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The visual backward masking deficit in Schizophrenia
Prog. Neuro-Psychopharmacol. &Biol. Psychiat. 2001, Vol. 25, pp. 301-311 Printed by Elsevier Science Inc. Printed in the USA. All rights reserved 0278-5846 / 01 / S-see front matter
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PII: 80278-5846100)00166-4
T H E V I S U A L B A C K W A R D M A S K I N G D E F I C I T IN S C H I Z O P H R E N I A
ROBERT K. McCLURE National Institute of Mental Health, Bethesda, Maryland, U.S.A
(Final form, January 2001)
Contents
1. 2. 2.1. 2.1.1 2.1.2 3. 4. 5. 6.
Abstract Introduction and Background Visual Backward Masking Studies in Schizophrenia Chronological Summary CSD and the No Mask Condition Antipsychotic Medication and Visual Information Processing Mechanisms of Backward Masking in Schizophrenia Association with other Neurocognitive Deficits in Schizophrenia A Candidate Intermediate Phenotype for Schizophrenia? Conclusions and Future Research Acknowledgements References
Abstract McClure, Robert, K.: The Visual Backward Masking Deficit in Schizophrenia. Prog. NeuroPsychopharm. & Biol. Psychiat. 2001, 25, pp. 301-311. Printed by Elsevier Science Inc. Subjects with schizophrenia have an impairment very early in visual information processing, requiring a longer minimal stimulus duration than normal controls to identify a target stimulus. Subjects with schizophrenia have a deficit in visual backward masking, identifying fewer target stimuli than normal controls when the target is briefly obscured by a second visual stimulus When interstimulus interval is increased parametrically, subjects with schizophrenia have trouble identifying target stimuli at intervals that do not affect the performance of normal controls. The visual backward masking deficit: is trait-related; is associated with negative symptoms but has also been associated with measures of thought disorder; may or may not be related to treatment with neuroleptic medication or other neurocognitive deficits of schizophrenia; is of unclear etiology, though researchers have speculated that it involves magnocellular channels and/or the cortical dorsal visual processing stream; has been shown to be heritable in one
study. 3.
If visual information processing deficits are observed in the unaffected siblings of schizophrenic patients, it may be a candidate intermediate phenotype. 301
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Keywords: backward masking, intermediate phenotype, neurocognitive deficits, schizophrenia, visual masking, visual-spatial working memory. Abbreviations: interval (ISI).
critical interstimulus interval (CSI), critical stimulus duration (CSD), interstimulus
1. Introduction and Background It
Backward visual masking is a parametric, experimental paradigm used to examine the earliest stages of visual information processing (Fig 1). In this paradigm, the experimenter finds the minimal duration a subject needs to identify an informational stimulus (the target) by varying the stimulus duration, usually 10-20 msec. The target (usually a letter) is followed by a brief, noninformational stimulus (the mask) of 10-20 msec duration. The visual system's processing of the target is disrupted by the mask and is called backward visual masking.
tarset
mask
target~ation > prepatory interval
<
) interstimulus interval
Fig 1. The backward visual masking paradigm. There are four important quantities measured in backward masking studies: (1.) critical stimulus duration (CSD) is the minimal time a subject needs to identify a target in the absence of a mask. CSD is determined during pretesting procedures, prior to introduction of the masking condition; (2.) interstimulus interval (ISI) is the time period between the offset of the target and the onset of the mask. ISI typically varies between 10-700 msec; (3.) critical interstimulus interval (CSI) is the interstimulus interval when identifying the target is no longer disrupted by the mask (4.) visual performance, or just performance, is the number of targets correctly identified during a visual masking experiment. 2. Visual Backward Masking Studies in Schizophrenia 2.1. Chronological Summary. Scientists in the 1970's first identified a deficit in early visual information processing schizophrenia. Miller et al (1979) reported a deficit in the performance of remitted schizophrenic patients on antipsychotics compared to normal controls in a backward visual masking experiment. Early studies of visual backward masking in schizophrenia examined the relationship of the deficit to clinical state and prognosis. As previously mentioned, Miller et al (1979) found a deficit in the performance of non-psychotic remitted schizophrenic subjects compared to normal controls. Saccuzzo and Braff(1981) found the CSI was significantly smaller (P <.01) in psychotic schizophrenics with poor prognosis than with good prognosis subjects. CSI decreased with improved clinical state in the good prognosis subjects, but not in the poor prognosis subjects. The deficit in the
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poor prognosis patients was stable and did not change with improved clinical state. Findings are reviewed chronologically below and summarized in Table I. Other early studies examined the relationship of the deficit to treatment with antipsychotic medication, as well as the presence of the deficit in schizophrenia-spectrum and other psychotic illnesses. Braffand Saccuzzo (1982) showed that hospitalized subjects with schizophrenia on antipsychotics had a smaller CSI than hospitalized subjects with schizophrenia off antipsychotics, despite the fact that the subjects receiving medications were more symptomatic. Saccuzzo and Schubert (1981)
Table 1 Backward Visual Masking Studies in Schizophrenia Authors (Year) Subjects
CSD (Significance) Standard Deviation
CS1 (Significance)
Performance with Mask (Significance)
Miller et al (1979) Remitted schizophrenics vs normal controls Brody et al, ([ 980) Schlzophronlcs on/off antlpsychoacs (psychotic) vs depressed (nonpsychotlc) vs Elderl)~ outpaUonts Saccuzzo and Braff (1981 ) Schlzophronic (good/poor prognosis) vs manic and depressed (nonpsychotlc) vs normal controls
CSD not measured SDs used" 2-, 4-msec
CSi not measured
Schlzephrcnics < controls 2-reset (p < 01), 4-mscc (p <.05)
Sch]zophremc < controls
CSDs schz = dep (p < .05) SDs used' CSD, 5-, 25mecc
CSI not measured
Not measured
CSDs pr prog schz > Others (p < 05) SD's used CSD
CSI schz > others (p < .01)
Schizophrenics < depressed at CSD (p<.01), SD 5-meec (p < 01), SD 25-msec (p <.05), Schizophrenic off< on (p < 005) Not measured
Braff and Saccuzzo (1982) Schlzophremcs on/off antlpsychottcs vs depressed
CSDs schz off > schz on > dep (p < 05) SD's used' CSD
Not measured
Kmght and Ellmt (1985) Schlzophremc (good/bad premorbld), non-schlzophremc psychotics, Normal controls
CSD not measured
Not measured
Saccuzzo and Braff (1986) Schlzophremc, mamc schlzoaffectwe (psychotic) vs depressed (nonpsychotlc)
CSDs schz > dep (p < 05) SD's used CSD
Green and Walker (1986) Schizophrenic, manic vs normal controls
Performance Without Mask
{Sl.~nifieance I
Not measured
ISI=20, 60-msec all groups = ISI=120-msec sch off < schz on (p = 01 ), schz on < dep lSi=300-mscc sch on/off < dcp ~p < .05) Poor premorbld schz processed pattern like a cognmve mask, others process pattern and cogmt~ve masks differently
Schizophrenic < controls Schz on = schz off Not measured
Not measured
Schizophrenics < depressed (p < 01)
Schlzophremc < controls
CSD not measured SD's used. 2-mscc
CSI schz > dcp (p <.05)
Not measured
Not measured
Green et a l , (1994) I and II: Schizophrenic, btpolar-mamc, vs normal controls
CSD not measured SD's used. > 10 msec
CSI not measured
ISl=10, 20, 40, 70, 100 mscc, schz, bip < controls for high and low energy mask (p < .0001) Location task. schz < blp, cOntrols
Not measured
Rand et al, (1996) Adolescents vath ADHD, Schlzophrema vs normals
CSD not measured SD's used 16 5 mscc
Not measured
Schizophrenic < controls [Sl=33-mscc (p =.07 ) ISl=49.5-msec ( p ffi .02)
Schtzophremc = controls
Butler et al, (1996) Schlzophremcs on/off antlpsychotlcs vs normal controls
CSDs schz on > controls (p < 03) CSDs schz on > schz off (p =.343) SD's used CSD
Not measured
Controls > schz on (p <.05) Schz off < on (p = 19)
Cadonhead ot al, (1998) Schizophrenics on/off antlpsychotlcs vs normal controls
CSDs schz > controls (p < 005) CSDs schz on > schz off (p<.05) SD's used CSD
Not measured
Schizophrcmc < controls (p < .001) Schizophrenic on < off (p < 06)
Schizophrenic < controls (p < 05) Schzoff < $ch on Schlzophremc < controls Schz off < sch on
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Table 2 Forward Visual Masking Studies in Schizophrenia Authors (Y~r) Subjects
Findings
Slaughius and Baldcer(1995) Schizophrenicsubjects and controls. Saeeuzzoet al. (1996)
Schizophrenic subjects showed no difference from controls on forward maskin~ task. Schizophrenic subjects showed no difference from controls on forward nmskin 8 task.
found that nonpsychotic subjects with schizotypal personality disorder, not receiving antipsychotics, had backward masking performance as impaired as schizophrenic subjects, many of whom required antipsychotic medications. Schubert et al (1985) demonstrated a masking deficit in schizoaffective, manic and unipolar depressed patients. Saccuzzo and Braff (1986) replicated the finding in schizoaffective and manic patients. The deficit in bipolar patients was not related to the presence or absence of psychotic symptoms; persisted when manic symptoms resolved; and was at least partially attributable to lithium (Fleming and Green, 1995). Lithium appears to have a detrimental effect on visual processing (Kropf and Muller-Oerlinghausen, 1985).
Knight (1984) has speculated that a subgroup of schizophrenic patients with poor premorbid status and severe negative symptoms are deficient in their ability to schematize visual stimuli. Knight and Elliot (1985) found that a subgroup of schizophrenics with poor premorbid function did not differentially process a pattern mask and information mask. Green and Walker (1986) revisited the relationship of the deficit with positive and negative symptoms, finding that, among schizophrenic subjects, greater negative symptoms were associated with a larger CSI (P < .05). The negative symptom scale included items associated with poor prognosis like poor social competence and fiat affect. Perry and Braff (1994) have found associations between measures of thought disorder and performance on visual backward masking tasks. Of interest, schizophrenic subjects show no difference from normal controls on forward masking studies (Table 2), an observation that Saeeuzzo et al. (1996) cite as support for a centrally-mediated (rather than peripherally-mediated) mechanism for visual masking. 2.1.1. CSD and the No Mask Condition. Saccuzzo and Braff(1981) first noted schizophrenic subjects require a longer minimal stimulus duration to identify a target, even in the absence of a mask. The finding that schizophrenic subjects have a longer critical stimulus duration was replicated in four studies (Table 1). Similarly, Miller et al (1979) observed schizophrenic subjects perform more poorly than controls in the "no-mask" condition. This finding was also replicated in four studies. Schizophrenics, compared to normal controls, have a longer critical stimulus duration, and deficits in performance, even in the absence of a visual mask. The observation that schizophrenics have deficits in the absence of a visual mask, is consistent with the deficit in visual-spatial working memory observed by other investigators (O'Dormell et al. 1996; Goldberg and Weinberger, 1994). Whether these two deficits are related is the subject of speculation. 2.1.2. Antipsychotic Medication and Visual Information Processing. Five studies address the effect of antipsychotic medications on visual information processing (Table 1). Generally, schizophrenic subjects off medications perform more poorly on visual backward masking tasks than subjects on medications. This is consistent with the finding that chlorpromazine slow the decay of
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visual short-termmemory (Stone et al, 1969). The relationshipof antipsychoticmedications and criticalstimulus durationhas not been studied.
3. Mechanisms of Backward Masking in Schizophrenia It is generally accepted that magnocellular (transient) and parvocellular (sustained) neurons: respond to different characteristics of visual stimuli; are activated at different times during early visual information processing; and have unique anatomic distribution with regard to retinal origin, thalamic and cortical projections (Livingstone and Hubel, 1987, 1988). Both types of channels contribute input to a cortical dorsal visual information processing stream, beginning at the level of layer 4 in V1 in the posterior parietal cortex. The dorsal stream appears to be involved in locating objects, while the ventral stream appears to be involved in identifying objects (Van Essen et al 1992). Breitmeyer and Ganz (1976) and Breitmeyer (1984) first proposed a mechanism that underlies backward visual masking. Specifically, they hypothesize that "transient neurons inhibit sustained ones via internuncial neurons at the (lateral geniculate nucleus) and cortex". The hypothesis that inhibitory interneurons, driven by magnocellular neurons, synapse on parvocellular neurons is certainly reasonable. Clinical studies provide indirect evidence that a subcortical abnormality in the magnocellular eharmels or a cortical abnormality in the dorsal processing stream, may exist :in schizophrenia. Green et al (1994) tested the hypothesis that overactive magnoeellular visual channels in schizophrenic subjects could cause the backward visual masking deficit. By altering characteristics of the target and the experimental task, Green's group increased reliance on magnoeellular pathways. Specifically, they altered the characteristics of visual stimuli by blurring the target and using a location task. Under these conditions, the schizophrenic subjects performed more poorly on a visual backward masking task than normal controls. Cadenhead et al (1998) also tested the hypothesis that a subcortical abnormality in the magnocellular eharmels or a cortical abnormality in the dorsal processing stream eanses the backward masking deficit. They increased reliance on magnocellular pathways and the dorsal processing stream using a similar strategy. Specifically, they used a backward masking identification and location task. Under these conditions, the schizophrenic subjects performed more poorly than normal controls on a backward masking location task. In contrast to the clinical studies of Green et al (1994) and Cadenhead et al (1998), neuroanatomic and neurophysiologic studies in animals do not suggest that inhibitory intemeurous are associated with magnocellular channels in the lateral genieulate nucleus. Investigators initially observed inhibitory converg~ace of magno- and parvocellular pathways in cat lateral geniculate nucleus (Singer and Bedworth, 1973). Further investigation identified inhibitory intemeurons in the lateral geniculate, with response properties of characteristic of parvocellular neurons, driven by parvocellular retinal cells (Hamos et al, 1985). Investigators who replicated the latter finding, observed no inhibitory intemeurons in the magnocellular pathways of the lateral geniculate nucleus (Sherman and Freidlander, 1988). Sherman and Freidlander (1988) concluded that inhibitory, gamma-aminobutric acid intemeurons were firmly embedded in the parvocellular, but not in the magnocellular, system. Thus, an apparent discrepancy exists between the findings of clinical and animal studies. The findings of the former supports the hypothesis that overactive magnocellular visual channels in
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R.K. McClure schizophrenic subjects could cause the backward visual masking deficit. The findings of the latter suggest that inhibitory interneurons in the lateral geniculate are associated with, and have the response properties of parvocellular, not magnocellular, neurons. Further neuroanatomic and neurophysiologic studies should address this apparent discrepancy. If it persists, any etiologic theory of the backward masking deficit of schizophrenia must ultimately contend with this discrepancy. Reductions in glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis, and the level of expression of GAD-67 mRNA, have both been reported to be reduced in the dorsolateral prefrontal cortex of subjects with schizophrenia (Bird et al., 1979, Sherman et al., 1992, Akbarian et al., 1995). Alterations in GABA-A receptors have been reported in ligand binding studies (Benes et al., 1996). There are two recent reports of selective alteration of chandelier axon terminals, a particular subclass of GABAergic receptors, in the prefrontal cortex of schizophrenic subjects (Woo et al., 1998, Pierri et al., 1999). Thus a deficit in GABAergic transmission in subcortical parvocellular pathways is plausible. Other neurotransmitter systems (dopamine, serotonin, norepinephrine, and glutamate) have also been implicated in schizophrenia (McClure and Weinberger, 1999). A deficit in GABAergic subcortical parvocellular pathways would require revision of the current magno-/parvocellular hypothesis. Alternatively, a cortical abnormality in the magno/parvocellular pathways of the dorsal processing stream might explain this discrepancy.
There are currently no neuroanatomic or neurophysiologic studies describing the association of inhibitory intemeurons within magno-/parvoeeUular pathways in the dorsal processing pathways of the cortex. The clinical studies of O'Dormell et al. (1996) do not contradict the existence of a deficit in dorsal processing stream function. O'Donnell and colleagues identified performance deficits on visual trajectory discrimination and recognition tasks in schizophrenic subjects compared to normal controls. The authors attribute impaired visual spatial perception and representation to deficits in the dorsal processing stream and prefrontal systems associated with working memory. They suggest the deficits in trajectory discrimination may reflect a disturbance of the dorsal pathway of the visual system, while the disturbances of trajectory recognition may reflect a deficit in prefrontal systems involved in working memory operations. Eslinger et al. (1997) predict that specific areas in the prefrontal cortex are dedicated to visual recognition, and that these areas may be disrupted in schizophrenia. Deficits in the performance of schizophrenic subjects on visual-spatial tasks has been observed by other investigators (Goldberg and Weinberger, 1994) and attributed to dysfunction of prefrontal systems involved in visual working memory. Weinberger (1993) theorizes that functional dyseonnectivity of the prefrontal cortex and hippocampus are dysfunctional in schizophrenia, while other investigators (Andreasen et al., 1999) emphasize deficits in corticothalamocerebellar pathway dysfunction in schizophrenia. Further study of the behavior of neurons and groups of neurons may eventually clarify the underlying etiology of the visual backward masking deficit in light of the apparent disrepancy between clinical and neuroanatomical and neurophysiological findings. There continue to be updates and refinements to this approach (Breitmeyer, 1992; Bachrnan, 1994). Green et al (1997) speculate that the backward masking deficit of schizophrenia involves two components. They suggest an early component, determined primarily by "inherent characteristics of visual information processing", occurs at ISI's less than 70 milliseconds. A late component, determined by "attentional disengagement", occurs at ISI's greater than 70 msec. Francis (1997) has developed a neural network model of visual perception, "the boundary contour system". Computer simulation of this model with a single set of parameters, demonstrate that it accounts for nine key properties of metacontrast masking. The model's dynamic properties explain the characteristics of
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metacontrast visual masking. Metacontrast masking continues to be a favorite psychophysical tool used to investigate visual information processing in schizophrenia. 4. Association with other Neurocognitive Deficits in Schizophrenia
Voruganti et al (1997) examined the association of performance on a visual backward masking task, a span of apprehension task, Wisconsin card sorting, and a continuous performance task with positive and negative symptoms. Visual backward masking tasks and other neurocognitive deficits have been examined simultaneously in schizophrenic patients (Wong et al, 1996; Suslow and Volker, 1997). The studies that correlate visual backward masking to other neurocognitive deficits in schizophrenia (Cadenhead et al., 1998) are not adequate to clearly understand their interrelationship. The relationship between smooth eye pursuit dysfunction and visual backward masking deficit has not been examined (Allen, 1995). It would be worthwhile to examine statistical associations between the backward masking deficit and other neurocognitive deficits in schizophrenia. If such an association exists, it would support the existence of a generalized neurocognitive deficit in schizophrenia, an idea supported by the observation that schizophrenic subjects perform more poorly on neurocognitive tasks as they become more difficult and/or more discriminating. 5. A Candidate Intermediate Phenotype for Schizophrenia ? Two studies have examined if a deficit exists in the first degree relatives of schizophrenic patients. Green et al (1997) demonstrated the backward masking deficit in unaffected siblings of patients with schizophrenia on the early but not the late components. Lieb et al (1996) were unable to detect a backward masking defect in seventeen adolescent children of schizophrenic patients. However, additional studies of first degree relatives of schizophrenics are needed to confirm that backward masking, like abnormalities in smooth pursuit eye movements, reflect a genetic vulnerability to schizophrenia. If visual information processing deficits are clearly determined to be heritable (observed in the unaffected siblings of schizophrenic patients in further studies) such deficts could be candidate intermediate phenotypes for schizophrenia. Phenotyping large numbers of subjects would be relatively easy, since these procedures can be performed in thirty minutes as part of a neuropsychological battery. The equipment required (a microcomputer or a tachistoscope) is relatively inexpensive and readily available. 6. Conclusions and Future Research The backward masking deficit in schizophrenia cannot be attributed to hospitalization or active thought disorder (Saeeuzzo and Braff, 1986). Negative symptoms and measures of poor prognosis are associated with the deficit. The backward masking deficit can be detected in schizophrenia spectrum disorders and affcctive disorders with a psychotic component. In bipolar disorder, the deficit persists in the absence of manic and psychotic symptoms and appears to be related to lithium. Generally, schizophrenic subjects offmedications perform more poorly on visual backward masking tasks than subjects on medications. Antipsychotic medications may slow the decay of visual shortterm memory.
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R.K. McClure A deficit in early visual information processing occurs in the first few milliseconds of visual information processing, even in the absence of a visual mask. The neurobiological mechanism of visual backward masking is unclear. Neuroanatomic and neurophysiologic evidence derived from animal studies does not support the hypothesis that magnocellular neurons drive inhibitory intemeurons that synapse on parvocellular neurons. Studies examining of the association of performance on visual backward masking tasks with other neurocognitive deficits in schizophrenia have not been performed. Future research should examine if a statistical association exists between the backward masking deficit and other neuroeognitive deficits in schizophrenia. If visual information processing deficits are heritable traits, such deficits could be eandidate intermediate phenotypes. Acknowledgements Richard Coppolla, Ph.D. for his observations about CSD and the "no mask" condition; Daniel Weinberger, M.D. for his thoughts about visual working memory and the function of the prefrontal cortex; Terry Goldberg, Ph.D. for his comments about neuropsychological testing and the integrity of the visual system in schizophrenia, Joseph Callicott and Michael Egan, M.D for their comments about intermediate phenotypes.
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SHERMAN, S.M. and FRIEDLANDER, M.J. (1988) Identification of X Versus Properties for lnterneurons in the A-laminae of the Cat's Lateral Geniculate Nucleus. Exp Brain Res. 73..__5: 384-392. SLAGHIUS and BAKKER (1995) Schizophrenic Subjects Show No Difference from Controls on Forward Masking Tasks. J Abn Psycho1104(1):41-54. SINGER, W, and BEDWORTH, N. (1973) Inhibitory Interactions between X and Y Units in the Cat Lateral Geniculate Nucleus. Brain Res. 49_:291-307. STONE G.C., CALLAWAY, E., REESE, T.J. and GENTRY, T. (1969) Chlopromazine Slows Decay of Visual Short-term Memory. Psychon. Sci. 16(5): 229-230. SUSLOW, T. and VOLKER, A. (1997) Paranoid Schizophrenia: Non-specificity of Neuropsychological Vulnerability markers. Psychiat Res. 72:103-114. VAN ESSEN, D.C., ANDERSON, D.H., and FELLEMEN, D.J. (1992) Information Processing in the Primate Visual System: An Integrated Systems Perspective. Science. 25____55419-423. : VORUGANTI, L.N.P., HELSEGRAVE, R.J. and AWAD, A.G. (1997) Neurocognitive Correlates of Positive and Negative Syndromes in Schizophrenia. Can J Psychiat. 42.__5:10661071. WEINBERGER, D.R. (1993) A Connectionist Approach to the Prefrontal Cortex. J Neuropsychiatry and Clin Neurosciences 5(3): 241-53. WONG, H.C., VORUGANTI, L.N.P., HELSEGRAVE, R.J., and AWAD, G.A. (1996) Neurocognitive Deficits and Neurological Signs in Schizophrenia. Schiz Res 23:139-146. WOO, T-U, WHITEHEAD, R.E., MELCHITSKY, D.S., LEWIS, D.A. (1998) A Subclass of Prefrontal Gamma-aminobutyric Acid Axon Terminals Are Selectively Altered in Schizophrenia. Proc. Natl. Acad. Sci. USA. 95:5341-5346. Inquiries and reprint requests should be addressed to: Robert K. McClure, M.D. 10 Center Drive, Rm 4D18-20 Bethesda, MD, 20892, U.S.A Tel: (301)-402-3093 Fax: (301)480-7795 or emall: rn¢[email protected]
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ELSEVIER
PII: 80278-5846100)00166-4
T H E V I S U A L B A C K W A R D M A S K I N G D E F I C I T IN S C H I Z O P H R E N I A
ROBERT K. McCLURE National Institute of Mental Health, Bethesda, Maryland, U.S.A
(Final form, January 2001)
Contents
1. 2. 2.1. 2.1.1 2.1.2 3. 4. 5. 6.
Abstract Introduction and Background Visual Backward Masking Studies in Schizophrenia Chronological Summary CSD and the No Mask Condition Antipsychotic Medication and Visual Information Processing Mechanisms of Backward Masking in Schizophrenia Association with other Neurocognitive Deficits in Schizophrenia A Candidate Intermediate Phenotype for Schizophrenia? Conclusions and Future Research Acknowledgements References
Abstract McClure, Robert, K.: The Visual Backward Masking Deficit in Schizophrenia. Prog. NeuroPsychopharm. & Biol. Psychiat. 2001, 25, pp. 301-311. Printed by Elsevier Science Inc. Subjects with schizophrenia have an impairment very early in visual information processing, requiring a longer minimal stimulus duration than normal controls to identify a target stimulus. Subjects with schizophrenia have a deficit in visual backward masking, identifying fewer target stimuli than normal controls when the target is briefly obscured by a second visual stimulus When interstimulus interval is increased parametrically, subjects with schizophrenia have trouble identifying target stimuli at intervals that do not affect the performance of normal controls. The visual backward masking deficit: is trait-related; is associated with negative symptoms but has also been associated with measures of thought disorder; may or may not be related to treatment with neuroleptic medication or other neurocognitive deficits of schizophrenia; is of unclear etiology, though researchers have speculated that it involves magnocellular channels and/or the cortical dorsal visual processing stream; has been shown to be heritable in one
study. 3.
If visual information processing deficits are observed in the unaffected siblings of schizophrenic patients, it may be a candidate intermediate phenotype. 301
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Keywords: backward masking, intermediate phenotype, neurocognitive deficits, schizophrenia, visual masking, visual-spatial working memory. Abbreviations: interval (ISI).
critical interstimulus interval (CSI), critical stimulus duration (CSD), interstimulus
1. Introduction and Background It
Backward visual masking is a parametric, experimental paradigm used to examine the earliest stages of visual information processing (Fig 1). In this paradigm, the experimenter finds the minimal duration a subject needs to identify an informational stimulus (the target) by varying the stimulus duration, usually 10-20 msec. The target (usually a letter) is followed by a brief, noninformational stimulus (the mask) of 10-20 msec duration. The visual system's processing of the target is disrupted by the mask and is called backward visual masking.
tarset
mask
target~ation > prepatory interval
<
) interstimulus interval
Fig 1. The backward visual masking paradigm. There are four important quantities measured in backward masking studies: (1.) critical stimulus duration (CSD) is the minimal time a subject needs to identify a target in the absence of a mask. CSD is determined during pretesting procedures, prior to introduction of the masking condition; (2.) interstimulus interval (ISI) is the time period between the offset of the target and the onset of the mask. ISI typically varies between 10-700 msec; (3.) critical interstimulus interval (CSI) is the interstimulus interval when identifying the target is no longer disrupted by the mask (4.) visual performance, or just performance, is the number of targets correctly identified during a visual masking experiment. 2. Visual Backward Masking Studies in Schizophrenia 2.1. Chronological Summary. Scientists in the 1970's first identified a deficit in early visual information processing schizophrenia. Miller et al (1979) reported a deficit in the performance of remitted schizophrenic patients on antipsychotics compared to normal controls in a backward visual masking experiment. Early studies of visual backward masking in schizophrenia examined the relationship of the deficit to clinical state and prognosis. As previously mentioned, Miller et al (1979) found a deficit in the performance of non-psychotic remitted schizophrenic subjects compared to normal controls. Saccuzzo and Braff(1981) found the CSI was significantly smaller (P <.01) in psychotic schizophrenics with poor prognosis than with good prognosis subjects. CSI decreased with improved clinical state in the good prognosis subjects, but not in the poor prognosis subjects. The deficit in the
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poor prognosis patients was stable and did not change with improved clinical state. Findings are reviewed chronologically below and summarized in Table I. Other early studies examined the relationship of the deficit to treatment with antipsychotic medication, as well as the presence of the deficit in schizophrenia-spectrum and other psychotic illnesses. Braffand Saccuzzo (1982) showed that hospitalized subjects with schizophrenia on antipsychotics had a smaller CSI than hospitalized subjects with schizophrenia off antipsychotics, despite the fact that the subjects receiving medications were more symptomatic. Saccuzzo and Schubert (1981)
Table 1 Backward Visual Masking Studies in Schizophrenia Authors (Year) Subjects
CSD (Significance) Standard Deviation
CS1 (Significance)
Performance with Mask (Significance)
Miller et al (1979) Remitted schizophrenics vs normal controls Brody et al, ([ 980) Schlzophronlcs on/off antlpsychoacs (psychotic) vs depressed (nonpsychotlc) vs Elderl)~ outpaUonts Saccuzzo and Braff (1981 ) Schlzophronic (good/poor prognosis) vs manic and depressed (nonpsychotlc) vs normal controls
CSD not measured SDs used" 2-, 4-msec
CSi not measured
Schlzephrcnics < controls 2-reset (p < 01), 4-mscc (p <.05)
Sch]zophremc < controls
CSDs schz = dep (p < .05) SDs used' CSD, 5-, 25mecc
CSI not measured
Not measured
CSDs pr prog schz > Others (p < 05) SD's used CSD
CSI schz > others (p < .01)
Schizophrenics < depressed at CSD (p<.01), SD 5-meec (p < 01), SD 25-msec (p <.05), Schizophrenic off< on (p < 005) Not measured
Braff and Saccuzzo (1982) Schlzophremcs on/off antlpsychottcs vs depressed
CSDs schz off > schz on > dep (p < 05) SD's used' CSD
Not measured
Kmght and Ellmt (1985) Schlzophremc (good/bad premorbld), non-schlzophremc psychotics, Normal controls
CSD not measured
Not measured
Saccuzzo and Braff (1986) Schlzophremc, mamc schlzoaffectwe (psychotic) vs depressed (nonpsychotlc)
CSDs schz > dep (p < 05) SD's used CSD
Green and Walker (1986) Schizophrenic, manic vs normal controls
Performance Without Mask
{Sl.~nifieance I
Not measured
ISI=20, 60-msec all groups = ISI=120-msec sch off < schz on (p = 01 ), schz on < dep lSi=300-mscc sch on/off < dcp ~p < .05) Poor premorbld schz processed pattern like a cognmve mask, others process pattern and cogmt~ve masks differently
Schizophrenic < controls Schz on = schz off Not measured
Not measured
Schizophrenics < depressed (p < 01)
Schlzophremc < controls
CSD not measured SD's used. 2-mscc
CSI schz > dcp (p <.05)
Not measured
Not measured
Green et a l , (1994) I and II: Schizophrenic, btpolar-mamc, vs normal controls
CSD not measured SD's used. > 10 msec
CSI not measured
ISl=10, 20, 40, 70, 100 mscc, schz, bip < controls for high and low energy mask (p < .0001) Location task. schz < blp, cOntrols
Not measured
Rand et al, (1996) Adolescents vath ADHD, Schlzophrema vs normals
CSD not measured SD's used 16 5 mscc
Not measured
Schizophrenic < controls [Sl=33-mscc (p =.07 ) ISl=49.5-msec ( p ffi .02)
Schtzophremc = controls
Butler et al, (1996) Schlzophremcs on/off antlpsychotlcs vs normal controls
CSDs schz on > controls (p < 03) CSDs schz on > schz off (p =.343) SD's used CSD
Not measured
Controls > schz on (p <.05) Schz off < on (p = 19)
Cadonhead ot al, (1998) Schizophrenics on/off antlpsychotlcs vs normal controls
CSDs schz > controls (p < 005) CSDs schz on > schz off (p<.05) SD's used CSD
Not measured
Schizophrcmc < controls (p < .001) Schizophrenic on < off (p < 06)
Schizophrenic < controls (p < 05) Schzoff < $ch on Schlzophremc < controls Schz off < sch on
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Table 2 Forward Visual Masking Studies in Schizophrenia Authors (Y~r) Subjects
Findings
Slaughius and Baldcer(1995) Schizophrenicsubjects and controls. Saeeuzzoet al. (1996)
Schizophrenic subjects showed no difference from controls on forward maskin~ task. Schizophrenic subjects showed no difference from controls on forward nmskin 8 task.
found that nonpsychotic subjects with schizotypal personality disorder, not receiving antipsychotics, had backward masking performance as impaired as schizophrenic subjects, many of whom required antipsychotic medications. Schubert et al (1985) demonstrated a masking deficit in schizoaffective, manic and unipolar depressed patients. Saccuzzo and Braff (1986) replicated the finding in schizoaffective and manic patients. The deficit in bipolar patients was not related to the presence or absence of psychotic symptoms; persisted when manic symptoms resolved; and was at least partially attributable to lithium (Fleming and Green, 1995). Lithium appears to have a detrimental effect on visual processing (Kropf and Muller-Oerlinghausen, 1985).
Knight (1984) has speculated that a subgroup of schizophrenic patients with poor premorbid status and severe negative symptoms are deficient in their ability to schematize visual stimuli. Knight and Elliot (1985) found that a subgroup of schizophrenics with poor premorbid function did not differentially process a pattern mask and information mask. Green and Walker (1986) revisited the relationship of the deficit with positive and negative symptoms, finding that, among schizophrenic subjects, greater negative symptoms were associated with a larger CSI (P < .05). The negative symptom scale included items associated with poor prognosis like poor social competence and fiat affect. Perry and Braff (1994) have found associations between measures of thought disorder and performance on visual backward masking tasks. Of interest, schizophrenic subjects show no difference from normal controls on forward masking studies (Table 2), an observation that Saeeuzzo et al. (1996) cite as support for a centrally-mediated (rather than peripherally-mediated) mechanism for visual masking. 2.1.1. CSD and the No Mask Condition. Saccuzzo and Braff(1981) first noted schizophrenic subjects require a longer minimal stimulus duration to identify a target, even in the absence of a mask. The finding that schizophrenic subjects have a longer critical stimulus duration was replicated in four studies (Table 1). Similarly, Miller et al (1979) observed schizophrenic subjects perform more poorly than controls in the "no-mask" condition. This finding was also replicated in four studies. Schizophrenics, compared to normal controls, have a longer critical stimulus duration, and deficits in performance, even in the absence of a visual mask. The observation that schizophrenics have deficits in the absence of a visual mask, is consistent with the deficit in visual-spatial working memory observed by other investigators (O'Dormell et al. 1996; Goldberg and Weinberger, 1994). Whether these two deficits are related is the subject of speculation. 2.1.2. Antipsychotic Medication and Visual Information Processing. Five studies address the effect of antipsychotic medications on visual information processing (Table 1). Generally, schizophrenic subjects off medications perform more poorly on visual backward masking tasks than subjects on medications. This is consistent with the finding that chlorpromazine slow the decay of
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visual short-termmemory (Stone et al, 1969). The relationshipof antipsychoticmedications and criticalstimulus durationhas not been studied.
3. Mechanisms of Backward Masking in Schizophrenia It is generally accepted that magnocellular (transient) and parvocellular (sustained) neurons: respond to different characteristics of visual stimuli; are activated at different times during early visual information processing; and have unique anatomic distribution with regard to retinal origin, thalamic and cortical projections (Livingstone and Hubel, 1987, 1988). Both types of channels contribute input to a cortical dorsal visual information processing stream, beginning at the level of layer 4 in V1 in the posterior parietal cortex. The dorsal stream appears to be involved in locating objects, while the ventral stream appears to be involved in identifying objects (Van Essen et al 1992). Breitmeyer and Ganz (1976) and Breitmeyer (1984) first proposed a mechanism that underlies backward visual masking. Specifically, they hypothesize that "transient neurons inhibit sustained ones via internuncial neurons at the (lateral geniculate nucleus) and cortex". The hypothesis that inhibitory interneurons, driven by magnocellular neurons, synapse on parvocellular neurons is certainly reasonable. Clinical studies provide indirect evidence that a subcortical abnormality in the magnocellular eharmels or a cortical abnormality in the dorsal processing stream, may exist :in schizophrenia. Green et al (1994) tested the hypothesis that overactive magnoeellular visual channels in schizophrenic subjects could cause the backward visual masking deficit. By altering characteristics of the target and the experimental task, Green's group increased reliance on magnoeellular pathways. Specifically, they altered the characteristics of visual stimuli by blurring the target and using a location task. Under these conditions, the schizophrenic subjects performed more poorly on a visual backward masking task than normal controls. Cadenhead et al (1998) also tested the hypothesis that a subcortical abnormality in the magnocellular eharmels or a cortical abnormality in the dorsal processing stream eanses the backward masking deficit. They increased reliance on magnocellular pathways and the dorsal processing stream using a similar strategy. Specifically, they used a backward masking identification and location task. Under these conditions, the schizophrenic subjects performed more poorly than normal controls on a backward masking location task. In contrast to the clinical studies of Green et al (1994) and Cadenhead et al (1998), neuroanatomic and neurophysiologic studies in animals do not suggest that inhibitory intemeurous are associated with magnocellular channels in the lateral genieulate nucleus. Investigators initially observed inhibitory converg~ace of magno- and parvocellular pathways in cat lateral geniculate nucleus (Singer and Bedworth, 1973). Further investigation identified inhibitory intemeurons in the lateral geniculate, with response properties of characteristic of parvocellular neurons, driven by parvocellular retinal cells (Hamos et al, 1985). Investigators who replicated the latter finding, observed no inhibitory intemeurons in the magnocellular pathways of the lateral geniculate nucleus (Sherman and Freidlander, 1988). Sherman and Freidlander (1988) concluded that inhibitory, gamma-aminobutric acid intemeurons were firmly embedded in the parvocellular, but not in the magnocellular, system. Thus, an apparent discrepancy exists between the findings of clinical and animal studies. The findings of the former supports the hypothesis that overactive magnocellular visual channels in
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R.K. McClure schizophrenic subjects could cause the backward visual masking deficit. The findings of the latter suggest that inhibitory interneurons in the lateral geniculate are associated with, and have the response properties of parvocellular, not magnocellular, neurons. Further neuroanatomic and neurophysiologic studies should address this apparent discrepancy. If it persists, any etiologic theory of the backward masking deficit of schizophrenia must ultimately contend with this discrepancy. Reductions in glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis, and the level of expression of GAD-67 mRNA, have both been reported to be reduced in the dorsolateral prefrontal cortex of subjects with schizophrenia (Bird et al., 1979, Sherman et al., 1992, Akbarian et al., 1995). Alterations in GABA-A receptors have been reported in ligand binding studies (Benes et al., 1996). There are two recent reports of selective alteration of chandelier axon terminals, a particular subclass of GABAergic receptors, in the prefrontal cortex of schizophrenic subjects (Woo et al., 1998, Pierri et al., 1999). Thus a deficit in GABAergic transmission in subcortical parvocellular pathways is plausible. Other neurotransmitter systems (dopamine, serotonin, norepinephrine, and glutamate) have also been implicated in schizophrenia (McClure and Weinberger, 1999). A deficit in GABAergic subcortical parvocellular pathways would require revision of the current magno-/parvocellular hypothesis. Alternatively, a cortical abnormality in the magno/parvocellular pathways of the dorsal processing stream might explain this discrepancy.
There are currently no neuroanatomic or neurophysiologic studies describing the association of inhibitory intemeurons within magno-/parvoeeUular pathways in the dorsal processing pathways of the cortex. The clinical studies of O'Dormell et al. (1996) do not contradict the existence of a deficit in dorsal processing stream function. O'Donnell and colleagues identified performance deficits on visual trajectory discrimination and recognition tasks in schizophrenic subjects compared to normal controls. The authors attribute impaired visual spatial perception and representation to deficits in the dorsal processing stream and prefrontal systems associated with working memory. They suggest the deficits in trajectory discrimination may reflect a disturbance of the dorsal pathway of the visual system, while the disturbances of trajectory recognition may reflect a deficit in prefrontal systems involved in working memory operations. Eslinger et al. (1997) predict that specific areas in the prefrontal cortex are dedicated to visual recognition, and that these areas may be disrupted in schizophrenia. Deficits in the performance of schizophrenic subjects on visual-spatial tasks has been observed by other investigators (Goldberg and Weinberger, 1994) and attributed to dysfunction of prefrontal systems involved in visual working memory. Weinberger (1993) theorizes that functional dyseonnectivity of the prefrontal cortex and hippocampus are dysfunctional in schizophrenia, while other investigators (Andreasen et al., 1999) emphasize deficits in corticothalamocerebellar pathway dysfunction in schizophrenia. Further study of the behavior of neurons and groups of neurons may eventually clarify the underlying etiology of the visual backward masking deficit in light of the apparent disrepancy between clinical and neuroanatomical and neurophysiological findings. There continue to be updates and refinements to this approach (Breitmeyer, 1992; Bachrnan, 1994). Green et al (1997) speculate that the backward masking deficit of schizophrenia involves two components. They suggest an early component, determined primarily by "inherent characteristics of visual information processing", occurs at ISI's less than 70 milliseconds. A late component, determined by "attentional disengagement", occurs at ISI's greater than 70 msec. Francis (1997) has developed a neural network model of visual perception, "the boundary contour system". Computer simulation of this model with a single set of parameters, demonstrate that it accounts for nine key properties of metacontrast masking. The model's dynamic properties explain the characteristics of
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metacontrast visual masking. Metacontrast masking continues to be a favorite psychophysical tool used to investigate visual information processing in schizophrenia. 4. Association with other Neurocognitive Deficits in Schizophrenia
Voruganti et al (1997) examined the association of performance on a visual backward masking task, a span of apprehension task, Wisconsin card sorting, and a continuous performance task with positive and negative symptoms. Visual backward masking tasks and other neurocognitive deficits have been examined simultaneously in schizophrenic patients (Wong et al, 1996; Suslow and Volker, 1997). The studies that correlate visual backward masking to other neurocognitive deficits in schizophrenia (Cadenhead et al., 1998) are not adequate to clearly understand their interrelationship. The relationship between smooth eye pursuit dysfunction and visual backward masking deficit has not been examined (Allen, 1995). It would be worthwhile to examine statistical associations between the backward masking deficit and other neurocognitive deficits in schizophrenia. If such an association exists, it would support the existence of a generalized neurocognitive deficit in schizophrenia, an idea supported by the observation that schizophrenic subjects perform more poorly on neurocognitive tasks as they become more difficult and/or more discriminating. 5. A Candidate Intermediate Phenotype for Schizophrenia ? Two studies have examined if a deficit exists in the first degree relatives of schizophrenic patients. Green et al (1997) demonstrated the backward masking deficit in unaffected siblings of patients with schizophrenia on the early but not the late components. Lieb et al (1996) were unable to detect a backward masking defect in seventeen adolescent children of schizophrenic patients. However, additional studies of first degree relatives of schizophrenics are needed to confirm that backward masking, like abnormalities in smooth pursuit eye movements, reflect a genetic vulnerability to schizophrenia. If visual information processing deficits are clearly determined to be heritable (observed in the unaffected siblings of schizophrenic patients in further studies) such deficts could be candidate intermediate phenotypes for schizophrenia. Phenotyping large numbers of subjects would be relatively easy, since these procedures can be performed in thirty minutes as part of a neuropsychological battery. The equipment required (a microcomputer or a tachistoscope) is relatively inexpensive and readily available. 6. Conclusions and Future Research The backward masking deficit in schizophrenia cannot be attributed to hospitalization or active thought disorder (Saeeuzzo and Braff, 1986). Negative symptoms and measures of poor prognosis are associated with the deficit. The backward masking deficit can be detected in schizophrenia spectrum disorders and affcctive disorders with a psychotic component. In bipolar disorder, the deficit persists in the absence of manic and psychotic symptoms and appears to be related to lithium. Generally, schizophrenic subjects offmedications perform more poorly on visual backward masking tasks than subjects on medications. Antipsychotic medications may slow the decay of visual shortterm memory.
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R.K. McClure A deficit in early visual information processing occurs in the first few milliseconds of visual information processing, even in the absence of a visual mask. The neurobiological mechanism of visual backward masking is unclear. Neuroanatomic and neurophysiologic evidence derived from animal studies does not support the hypothesis that magnocellular neurons drive inhibitory intemeurons that synapse on parvocellular neurons. Studies examining of the association of performance on visual backward masking tasks with other neurocognitive deficits in schizophrenia have not been performed. Future research should examine if a statistical association exists between the backward masking deficit and other neuroeognitive deficits in schizophrenia. If visual information processing deficits are heritable traits, such deficits could be eandidate intermediate phenotypes. Acknowledgements Richard Coppolla, Ph.D. for his observations about CSD and the "no mask" condition; Daniel Weinberger, M.D. for his thoughts about visual working memory and the function of the prefrontal cortex; Terry Goldberg, Ph.D. for his comments about neuropsychological testing and the integrity of the visual system in schizophrenia, Joseph Callicott and Michael Egan, M.D for their comments about intermediate phenotypes.
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