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A pilot study of visual backward masking performance among affected versus unaffected offspring of parents with bipolar disorder

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A pilot study of visual backward masking performance among affected versus unaffected offspring of parents with bipolar disorder
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  Original Article A pilot study of visual backward maskingperformance among affected versus unaffectedoffspring of parents with bipolar disorder Cognitive deficits that are not restricted to thesymptomatic phase of bipolar disorder (BD) arenow a well-recognized feature of the illness (1–6).Visual backward masking (VBM) refers to a visualtask in which a briefly presented target is quicklyreplaced in the visual field by a non-informativemask (7, 8). Reduced ability to identify or locatetargets in VBM tasks is one of the most reliablecognitive findings in adults with BD (9); in fact,Goldberg noted that patients with BD usually havecognitive dysfunction that is mild compared withthat of patients with schizophrenia  except  on VBMtasks (10). VBM deficits are readily detectable inremitted patients, raising the possibility of a traitmarker of the illness; however, a previous studyreported that never ill siblings of probands withBD did not have VBM deficits (11).Breitmeyer and colleagues developed a modelthat integrates behavioural data on masking withknown neurophysiological mechanisms of visualperception (12, 13). Their model proposed thattransient (magnocellular) visual channels areinvolved in processing the stimulus for location,while sustained (parvocellular) visual channels arerequired for further processing the identification of the stimulus. This model has been expanded toinclude oscillations in the gamma range in the MacQueen GM, Grof P, Alda M, Marriott M, Young LT, Duffy A.A pilot study of visual backward masking performance among affectedversus unaffected offspring of parents with bipolar disorder.Bipolar Disord 2004: 6: 374–378.  ª  Blackwell Munksgaard, 2004 Background:  Cognitive dysfunction is evident in some euthymicpatients with established bipolar disorder (BD), including deficits invisual backward masking (VBM) tasks which map to a specific neuralpathway. A high-risk paradigm would clarify the temporal relation of cognitive dysfunction to clinical course. Method:  We compared euthymic offspring (age range: 18–32 years) of lithium-responsive bipolar parents with and without a previous lifetimehistory of psychiatric illness to healthy comparison subjects with anegative family history, on a VBM task that requires target location. Results:  High-risk offspring with no lifetime psychiatric historyperformed the VBM task at levels of healthy controls. High-riskoffspring with a previous history of a mood disorder, in completeremission, made significantly more errors at short target-mask intervalsthan control or never ill offspring. These higher error rates were not aconsequence of faster response times. Conclusions:  There is preliminary evidence of specific cognitivedysfunction early in the course of illness in affected offspring of parentswith lithium responsive BD. VBM is ideal for future longitudinal studiesaddressing whether cognitive dysfunction in BD is a trait marker or aconsequence of illness manifestation. Glenda M MacQueen a , Paul Grof b ,Martin Alda c , Michael Marriott a ,L Trevor Young d and Anne Duffy b a McMaster University, Hamilton, Ontario, b University of Ottawa, Ottawa, Ontario,  c DalhousieUniversity, Halifax, Nova Scotia, d University ofToronto, Toronto, Ontario, CanadaKey words: adolescents – backward masking –bipolar disorder – cognition – high risk –neuropsychologyReceived 31 December 2003, revised and accep-ted for publication 25 June 2004Corresponding author: Glenda M. MacQueen, MD,PhD, 4N77A, Department of Psychiatry andBehavioral Neurosciences, McMaster UniversityMedical Center, 1200 Main St. W., Hamilton,Ontario, Canada L8N 3Z5. Fax: 905 522 8804;e-mail: macqueng@univmail.cis.mcmaster.ca The authors of this paper do not have any commercial associationsthat might pose a conflict of interest in connection with this manu-script. Bipolar Disorders 2004: 6: 374–378Copyright  ª  Blackwell Munksgaard 2004 BIPOLAR DISORDERS 374  activity of sustained channels (14) and the modelsthat describe the mechanisms underlying VBMhave been reviewed (15).Green et al. (7, 8) completed a series of studiesdemonstrating that, when studied carefully,patients with BD have significant impairment onVBM that may be isolated to particular visualchannels, suggesting that this methodology may bea useful tool to further examine the mechanismsunderlying the cognitive impairment experiencedby some patients with BD. A recent review of backward masking performance in patients withBD, however, noted that completed studies cannotreliably differentiate whether observed deficits onthe masking tasks are related to a trait character-istic of certain subtypes of BD or a state charac-teristic reflecting residual symptoms and/orconcurrent psychopharmacological treatments (9).Thus while the mechanisms underlying the VBMtask are well described, the clinical factors under-lying the deficits observed in BD remain under-studied. These issues require clarification beforefurther examination of the mechanisms of VBMdeficit in patients with BD.In this study, we compared VBM performanceamong affected and unaffected offspring of arelatively homogeneous subgroup of lithium-responsive bipolar parents who are being followedas part of an ongoing genetic study (16). Subjectsfrom this high-risk cohort constitute an ideal groupin which to study the emergence of VBM deficits inBD to determine whether such deficits precede orfollow the onset of a mood disorder. Method Subjects Eligible offspring were identified from familiesparticipating in ongoing molecular genetic studiesas previously described (17). Parent probands metDSM-IV/RDC criteria for BD based on a Schedulefor Affective Disorders-Lifetime Version (SADS-L)interview and strict research criteria for long-termresponse to lithium monotherapy. Lithiumresponse identifies a homogenous subgroup of BD(18). Briefly, all consenting offspring (ages8–20 years) of these proband parents have beenassessed prospectively annually or at anytimesymptoms develop via semi-structured interviewas part of an ongoing high-risk study (19, 20). FinalDSM-IV diagnoses are based on blind consensusreview. For this pilot study, we selected a subset of high-risk offspring (four women and three men)with a lifetime history of a bipolar spectrumdisorder based on the Kiddie Schedule for AffectiveDisorders and Schizophrenia who were in completeremission based on prospective repeated researchassessments and matched them with other high-riskoffspring with no lifetime psychiatric disorder. Themedian number of lifetime fullblown mood epi-sodes (either hypomanic or major depressive) was2.5 (range: 1–4) for the affected group. An age-matched control cohort of university students withno lifetime psychiatric disorder according to semi-structureddiagnosticinterviewandnegativehistoryof psychiatric disorders in first-degree relatives(according to family history method single inform-ant) were enrolled for comparison. Affected off-spring all met DSM-IV (21) criteria for a bipolarspectrum disorder (bipolar II/not otherwise speci-fied (NOS) n  ¼  3 or recurrent major depressionn  ¼  4). When assessed, two affected offspring werereceiving pharmacotherapy, one with 900 mg lith-ium and one with 75 mg venlafaxine daily. Noother offspring had past exposure to psychotropicmedication. All affected children were in completeremission for a minimum of 3 months prior tocognitive testing (no detectable symptoms oninterview) with a median Beck Depression Scalerating of 3, Young Mania Rating Scale medianscore of 0. No assessed subjects met criteria for anyother Axis I disorder at the time of assessment;notably, they were free of anxiety disorders,substance abuse/dependence disorders and eatingdisorders. VBM task The backward masking task was presented on anIBM compatible microcomputer with an SVGA3monitor and circuitry capable of millisecondtiming and following a method that we havepreviously employed in adults with establishedBD (22). Visual angles subtended by the stimuliwere approximately 0.57   on the vertical andhorizontal dimensions. The target stimuli wereletters (O, S, U, C) presented at one of fourpossible target locations (up, down, left or right,approximately 2.2   of visual angle away fromfixation); the mask consisted of overlapping Xs andOs. The mask appeared over each of the possibletarget locations (up, down, left and right) on eachtrial so that subjects were not cued to the locationof the target by the presence of the mask. Subjectsidentified the location of the target by pointing inthe correct direction using a joystick; they were notrequired to identify the target. This conditionoptimizes transient channel responses. Prior toeach task five blocks of 16 target location practicetrials were presented: initially in the absence of anymask; then three blocks with increasingly short Backward masking in bipolar disorder 375  target-to-mask intervals; and ending with a blockof variable target-to-mask intervals identical to theformat of the upcoming task.Trials began with presentation of a fixationpoint, followed 400 ms later by the appearance of atarget for 14 ms and then by a 14-ms mask. Thetarget-mask inter-stimulus intervals (ISIs) were 14,29, 43, 57, 86 and 114 ms. There were 48 non-practice trials at each ISI, distributed evenly acrossthe four possible target locations, with an overalltotal of 368 trials including all practice trials.Percentage of incorrect responses and medianreaction time (RTs) at each ISI constituted thedependent measures. Statistical analysis A 3 (group) by 6 (ISI) repeated measures analysisof variance compared subjects   performance on theVBM task using SPSS (Version 10; SPSS Inc.,Chicago, IL, USA). Results The triads (n  ¼  7) were age matched as closely aspossible (age range: 18–32; see Table 1); healthycontrols had a mean age of 22.3 years (SD  ¼  3.2),unaffected offspring had a mean age of 22.3 years(SD  ¼  2.1) and affected offspring had a mean ageof 23.7 years (SD  ¼  5.3).Reaction times and error rates for each group ateach ISI are shown in Fig. 1. The analysis of theerror rates revealed a group  ·  ISI interaction(F[10,60]  ¼  5.9, p < 0.001) and a main effect of ISI (F[5,30]  ¼  104.5, p < 0.001), demonstratingthat while all subjects made more errors when theISI was short, affected offspring made more errorsthan either healthy low risk controls or unaffectedoffspring. There was a main effect of ISI for RTs(F[5,30]  ¼  25.9, p < 0.001) and an interactionbetween group and ISI (F[10,60]  ¼  2.5,p < 0.02), showing that the affected offspringhad greater slowing of their response times thanthe other groups as the ISIs became shorter, andconfirming that the increased error rates in theaffected offspring were not a function of a speed-accuracy trade-off (see Fig. 1). Discussion Unaffected offspring were not more adverselyaffected than controls by the demands of a VBMtask, consistent with a previous report of never-illrelatives of BD probands in which VBM deficitswere not observed (11). Together these two studiessuggest that VBM deficits are not likely to reflect avulnerability to early information processing def-icits that is present in unaffected relatives of BDprobands. In contrast, affected but fully remittedoffspring made significantly more errors when theISI was shortest and the task was therefore mostdifficult. The VBM task used here requires activa-tion of neural pathways involving projections fromprimary visual cortex to the posterior parietalregion and subsequently to the prefrontal cortex(23–25). Deficits in this pathway were apparent inyoung, symptom-free, high-risk offspring early intheir own course of illness. These deficits cannot beattributed to current mood state as all patientswere euthymic, or to medication status as only twosubjects were receiving pharmacotherapy, and theirperformance was comparable with that of theiruntreated peers. Interestingly, these young subjectswith relatively minimal illness histories made asmany errors as previously studied much older BDsubjects with a high number of lifetime episodes(17) suggesting that the deficit is established earlyin the course of illness.These are preliminary data with a small samplesize. As the data are not within-subject longitudinaldata, it is not possible to confirm whether the VBMabnormality is actually a vulnerability marker for Table 1. Data for individual subjects within age-matched triads highlighting the error rates for each subject at the shortest, and most difficult, inter-stimulusinterval MeasureTriad 1 Triad 2 Triad 3 Triad 4 Triad 5 Triad 6 Triad 7LR HRu HRa LR HRu HRa LR HRu HRa LR HRu HRa LR HRu HRa LR HRu HRa LR HRu HRaAge 19 20 18 a 19 20 18 b 20 21 20 23 23 24 24 24 26 26 23 28 26 25 32Sex F F F F M F F F F F M M M M M F M M F F FBDI-II 9 2 2 7 5 11 8 3 1 2 2 6 3 0 n/a 0 0 4 0 0 1Error rates atshortest ISI (14 ms)17 0 29 8 0 38 2 15 21 19 8 6 2 13 29 2 8 29 17 6 31 a Subject was receiving 75 mg of venlafaxine daily. b Subject was receiving 900 mg of lithium daily.LR  ¼  low risk; HRu  ¼  high risk – unaffected; HRa  ¼  high risk – affected. MacQueen et al. 376  disease expression or whether the VBM deficitsemerged following onset of mood symptoms.Another potential limitation of the data is thatnotallaffectedsubjectshadpastsymptomsmeetingcriteria for mania or hypomania. We consideredoffspring with recurrent depressive disorder as partof the bipolar spectrum given the estimation thatdepression, particularly early onset and recurrent,in family members of bipolar probands is verylikely latent BD (26). Bipolar NOS in this studyreferred to offspring with a lifetime history of recurrent major depressive episodes and significanthypomanicsymptomsnotmeetingthefullDSM-IVduration criteria. Although there is limited infor-mation regarding VBM deficits in patients withunipolar major depressive disorder, the evidencethatisavailablesuggeststhatpatientswithunipolardepression do not differ from healthy comparisonsubjects on VBM tasks (27). This suggests that theVBM deficits may be related specifically to BD andnot to presence or lifetime history of a mooddisorder more generally.Despite the preliminary nature of these findings,the consistency of the results between patientsstrongly supports the need for prospective longi-tudinal investigations of the evolution of cognitivedysfunction in groups at high-risk for BD. Theseand other data in first-degree relatives of patientswith BD (11, 28, 29) emphasize the need forthorough cognitive assessment of young patientswith BD, and of adolescents with a family historyand psychiatric symptoms who have not manifes-ted classical manic or hypomanic symptoms. Thefact that significant changes in task performancewere apparent in affected subjects without thepresence of classical manic or hypomanic symp-toms emphasizes the need for early monitoring of at risk groups and a better understanding of theearly symptoms of pediatric and adolescent BD, asadolescents with BD subjectively experience diffi-culty with cognitive tasks, particularly when thetask is difficult or challenging (30).We must acquire a better understanding of theeffect of this dysfunction on academic andoccupational performance, as the associationbetween cognitive deficit and function in mooddisorders is poorly understood overall. Furtherempirical studies to determine whether prophylac-tic treatment could prevent or delay these cognitivedeficits will also be useful, as to date there is littleinformation regarding whether pharmacological ornon-pharmacological interventions can influencesubstantially the emergence or progression of suchcognitive changes. Acknowledgements This work was supported by a grant from the CanadianInstitutes of Health Research to A. Duffy. A. Duffy andG. MacQueen are New Investigators of the Canadian Institutesof Health Research. References 1. Martinez-Aran A, Vieta E, Colom F et al. Neuropsycho-logical performance in depressed and euthymic bipolarpatients. Neuropsychobiology 2002; 46: 16–21.2. VanGorp WG, Altshuler L, Theberge DC, Wilkins J,Dixon W. Cognitive impairment in euthymic bipolarpatients with and without prior alcohol dependence. ArchGen Psychiatry 1998; 55: 41–463. Rubinsztein J, Michael A, Paykel E, Sahakian B. Cognitiveimpairment in remission in bipolar affective disorder.Psychol Med 2000; 30: 1025–1036.4. Tham A, Engelbrektson K, Mathe A, Johnson L, OlssonE, Aberg-Wistedt A. Impaired neuropsychological per-formance in euthymic patients with recurring mooddisorders. J Clin Psychiatry 1997; 58: 26–29.5. Kessing L. Cognitive impairment in the euthymic phase of affective disorder. 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Implications of sustained andtransient channels for theories of visual pattern masking,saccadic suppression, and information processing. PsycholRev 1976; 83: 1–36. 051015202530ISI=14 ISI=29 ISI=43 ISI = 57 ISI=86 ISI=114 Time interval between target and mask (ms)    P  e  r  c  e  n   t  a  g  e  e  r  r  o  r  s   (   b  a  r  s   ) 0100200300400500600    M   i   l   l   i  s  e  c  o  n   d  r  e  s  p  o  n  s  e   t   i  m  e   (  m  a  r   k  e  r  s   ) Low-risk control High-risk: unaffected High risk: affected Fig. 1. Error rates and reaction times on a VBM task requiringsubjects to locate the target letter at various ISIs. Trials withshort ISIs are more difficult, apparent in the increasing numberof errors for each group at short ISIs. Backward masking in bipolar disorder 377  13. Breitmeyer BG. Visual Masking: an Integrative Approach.Oxford: Oxford University Press, 1984.14. Purushothaman G, Ogmen H, Bedell HE. 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