate (g*) ranging from 0.98 (fixation frequency) to0.64 (fixation duration). Standard deviations for the mean ef-fect sizes suggest that a high variation across studies is alsopresent. To date, studies of scanpath dysfunction in patientswith schizophrenia have varied considerably in both taskand stimulus conditions and methods of data analysis. Taskselection can alter the cognitive and neural mechanisms im-plicated in viewing behaviour (e.g., free-viewing tasks com-pared with visual search), and it is vital to consider such is-sues during study design. Further sources of variation arisein the operationalization of dependent measures betweenstudies. For example, some stud ies define scanpath length asthe sum of the distance between successive fixations, where-as other studies measure the true path of the point of gaze.Methodologie variation may not only impact on the poten-tial for generalization across studies but may constitute animportant consideration in the accurate interpretation ofviewing behaviours and perceptual experience. Stimulussize and interest need to be sufficient to elicit eye move-ments and visual exploration."' It is important to provide ad-equate reason to make fixations and saccades around the im-age to allow researchers to make inferences about cognitiveprocesses involved during integration of perceptual infor-mation. If scanpath measures are to provide a potential tar-get for trait marker research, it will be critical to considerstandardization of practices. The magnitude of the prelim-inary effect sizes here support the potential value of scan-path measures as a discriminatory tool, and further analysisof the sources of variation across studies will help to buildan optimized protocol for the identification of the scanpathdeficit in future studies.Sensitivity and specificityNumerous trait markers may be associated with a given dis-order. As each trait is hoped to reflect the actions of a morediscrete genetic profile than the disease phenotype, eachmarker may represent only part of the risk for that disorder.It may be argued, therefore, that weak associations betweendisorder and marker should not automatically result in dis-counting of the candidate trait measure." Nevertheless, at-tempts to use scanpath parameters to distinguish individ-uals with schizophrenia from other clinical samples havedemonstrated promising levels of sensitivity and specificity,beyond those of i"nore traditional candidate markers, such assmooth pursuit deficits.' Sensitivity denotes the proportionof individuals correctly identified as belonging to the af-fected group (true positives). Specificity refers to the propor-tion of individuals correctly identified as not belonging tothe affected group (true negatives). Kojima and colleagues'"


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reported responsive search score (RSS; a mea sure of the spa-tial distribution of visual attention) to provide 71%-80%sensi t iv i ty and 80%-88% specif ici ty in dist in guis hingindividuals with schizophrenia from those with unipolardepression, epilepsy and amphetamine psychosis and non-clinical comparison groups. Matsushima and colleagues"'found similar efficiency (76.7% sensitivity and 81.4% speci-ficity) using discriminant analysis to separate outpatientswi th schizophrenia f rom individuals wi th depression.

methamphetamine psychosis (MAP), anxiety disorders, teporal lobe epilepsy or frontal lobe lesions and healthy cotrols. Predictor variables in the discriminant function wRSS and fixation frequency. App lying this same discriinant function, Kojima and colleagues'" found even highlevels of sensitivity (89.0%) and specificity (86.7%) in gro uof individuals with schizophrenia and depression. Scanpamay be a valuable addition to more traditional eye movment trait markers in discriminating between patients w

Table 1: Methods of studies examining scanpath behaviour in ind iv idua ls wi th schizophrenia (part 1 of 2)

StudyBenson at a l . * *Bestelmeyer et al.'"*De Wiide et al . "*Gaebel et al ."Green et al ." *Green et al. ' '*Hori et al.*"*

Kojima et al."

Kojima et al.'"*

Kojima et al."*

Kojima et al."*Koj ima et al ."*Kurachi et al."Leonards e t a l . "

Loughlandet a l . " *Loughiand et al ." *Loughland et al ." *Manor e t a l . " *Matsukawae ta l . "Matsushima et al ." *Matsushima et al."'*

Mikami et al.^*Minassian et ai ." *Moriya et al . "

Schizophrenia group,no. and type11 paranoid2250202411 deluded

8 nondeluded37

105

25

80

1452912

8 paranoid1 disorganized9 undifferentiated656563251 5 -2030

303824

Comparison group22 healthy controls6 cannabis-induced psychosis37 healthy controls19 bipolar disorder36 healthy controls23 siblings^20 healthy controls26 healthy controls22 healthy controls36 healthy controls

50 healthy controls30 unipolar depression28 amphetamine psychosis50 epilepsy25 healthy controls25 unipolar depression10 obsessive-compulsive disorder50 healthy controls25 methamphetamine psychosis21 temporal lobe epilepsy (L)12 temporal lobe epilepsy (R)

124 healthy controls116 depression23 healthy controls12 healthy controls28 healthy controls

61 healthy controls52 affective disorder61 healthy controls61 healthy controls37 first-degree relative^25 healthy controls19 healthy controls20 systemic lupus erythematosus20 healthy controls18 frontal lobe lesion10 healthy controls10 unipolar depression10 methamphetamine psychosis10 alcohol psychosis10 anxiety disorder10 temporal lobe epilepsy10 frontal lobe lesion30 healthy controls48 methamphetamine psychosis30 healthy controls20 healthy controls

StimuliFaces, landscapes, fractalsFaces, fractals, landscapes, noiseImages from Thematic ApperceptionTestDrawings depicting proverbsFaces (context-free and context-embedded)FacesRorschach stimuli

S-shaped figures

S-shaped figures

S-shaped figures *

S-shaped figuresS-shaped figuresPicture completion test of the W AISFaces, fractals, landscapes

Faces, degraded facesFacesFaces, degraded facesNeutral face. Rey Complex FigureS-shaped figuresS-shaped figureS-shaped figures

S-shaped figuresRorschach stimuliHuman figures, S-shaped figures

Task tFree-viewingFree-viewingThematic Apperception TestFree-viewing"Decide what the person is feelingthinking""Think about how the person seemto be feeling"Eye movements recorded duringfree response period in RorschachtestS-shaped figures procedure

S-shaped figures procedure

S-shaped figures procedure

S-shaped figures procedureS-shaped figures procedureWAIS picture completion test

(i) Face recognition(ii) Affect recognitionAffect recognition(i) Face recognition(ii) Affect recognition

S-shaped figures procedureS-shaped figures procedureS-shaped figures procedure

S-shaped figures procedureViewing for subsequent Rorschachresponse periodFree-viewing


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schizophrenia and healthy controls. Recent findings haveshown that a multivariate eye movement phenotype com-bining scanpath with tracking and fixation stability meas-ures may accurately distinguish cases from controls at a rateapproaching 100%, far beyond the accuracy rate of any sin-gle traditional p sychophysiologic or neuropsychologic meas-yj.g 7172 jj^jg Yvork is currently in preparation for publicationby our research group.Despite the practical significance of the current classifica-

tion system of psychiatric diagnoses, it is widely acknow-ledged that these hypothetical categorizations are unlikely toreflect the natural boundaries of the disorders. One of thebenefits of the endophenotype approach is that externalmarkers may be used to validate and refine these bound-aries. Trait markers may th us be shared across disorders, re-flective of shared genetic pathways or common biologicalbases. Equally, however, it is important to develop markerswith sufficient specificity to support genetic analysis for a

Table 1 : Methods o f studies examining scanpath behaviour in individuals with schizophrenia (part 2 of 2)StudyNishiura et al ." *Obayashi et al . "*Obayashi et ai."'

Philips and David"Phillips and David'"Phillips and David"Phillips a nd DavidPhill ips and D avid "

Philips and David"'*Philips and David*Phillips et al. "Phillips et a l.'"Quirk and S trauss"*Rosse et al . "Ryue ta l . ' ' *Schwartz et al . "Streit et al."Takahashi et al . "Takahashi et al.'"*Tsunoda et al . "Tsunoda et al ." *Williams et al."*Williams e t a l . " *Xia et al ."

Schizophrenia group,no. and type28 paranoid16 nonparanoid2718 paranoid7 disorganized2 undifferentiated

1 catatonic7 deluded7 nondeiuded7 deluded7 minimally deluded812 pers. delusions10 nonpers. delusions

7 deluded7 nondeiuded6 deluded5 minimally deluded19 pers. delusions8 nonpers. delusions19 pers. delusions8 nonpers. delusions20166016 .163823391132632814

Comparison group72 healthy controls20 healthy controls29 healthy controls

10 healthy controls10 healthy controls9 healthy controls10 healthy controls

10 healthy controls9 healthy controls

17 healthy controls18 healthy controls10 addiction recovery patients38 cocaine users30 healthy controls10 healthy controls18 healthy controls37 parentst47 siblings^43 healthy controls23 siblings^32 healthy controls60 healthy controls28 healthy controls41 healthy controls23 parents^

StimuliFaces with emotion-congruentsound, circlesGeometric figijres (from BentonVisual Retention Test)S-shaped figures

Single faces, face pairsSingle faces, face pairsNeutral faces, chimeric facesScenes depicting neutral, ambiguousor threatening activity

Single faces and face pairs (fromRecognition Memory Test)Single faces and face pairs (fromRecognition Memory Test)Scene showing neutral, ambiguousor threatening activitiesScene showing neutral, ambiguousor threatening activitiesEmotional imagesFaces with direct and averted gazeCircles, faces symbols, landscapeUpright and inverted facesFacesS-shaped figuresS-shaped figuresS-shaped figuresBenton Visual Retention TestFaces, degraded facesFacesS-shaped figures

TasktJudge whether current picture differsfrom previousBenfon Visual Retention TestS-shaped figures procedure 2testsessions 6 months apartFace recognitionFace recognition

Neutral face: state whether face ispleasantChimeric faces: determine facialexpressionRecognition taskRecognition task

(i) F ree-viewing (ii) Asked to attendto threatening areasFree-viewing(i) Affect recognition(ii) Gaze direction discriminationVaried by stimulusAffect recognitionAffect recognition2 test sessions 4 weeks apartS-shaped figures procedureS-shaped figures procedureS-shaped figures procedureViewing for stimulus reproductionFree-viewing for later recogn itionViewing for subsequent affectrecognitionS-shaped figures procedure

(L) = left-side spike focus; nonpe rs. = nonpersecutory; pers. = persecutory; (R) = right-side spike focus: WAIS = W eschier Adult Intelligence Scale.'Study included in effect size calculations.fin most of these studies, it is not clear whether participants were aware of affect recognition tasks, reproduction tasks, etc., before viewing or whether they completed a free-viewing taskand were then informed of the additional task.First-degree relatives, parents and siblings were ail unaffected relatives of patients with schizophrenia.ln these tasks, participants are shown an S-shaped figure (target figure) and asked to state whether the figure differs from a similar figure presented previously. The question "Are thereany other differences?" is then repeated until the participant states that no further differences are present. Eye movements are recorded during each viewing period and duringquestioning.TlBoth schizophrenia and schizotypal disorder.


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particular illness.* Atypical visual scanning in itself is notspecific to the schizophrenia spectrum. Scanpath abnormal-it ies have been demonstrated in individuals with otherpsychiatric disorders, including social phobia," "" autism,"" ""bipolar affective disorder,''" attention-deficit/hyperactivitydisorder (ADHD),"" generalized anxiety disorder," ob sessive-compulsive disorder'"'"'* and Alzheimer disease."* Import-antly, these abnormalities differ from those found in indi-viduals with schizophrenia, suggesting that scanpath dys-function as seen in schizoph renia may ha ve value as adisorder-specific marker.Other psychotic disordersDifferential scanpath patterns in patients with other forms ofpsychosis suggest that restr icted scanpath behaviour inthose with schizophrenia is not simply the result of psycho-sis itself, tior does it itievitably lead to such symptoms. Forexample, patients with MAP show symptoms highly similarto those in patients with schizophrenia, including paranoidpsychosis with persecutory delusions and hallucinations. Al-though patients with MAP and those with schizophrenia donot differ in terms of fixation frequency or scanpath length,the spatial distribution of attention is substantially less im-paired in those with MAP. Similarly, individuals with sys-temic lupus erythematosus, manifestations of which includeschizophreniform psychosis, show more widespread disper-sion of fixations than patients with schizophrenia," and pa-tients with cannabis-induced psychosis reveal flxation clus-tering and restricted scanning that is more pronounced thanthat associated with schizophrenia.*' Investigation of saccadeand smooth pursuit performance in chronic ketamine use,which is associated with psychotic symptoms and cognitivedeficits similar to those of schizophrenia-spectrum disor-ders, has also suggested that ketamine administration is nota suitable model for oculomotor deficits in individuals withschizophrenia.'"^Developmental disordersAutism is litiked with an erratic, disorganized pattern of vis-ual exploration.'"^ As in schizophrenia, individuals withautism demonstrate impairments in face processing and so-cial functioning. Some similarities in scanning styles havebeen fotind between schizophrenia and autism groups. Dur-ing face viewing, both individuals with schizophrenia andthose with autism assign less attention to the eyes and attendmore to the mouth and nonface areas than do healthygroups"""-'''"''"^"'""" (although a different study found no dif-ference between autism and control groups in the proportionof time spent viewing the mouth and eye regions'"'). Alsomirroring viewing patterns in individuals with schizophrenia,adolescents and young adults with autism have dem onstrateddiminished visual attention to social contextual informationwhen judging mental state.*'"" Despite these similarities inscanning styles, individuals with autism do not show the de-viant temporal parameters that are characteristic of scanningbehaviours in patients with schizophrenia."'-""Reduced attention to salient scene regions in individualswith schizophrenia is also more extreme than that recorded

in people with ADH D."" Attention-deficit/hyperactivity dorder has been linked with a more extensive visual scannistyle, characterized by increased scanpath lengths comparwith healthy groups.'" Therefore, patients with schizophnia and those with ADHD may show distinguishable scapath behaviours despite the presence of social functioniand attention deficits in both group s.Affective disordersBipolar affective disorder (BPAD) almost certainly sharescommon genetic basis with schizophrenia spectrum disoders.-"'"' Individuals with BPAD produce exploratory emovements similar to those of patients with schizophrenbut BPAD is nevertheless distinguishable as an illness usicertain measures. Loughland and colleagues" investigatscanpath formation during face viewing in individuals wibipolar and unipolar depression. Whereas individuals wischizophrenia had scanning behaviour that was atypical both spatial and temporal domains, patients with affectidisorders differed from controls in reduced attention to facfeatures." A second study involving patients with bipoldisorder found this group to occupy an interm ediate positibetween healthy observers and viewers with schizophrenwith regards to a range of temporal scanpath variables duing free-viewing." This second study found that spatial dtribution of fixations differed significantly between patienwith bipolar disorder and healthy controls for fractals, noipatterns, landscapes and faces. Compared with healtviewers, individuals with unipolar depression demonstradiminished fixation frequency and decreased cognitisearch scores (an index of attention to predetermined rgions of interest during a figure comparison task). Howevin contrast with the scanning behaviours of patients wischizophrenia, unipolar depression is also associated winormal saccade amplitude and RSS (an index of the overfixation dispersion)."'"'Anxiety disordersPatients with generalized anxiety disorder fixate a siminumber of image regions as controls during scene viewinThis viewing pattern contrasts that in patients with schizphrenia, who allocate attention to a restricted spatial area. Idividuals w ith generalized social phobia dem onstrate a foof hyperscanning to faces, characterized by increased scapath length compared with healthy viewers.'"" Responsisearch scores (indexing attentional distribution during a fure comparison task) and fixation frequency are also rported to be lower in individuals with schizophrenia than patients with obsessive-compulsive disorder.-^Alzheimer dementiaIndividuals with Alzheimer dementia have been repoed to show increased fixation duration and smaller sacade ampl i tude and decreased at tent ion to sal ient rgions during clock reading compared with controls.However, data directly comparing scanpath behaviouof schizophrenia groups and individuals with Alzheimdisease or other forms of dementia are not yet available


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Stability and relation with clinical stateAssociation with clinical symptomsIn an early study, Gaebel and colleagues"' found that re-stricted scanning behaviour was related to negative symp-toms in schizophrenia, whereas posit ive symptoms werelinked with extensive scanning styles (or hyperscanning). Al-though not unequivocal, more recent studies have reportedthat scanpath variables correlate with measures of negativeclinical sym ptoms. Two stud ies have reported significant cor-relations with the Positive and Negative Syndrome Scale(PANSS)"^ negat ive symptom subscore wi th smal l - to-medium effect sizes for fixation frequency (R^ = 0.22 and0.08) and duration (R^ = 0.14 and 0.11), saccade amplitude(R2 = 0.17 and 0.16) and scanpath length {R ^ = 0.21)."" Al-though effects of larger magnitude (B? for significant correla-tions ranging from 0.20 to 0.32) were found for fixation fre-quency and scanpath length in a third study, patterns werenot consistent across stimuli.'^^ One report found no correl-ation of scanpath measures with PANSS scores, with theexcept ion of a smal l cor relat ion wi th scanpath length(R ^ = 0.09).'= Stu dies usin g i nd ivid ual Scale for the A ssess-ment of Negative Symptoms (SANS"^) subscales have foundthat restricted scanning can be associated with dimensions ofavolition/apathy*'"'"' and affective flattening or blunting.*'''"'Restricted scanning is less often associated with alogia andanhedonia subscales.^" There have also been reports of asso-ciations between restricted scanning and Brief PsychiatricRating Scale (BPRS"") subscales of blunted affect/"*""^ motorretardation,*' emotional w ithdrawal**"* and unusu al thoughtcontent.* However, null findings have also been reported ineach instance.*'* No single eye mo vement measure or clinicalstate measure has consistently linked scanpath dysfunctionwith negative symptoms. Other studies have found no rela-tion between scanpath measu res and negative symptoms."'^'*'Meta-analysis is also problematic since most of these studiesonly report effect sizes for significant correlations.

The exception to these inconsistent findings is the associa-tion of negative symptoms with RSS, which indexes the dis-tribution of visual attention during a visual comparison task.The RSS has been repe ated ly l inked with m eas ures ofblunted affect and emotional withdrawal with moderate ef-Table 3: Scanpath m easures in individuals with schizophreniacompared with nonclinical groups across 28 studiesMeasureFixation frequencyFixation durationSaccade frequencySaccade amplitudeScanpath lengthOverall

Hedges' g*0.980.640.730.740.770.81

SD0.540.520.410.510.480.53

95 % CI0.85-1.110.48-0.800.26-1.190.56-0.920.65-0.890.74-0.88

No.t6840

33061

20 2CI = confidence interval; SD = standard deviatie)n.'Studies included in the calculation of effect sizes are marked with an asterisk in Table 1 .tNum ber of comparisons for which effect sizes were calculated. When data wereavailable for more than 1 condition within a study (e.g.. for individual stimuii.schizophrenia subgroups or test sessions), effect sizes were calcuiated independentlyfor each condit ion.

feet sizes (blunted affect: mean R^ = 0.30; emotional with-drawal: mean R = 0.28).**-"' In studie s usin g RSS, the view eris presented with a simple geometric shape and asked to de-scribe in what way the figure differs from a similar stimuluspresented previously. After the viewer's respons e, the experi-menter asks whether there are any further differences, andRSS is measured during the viewer's response period at thisstage. Given that the viewer has already answered the initialquestion, the degree of visual exploration du ring the RSS per-iod is likely to reflect an interpersonal component and anability to engage in conscious, internally motivated visual ex-ploration that is not required under the free-viewing condi-tions of m any other stud ies.In contrast to the suggestion by Gaebel and colleagues'"that positive symptoms are associated with an extensivescanning style, findings suggest that scanpath dysfunctionoccurs relatively independently of positive symptomatology.Studies have found no evidence of association betw een scan-path measures and positive symptom scores, either with re-gard to PANSS subscales,--'"" individual BPRS items* '*" orBPRS composite scores for positive symptom items.*'"^ Onlyone study since that of Gaebel and colleagues has reportedsignificant correlations between extensive hypersca nning andpositive symptom scores.** Positive associations linking fixa-tion frequency with somatic concern (R- = 0.16) and excite-ment (R2 = 0.22) on the BPRS have not been replicated. In asecond study , a negative correlation between PANSS positivesymptom scores and scanpath length linking increased posi-tive symptoms with more restricted scanning also revealedonly a small effect (R^ = 0.09) and wa s seen for only 1 of3 stimuli. Similarly, a finding of more restricted distributionof visu al attentio n in a final stu dy wa s seen for only 1 of4 stimu li. Such findings su ggest that scan path dysfunction isnot associated with positive symptomatology. Additional re-ports have failed to find evidence of extensive scanning inpatients with schizophrenia* or have linked groups with pre-dominantly posit ive symptoms with a range of viewingstyles from restricted to extensive scanning behaviours."' Onepossibility is that that restricted scanning is more specificallylinked with delusional symptoms," at least with respect toface viewing, although scanpaths still remain atypical in pa-tients with only minimal delusional sym ptoms.

Investigations of associations between scanpath anomaliesand symptom clusters identified by factor analytic methodshave found the candidate marker to be relatively independe ntof symptom profiles. Williams and colleagues'^ examined as-sociations of scanpath behaviours with symptoms of psycho-motor poverty, assessing blunted affect, social withdrawaland poor rapport, disorganization, tapp ing positive and nega-tive aspects of thought disorder and reality distortion, whichdenotes delusions and grandeur."" Williams and colleaguessuggested that scanpath behaviour showed only minimal as-sociations with symptom factors and that most patients maybe characterized by restricted scanning styles. Only subtle as-sociations between symptom dimensions and scanpath vari-ables were found in other studies by the same group.' ' "Association w ith particular symptom s does not constitute ashortcoming in the use of scanpaths as a trait marker. In fact.


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links between symptom dimensions and particular scanpathstyles may suggest possible lines for investigation in attempt-ing to partition schizophrenia into natural subtypes. How-ever, the question of whether scanpath abnormalifies remainconstant during changes in symptom severity is central to as-certaining whether eye movement measures comprise stateor trait markers. Three studies have asserted that scanpathidiosyncrasies do not remain stable over time. Phillips andDavid"'"" reported that viewing abnormalities diminishedwith improvements in delusional symptoms. Individualswith schizophrenia have been found to be significantly moreimpaired in visual exploration during inpatient treatmentperiods than during outpatient treatment in cross-sectionalresearch.^" Importantly, neither of these studies demonstrateda complete recovery of "normal" scanning behaviour in re-mitted groups. Therefore, whereas changes in symptomseverity may generate some fluctuation in scanpaths, it ap-pears that at least some degree of scanpath deficit remains,regard less of clinical state.

Eye movemen ts generally show no associafion w ith globalsymptom ratings in individuals with schizophrenia in correl-ational analyses.' ' ' ' ' ' ' '" ' '" ' Moreover, other studies have re-vealed stability of scanpath abnormalities, regardless ofsymptom changes. Streit and colleagues"^ found that idiosyn-crasies of scanpath length, fixation duration and feature se-lecfion in patients with schizophrenia persisted across testingsessions 4 weeks apart, regardless of a decline in symptomseverity. Posifive, but not negafive, symptoms declined be-tween testing sessions, supporting a lack of associationbetween restricted scanning and positive symptoms. In an-other study, patients demonstrated relatively stable eyemovement behaviours over an 8-month period despite par-tial remission of both posifive and negafive symptoms."' Incontrast, patients in this study who showed no reducfion insymptoms across the course of the research demonstrated areduction in saccade amplitude between testing sessions."'The authors argued that exploratory eye movements are in-fluenced by both trait and mental state factors. That eyemovement idiosyncrasies do not improve with reductions insymptoms may support the use of scanpath parameters as avulnerability marker, whereas saccade amplitude may modelillness chronicity in patients with schizophrenia.Association with other clinical featuresAlthough Obayashi and colleagues"' suggested that saccadeamp litude m ay model chronicity in patients with schizophre-nia, other reports of the relation between scanpath patternsand illness duration are inconsistent. Evidence for a lack ofassociation of scanpath variables with illness duration hasbeen documented,"-"""'" although Manor and colleagues"found illness duration to correlate with scanpath length.Williams and colleagues"" reported significant correlationsbetween illness duration and scanpath variables in patientswith schizophrenia, with longer duration associated withdiminished scanning, although patterns of association wereinconsistent across sfimuli. Those few studies assessing otherclinical characterisfics in relafion to scanning have found no

association between scanpath variables and number of clical episodes,"' duration of current stay in hospital"' or tonumber of hospital admissions.'*A further question is whether atypical scanning is a conquence of pharmacologie treatment. Evidence of a subtle retion between neurolepfic dose and restricted scanpath behiour in patients with schizophrenia has been reported2 studies . Williams and colleagues"" found chlorp roma zequivalent dosage to correlate with fixafion frequency, but with fixafion durafion, distance between fixations or ovescanpath length. Hori and colleagues"" foimd a negafive crelation between fixation frequency and neurolepfic dadose, although this relation became notisignificant when thcontrolled for negative symptom ratings in the analysis.In contrast, numerous studies have found no significassociations between scanpath variables and neurolepdosage in patients with schizophrenia.""-"'""""'"'"'^'"''""" though many of these reports are based o n post hoc analythe findings are supported by comparisons of neuroleptnaiVe patients with patients receiving regular neuroleptreatment in both cross-secfional and longitudinal study signs. In 2 studies, the scanpaths of individuals with schiphrenia receiving neuroleptics did not differ from thosenever-medicated pafients (cross secfional design,"" longitinal design"'""). Other researchers have found no influencemedication type (typical v. atypical tteuroleptics" "') or dution'" on scanpath variables. Evidence that antipsychomedicafions may reduce abnormalifies in viewing behavialso suggests that restricted scanning is not a consequenceneurolepfic treatment."""" In some instances, correlations tween neurolepfics and eye mov ements m ay be due to higneurolepfic doses being associated with more pronouncposifive symptoms (and thus a tendency toward a more tensive sc anning style)."'Few studies have directly assessed the effects of specneuroleptic medications on scanpath behaviours in patiewith schizophrenia. A study examining face viewing in opafients with schizophrenia receiving either risperidonehaloperidol found that the 2 treatment groups did not difon fixation frequency, overall fixation durafion or scanplength."" However, patients treated with haloperidol showreduced attention to facial features compared with healviewers. The authors argued that the spatial distribufionattention may be subject to medicafion effects, whereas teporal variables are not.Genetic controlCompared with other putative candidate trait markers crently tmder invesfigafion, few studies have examined scpath anomalies in relafives of schizophrenia probands. Evfewer studies have looked at genetic linkage. However, edence of linkage of exploratory eye movement behavio(specifically number of fixations) to chromosome 22qnql2.1 has been reported."' Chromosome 22q is associated wseveral candidate genes for schizophrenia, and microdelefiin this region have been linked with increased risk for the dease. Further, characteristics of restricted scanpath behavio


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have been demonstrated in healthy relatives of individualswith schizophrenia. Such findings support the use of scanpathmeasures as a marker of genetic liability for schizophrenia."-Parents of schizophrenia probands have been found todemonstrate reductions in fixation frequency, scanpath lengthand indices of the distribution of visual attention comparedwith nonrelative g roups, suggesting that viewing behavioursmay be at least partly und er genetic control."" Loughland andcolleagues"* examin ed face-viewing patter ns in p atients ,healthy first-degree relatives of patients with schizophreniaand unrelated controls. Relatives' viewing behaviour was un-usual, with temporal measures of fixation patterns falling be-tween those of controls and the atypical patterns seen inprobands. Relatives also showed an atypical distribution offixations to face stimuli that was even m ore extreme than thatobserved in the schizophrenia group. Similarly, healthy sib-lings of schizophrenia probands have been found to occupyan intermediate position between patients with schizophreniaand healthy controls with regards to fixation frequency andspatial dispersion of fixations."Findings to the contrary have been reported in a study byde Wilde and colleagues."" They found that healthy siblingsof individuals with schizophrenia did not differ from age-matched controls on several scanpath measures, includingcanpath length, fixation numb er and fixation duration, d ur-ing viewing of complex scenes. Shorter scanpath length wasfound in patients with schizophrenia but not siblings, and theuthors suggested that scanpath length is not a suitable can-idate for a vulnerability marker of schizophrenia. Previousreports of .scanpath abnormalifies in healthy sibling groupswere argued to be attributable to a failure of previous studieso match sibling and nonsibling groups on age. Also of note,owever, is that the study by de Wilde and colleagues"' failedo find the prominent scanpath abnormalities in their group

ions or average duration of fixation. Sampling biases ornsensitivity of this particular protocol in identifying re-

ours in relatives of patients with schizophrenia may bey heterogeneous.ummary and future directionst this early stage in research, measures of visual scanpathormatioti appear to constitute an appealing opportunity forrait marker investigation in individuals with schizophrenia.

east in those areas stud ied to date.Atypical scanning behaviours are a widely replicated and

markers. In parallel with this, current findings on scan paths inindividuals with BPAD suggest that these measures may alsoinclude sufficient information to illuminate overlap in geneticvulnerability or clinical features between related disorders.There is some suggestion that restricted scanning may belinked with the negative symptoms of schizophrenia, or alter-natively w ith delusional sy mptom s, at least with regard to faceviewing. This may point to the possibility of scanpaths as aspecific marker for particular symptomatologies that may helpto stratify subtypes or indicate state. Some studies have re-ported state-related changes in scanpath behaviour in patientswith schizophrenia. However, there is evidence that viewingbehaviours still remain atypical to some extent despite symp-tom remission, supporting the argument that scanpath deficitsare likely to be a constant feature in these individuals.Genetic control of scanpath abnormalities is supported byinitial findin gs of linkage analysis and relative studies.Additional research is clearly merited to further define thestate and trait characteristics of atypical scanning in individ-uals with schizophrenia, particularly with regard to the herit-ability and genetic control of the deficit.The present review has not discussed cosegregation ofscanpath abnormalities in the families of patients w ith schizo-phrenia, as studies in this area have not yet been reported.Studies of scanpath behaviours in relatives of individualswith schizophrenia are not entirely unequivocal. Substantiveinvestigation of familial patterns of scanpath abnormalitieswill be necessary before such measures may be defined astrait markers.Standardization in scanpath methodology across studies isrequired. Although scanpath deficits appear reasonably ro-bust to detect differences in task an d stimuli between researchgroups, variance in the selection and defitiition of dependentmeasures to date create difficulties in comparability betweenstudies. Such investigation should also provide further infor-mation on the psychometric properties of scanpath dysfunc-tion such as test-retest statistics, which are not yet available,and separate meta-analyses will be usefitl in delineating theimpact in sou rces of variation in methodology across studies.Arguably, the most useful biological markers should bewell understood mechanisms that will augment understand-ing of the disease.'" However, little is understood about theunderlying etiology of atypical scanning in individuals withschizophrenia at present. Patterns of visual exploration mayreflect a more complex interplay of neurobiologie mechan-isms and cognitive functions compared with the more dis-crete mechanisms tapped by tasks such as smooth pursuittracking or inliibition of the P50 auditory evoked response.""That is not to say, however, that the impaired mechanism re-flected by the restricted scanning phenomenon must also beaffected by such variables. It may be that restricted scanningrepresents an anomaly in a low-level oculomotor or visuo-cognitive mechanism. A number of lines of inquiry havepointed to a role of the frontal lobes, and scanpath abnor-malities appear to comprise a generalized deficit in visualbehaviour. Additional impacts of cognitive and emotionaldeficits on scanpath behaviours have also been demon-strated in face viewing studies. Further exploration of the


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underlying neuropathologic and cognitive etiologies of scan-path abnormalities will clarify how scanpath abnormalitiescan further inform our understanding of schizophrenia. Al-though it could be suggested that scanpath deficits reflectprefrontal control mechanisms that are common to otherpsychiatric disorders, the relative specificity of restrictedscanning styles to schizophrenia suggests that this is not thecase. Clearly, further consideration of the cognitive andneurologic pathologies underlying the scanpath deficit is es-sential to build a biological explanation of the specific phys io-logic mechanisms assessed h ere. Deficits in the p rocessing ofreal-world visual information, as measured by the scanpathparadigm, may be highly informative with regard to cogni-tive or neurologic function and subjective experience in indi-viduals with schizophrenia. Indeed, this phenomenon ap-pears to merit further consideration in its own right, besidesany potential role in genetics or novel intervention studies.

Understanding potential association with specific geneswill require further linkage studies or candidate gene de-signs. More work is required in relatives of individuals withschizophrenia. Furthermore, understanding whether thosedeficits tapped by scanpath methodologies represent a causallink between genetics and diagnosable pathology is likely torequire longitudinal work and intervention studies.Limitations

neuroleptic medication. It is possible that scanpath dysfution may represent a stable, heritable trait marker of diseavulnerability, which is exaggerated with deterioration in clical state. Further, evidence for a strong association wschizophrenia and high levels of sensitivity and specificwarrants further investigation of scanpath behaviours astrait marker for schizophrenia and suggests that such meures may constitute a promising avenue of research to undstand the pathophysiology of the disease. At the least, scapaths may address the limited specificity of other motraditional biomarker targets and serve as an invaluable dition to alternative measures, such as smooth pursuit emovements or sensory gating indices, to substantially iprove the diagnostic specificity of psychophysiologic assement in trait marker research.Ack nowle dgem ents: This review is partly based on a cioctoral distation completed by Dr. Beedie under the supervision of Dr. Benand Professor St. Clair. During the preparation of this manuscrsalary support for Dr. Beedie was provicled by the Chief Scientist fice (CZB-4-734, awarded to Dr. Benson) and previously by the Eupean C ommission (SGENE, award ed to Professor St. Clair).Competing interests: As above.Contributors: Drs. Beedie and Benson acquired the data and wrthe article. All authors designed the review, analyzed the data,viewed the article and approved its publication.

This review is unable to give a definitive answer as to whichtasks (e.g., feature search, free viewing) or stimuli are themost appropriate for measuring scanpath dysfunction in in-dividuals with schizophrenia or whether it matters. Mitigat-ing cognitive and unknown perceptual disturbances may yetinfluence conformation. Until further work is done with fam-ilies of schizophrenia probands, it is difficult to assess howsimilar unaffected family m emb ers' scanpa ths are to those ofpatients. Whereas there is evidence to suggest that simplespatiotemporal measures of scanpaths during viewing cap-ture some sense of the abnormality, it is not yet clear whetherone of these measures, a combination of these measures or al-ternative higher order statistics will be best suited to discrim-inate between the scanpaths of individuals with schizophre-nia and those of individuals with other i l lnesses andnonclinical comparison groups. Nevertheless, scanpaths areunarguably affected in individuals with schizophrenia.ConclusionAlthough a numb er of questions are still to be addressed, eyemovements during scene inspection are emerging as a pow-erful and informative discriminatory tool in the study ofschizophrenia. Some studies have reported state-related fluc-tuation in the degree of scanpath dysfunction present in indi-viduals w ith schizophrenia. However, evidence of the decitin healthy relatives of individuals with schizophrenia andfindings that some degree of dysfunction remains regardlessof symptom remission also suggest that restricted scanningmay pre-empt the clinical manifestation of the disease. Scan-path dysfunction does not appear to be a consequence of

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