Early stage vision in schizophrenia and schizotypal personality disorder

Schizophrenia Research 86 (2006) 89 – 98 www.elsevier.com/locate/schres

Early stage vision in schizophrenia and schizotypal personality disorder Brian F. O'Donnell a,b,⁎, Andrew Bismark b , William P. Hetrick a , Misty Bodkins b , Jenifer L. Vohs a , Anantha Shekhar b a

b

Department of Psychology, Indiana University, Bloomington, IN, United States Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States Received 23 December 2005; received in revised form 12 May 2006; accepted 17 May 2006 Available online 10 July 2006

Abstract Previous studies of visual perception have reported deficits in contrast sensitivity and dot motion discrimination in schizophrenia. We tested whether these deficits also appear in schizotypal personality disorder (SPD). SPD appears to be genetically and symptomatically related to schizophrenia, but without the marked psychosocial impairment associated with psychotic disorders. The present study investigated contrast sensitivity for moving and static gratings, form discrimination and dot motion discrimination in 24 patients with schizophrenia or schizoaffective disorder (SZ), 16 individuals with SPD, and 40 control subjects. SZ, but not SPD subjects, showed impairments on tests of contrast sensitivity for static and moving gratings, form discrimination in noise, and dot motion discrimination. Visual performance did not differ between medicated SZ patients and patients withdrawn from medication. These results confirm early stage visual deficits in schizophrenia regardless of medication status. SPD subjects, in contrast, show intact early stage visual processing despite the presence of marked schizotypal symptoms. © 2006 Elsevier B.V. All rights reserved. Keywords: Vision; Perception; Contrast sensitivity; Schizophrenia; Schizotypal personality disorder

1. Introduction Schizophrenia is associated with disturbances of visual perception. Both interview and self-report scales indicate that patients with schizophrenia frequently suffer from visual distortions, which appear in the earliest stages of the illness (Bunney et al., 1999; Cutting and Dunne, 1986; Phillipson and Harris, 1985). ⁎ Corresponding author. Department of Psychology, Indiana University, Bloomington, IN, United States. Tel.: +1 812 856 4164; fax: +1 812 855 4691. E-mail address: [email protected] (B.F. O'Donnell). 0920-9964/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2006.05.016

Subjective disturbances are accompanied by visual processing deficits on psychophysical tests (Butler and Javitt, 2005). These psychophysical deficits have often been interpreted in terms of deficits in specific visual pathways or channels. Psychophysical tests measure visual performance thresholds as a function of such factors as contrast, noise, stimulus duration, or stimulus similarity. In primates and humans, two neural pathways for visual processing have been characterized by the differing response properties of the magnocellular (M) and parvocellular (P) neurons of the lateral geniculate nucleus (Livingstone and Hubel, 1988; Wandell,

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1995). The M pathway is characterized by high contrast sensitivity, high temporal resolution, low spatial resolution, and insensitivity to color. The P pathway has low contrast sensitivity, low temporal resolution, high spatial resolution, and strong color opponency responses. Human psychophysical performance also suggests the existence of a transient or broad-band visual channel, whose response properties are similar to those of the M pathway, and the sustained channel, which resembles the P pathway (Legge, 1978; Livingstone and Hubel, 1988; Merigan and Maunsell, 1993). Functional differentiation continues into the cortex, with a ventral cortical pathway from the occipital to the inferior temporal lobe for the analysis of color and object properties, and a dorsal pathway from the occipital to the parietal lobe for motion and spatial relationships (Ungerleider, 1985; Van Essen and Gallant, 1994; Merigan et al., 1997). The M pathway primarily projects to the dorsal stream of the cortex, while the P pathway primarily projects to the ventral cortical stream. A number of investigators have proposed that schizophrenia is associated with a more severe disturbance of M or transient channel relative to P or sustained channel processing (Butler and Javitt, 2005; O'Donnell et al., 1996; Green et al., 1994; Kéri et al., 2004). In the following section, findings are reviewed from studies of perception of coherent dot motion and contrast sensitivity for static and moving grating stimuli in terms of visual pathway function. One of the most consistent findings in schizophrenia has been impaired discrimination of the trajectory of moving dots in both medicated (Brenner et al., 2003; Chen et al., 2003b, 2005; Hooker and Park, 2000; Li, 2002; O'Donnell et al., 1996; Stuve et al., 1997) and unmedicated patients (Richardson et al., 1996). In a widely used paradigm, the motion coherence or dot kinetogram test, the percentage of dots moving in a uniform direction is varied (e.g. Brenner et al., 2003; Chen et al., 2003b). This percentage is usually referred to as motion coherence and constitutes the signal in the image. The percentage of motion coherence required for a specific level of discrimination performance, or threshold, is usually higher in schizophrenia than in control subjects. Li (2002) showed that this deficit was due to reduced sensitivity, rather than altered response bias. With respect to neural mechanisms, animal and human studies indicate that the dorsal visual pathway, particularly cortical region MT, is involved in the perception of coherent motion from an array of moving dots (Newsome and Pare, 1988). Chen et al. (2003b) found that patients with schizophrenia were impaired at

discrimination of coherent motion of moving dots, which requires global motion processing, but not at discrimination of moving gratings, which can be accomplished by local visual cues. Chen and colleagues argued that these findings suggest a late stage motion processing deficit in schizophrenia, probably in cortical regions specialized for motion perception. Contrast sensitivity for sinusoidal grating stimuli has also been studied in schizophrenia. Contrast sensitivity is the inverse of contrast threshold (the minimum physical contrast needed to reliably detect a stimulus). Some investigators (Butler et al., 2005; Kéri et al., 2002; Schwartz et al., 1987; Slaghuis, 1998, 2004) but not all (Chen et al., 1999a,b) have found deficient contrast sensitivity in schizophrenia. In monkeys, magnocellular lesions have their greatest impact on contrast sensitivity for low spatial frequencies (< 4 cycles/degree) at temporal frequencies above 8 Hz, while parvocellular lesions have their greatest impact at temporal frequencies below 4 Hz (Merigan and Maunsell, 1993). Human psychophysical studies indicate that transient channels are insensitive at spatial frequencies above 4 cycles/degree (Legge, 1978). Consequently, a differential contrast sensitivity deficit at low spatial and high temporal frequencies would be supportive of an M deficit. This pattern has not been consistently found. Schwartz et al. (1987) reported that contrast sensitivity deficits were most reliably observed for temporally modulated gratings, rather than static gratings, suggestive of a transient channel deficit. Butler et al. (2005) reported a greater schizophrenia deficit at low compared to high spatial frequencies. Slaghuis (1998, 2004), on the other hand, found that negative symptom schizophrenic patients showed a deficit for both stationary and moving patterns for both low and high spatial frequencies. Positive symptom patients showed deficits only at medium to high spatial frequencies (Slaghuis, 1998) or no impairment at any spatial frequency (Slaghuis, 2004). Chen et al. (2003a) hypothesized that the differences among studies of contrast sensitivity may have been related to medication levels. Chen and colleagues reported that patients receiving typical anti-psychotic medications showed elevated contrast thresholds and patients receiving novel anti-psychotic medications showed unimpaired contrast sensitivity levels for a moving grating stimulus. Moreover, unmedicated patients demonstrated decreased contrast threshold levels, indicative of performance which was better than that of control subjects. Chen et al. suggested that these medication effects might be mediated by dopaminergic cells in the retina which influence contrast sensitivity. Increased

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dopaminergic activity may increase contrast sensitivity (Tagliati et al., 1994), while reduced dopaminergic activity may reduce contrast sensitivity (Bodis-Wollner and Tagliati, 1993). An unresolved issue is whether these visual disturbances might be a liability marker, or endophenotype, for schizophrenia. Two groups have been evaluated to investigate this possibility: relatives of patients with schizophrenia, and individuals with schizotypal personality disorder (SPD). SPD is related to schizophrenia in terms of symptoms and genetic risk (Kety et al., 1994; Siever and Davis, 2004), but is usually not associated with severe psychosocial impairment or treatment with anti-psychotic medication. SPD thereby provides a vehicle to identify which neural or cognitive processes are common to schizophrenia spectrum disorders, and which are only associated with psychosis. SPD has been associated with subjective perceptual distortions (Camisa et al., 2005; Raine, 1991), and with deficits on tests of visual backward masking, cognition, and working memory (Cadenhead et al., 1999; Siever and Davis, 2004). With respect to early stage vision, a previous study by Farmer et al. (2000) found intact thresholds for discrimination of form and motion in noise in SPD, suggestive of spared early stage visual processing. Studies of firstdegree relatives of patients with schizophrenia have yielded inconsistent findings. Chen et al. (1999b) reported that first-degree relatives of patients with schizophrenia showed a deficit in velocity discrimination for moving grating stimuli. Subsequently, Chen et al. (2005) found that first-degree relatives were unimpaired on a test of coherent dot motion discrimination (Chen et al., 2005). The aim of the present study was to clarify whether early stage visual processing is differentially affected in schizophrenia and SPD. Tests of contrast sensitivity were designed to probe the M and P pathways. Motion and form coherence tests were used to assess the dorsal and ventral cortical pathways. By measuring performance thresholds, these paradigms allow for matching of task difficulty and internal reliability across conditions (Chapman and Chapman, 1973; Brenner et al., 2003). Because medication status may affect performance, patients receiving medication were compared with patients who had recently discontinued medication. Because visual task performance may be affected by the general intellectual deficit observed in a broad range of cognitive measures (Brenner et al., 2002; Chapman and Chapman, 1973; Mohamed et al., 1999), we also evaluated aspects of current intellectual function.

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2. Materials and methods 2.1. Subjects We tested 24 subjects (6 women) with schizophrenia or schizoaffective disorder (SZ), 16 subjects with SPD (9 women) and 40 comparison subjects (20 women). Four of the SZ patients were diagnosed with schizoaffective disorder, and 20 with schizophrenia. All subjects were between the ages of 18 and 61 years, had completed grade school level education, and had Snellen visual acuity of 20/30 or better. Exclusion criteria included history of neurological disease, history of a head injury that resulted in loss of consciousness, a current or previous diagnosis of substance dependence or alcohol dependence, or alcohol or substance use within 24 hours prior to testing. Table 1 provides group characteristics. ANOVA indicated that group differences in age were not significant (p = .45). Written and oral informed consent was obtained from all subjects. Patients with SZ were evaluated using the SCID I (First et al., 1995) and clinical records to obtain a DSMIV diagnosis. Mean age of onset was 19.7 years (S.D. = 6.8), and the mean illness duration was 15.2 years (S.D. = 10.3). Thirteen subjects were receiving novel anti-psychotic medications, one was receiving both conventional and novel anti-psychotic medication, and ten patients had discontinued medication prior to testing (mean days removed from medication = 20, S.D. = 19). SPD subjects were recruited through newspaper advertisements and were diagnosed using DSM-IV criteria based on a SCID II interview (First et al., 1997). No SPD subjects met criteria for an Axis I disorder or were receiving pharmacological treatment at the time of testing. None of the control subjects met criteria for an Axis I disorder, or Cluster A personality disorder. Control participants received a telephone screen for Table 1 Subject characteristics Measure

Control

Age (years) 36.6 (10.2) Similarities 9.3 (2.8) Picture Completion 10.9 (3.3) Digit Symbol 9.8 (2.8) Full Scale IQ 99.3 (13.9) SPQ: cognitive/perceptual 8.0 (6.2) SPQ: negative 6.4 (4.5) SPQ: disorganized 4.0 (3.1)

SPD

Schizophrenia

32.8 (9.2) 8.9 (2.4) 9.8 (3.0) 8.8 (1.9) 94.2 (12.3) 21.6 (4.7) 13.2 (5.8) 8.3 (4.1)

34.8 (12.1) 7.1 (2.6) 6.8 (2.7) 5.5 (2.4) 76.2 (12.3) – – –

Mean values are accompanied by standard deviation (S.D.) in parentheses. SPQ: Schizotypal Personality Questionnaire. Age scaled scores are provided for the Similarities, Picture Completion, and Digit Symbol tests from the WAIS-III.

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medical and psychiatric exclusion criteria. The Mini International Neuropsychiatric Interview (MINI; Sheehan et al., 1998) was subsequently used to detect possible Axis I psychiatric diagnoses. The SCID II modules for Schizoid, Paranoid, and Schizotypal Personality Disorder were administered in order to exclude participants presenting with these personality disorders from the control group. 2.2. Diagnostic assessment and clinical measures Tests from the Wechsler Adult Intelligence Scale-III (WAIS-III), Similarities, Picture Completion and Digit Symbol, were used to assess dimensions of current intellectual function (Wechsler, 1997). These tests typically are associated with three functionally distinct factors in psychometric and neuropsychological studies: verbal comprehension (Similarities), perceptual organization (Picture Completion), and psychomotor performance (Digit Symbol) (Lezak, 1995). These subtests of the WAIS have been shown to be highly sensitive to schizophrenia (Mohamed et al., 1999). A prorated Full Scale IQ score was also computed. Age scaled scores were used for all statistical analyses. The Schizotypal Personality Questionnaire (SPQ) was developed based on DSM-III-R criteria for SPD, and contains 74 items (Raine, 1991). The SPQ was completed by the SPD (N = 16) and control subjects (N = 39). The SPQ was subdivided into three symptom factors (Raine et al., 1994): a cognitive–perceptual deficits factor, an interpersonal deficits factor, and a disorganization factor. The Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987) was used to assess symptoms in 16 SZ patients. Summary scores were calculated for the positive scale (Mean = 19.6, S.D. = 5.4) and negative scale (Mean = 15.0, S.D. = 5.1). 2.3. Form and motion noise thresholds Perception of form and dot motion properties were evaluated using psychophysical tests (for detailed methods, see Farmer et al., 2000; Brenner et al., 2003). In the form discrimination task, subjects were required to discriminate between two shapes (circle vs. square with rounded corners) at different levels of static noise. The stimuli subtended 2.9° of visual angle and were presented for 3 s, with a viewing distance of 70 cm. The subject responded with a key press to indicate which stimulus was presented. The dot motion trajectory discrimination task consisted of a field of moving dots moving either right or left across the screen at an apparent velocity of 3.5°/s. One hundred dots were

presented for 500 ms in a rectangular display subtending 8.1° visual angle with a viewing distance of 70 cm. The percentage of dots moving in random trajectories was varied to obtain thresholds. The subject responded by key press to indicate the direction of the coherent dot motion. Both tasks used an adaptive staircase method to estimate performance thresholds (Levitt, 1970). If the subject was correct on two successive trials, noise was added to the stimulus. This made the next judgment more difficult. If the subject was incorrect, noise was removed from the stimulus. Noise was first introduced in increments of 10%, then, after the first error, in increments of 5%. After the fourth error, the increments were reduced to 2%. The subject's performance gradually converged around a threshold value, which was the amount of coherence (signal) required to obtain a 70.7% performance level. The coherence threshold, calculated as the mean value of the final six trials of the staircase (Brenner et al., 2003), was the dependent measure used for analysis. Lower coherence thresholds indicated better performance. 2.4. Contrast sensitivity tests Contrast sensitivity for gratings was tested for both static and moving spatial frequency gratings. Sinusoidally modulated, vertically oriented gratings were presented as stimuli using the Morphonome Image Psychophysics System (Tyler and McBride, 1995) on a PowerMac computer platform with a luminance calibrated CRT monitor. Gratings were spatially modulated with a Gaussian envelope subtending 8.37° of visual angle at a viewing distance of 115 cm. Two types of tasks were used. A grating detection task with a static, high spatial frequency grating was used to probe the P pathway. A low spatial frequency grating which was temporally modulated to produce apparent motion was used to probe the M pathway. In the static grating detection task, a grating with a spatial frequency of 9.9 cycles/degree of visual angle was used as the target. The grating was initially presented for 1000 ms at 42% Michelson contrast. Tone pips signaled the onset and offset of the trial. Fifty percent of the trials presented a grating, and 50% were null trials. The subject responded verbally regarding whether a grating was present or not, and the experimenter entered the response and initiated the next trial. In the moving grating discrimination task, a sinusoidal grating with a spatial frequency of 1.3 cycles/ degree was modulated to produce apparent motion at one of three temporal frequencies (2.1, 9.3 and

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18.8 cycles/s) for 480 ms. The grating was initially presented at 30% Michelson contrast. Tone pips signaled the onset and offset of each trial. On each trial, the subject indicated whether the grating appeared to move to the right or to the left. For both the static and moving grating tasks, a staircase method was used to estimate contrast thresholds (Tyler, 1991; Tyler and McBride, 1995) Contrast was varied in steps of 0.05 log units. The staircase procedure varied contrast based on correct and incorrect responses, increasing the contrast by three steps (0.15 log units) for each incorrect response and decreasing by one step for each correct response. At asymptote, this procedure provides a 75% correct threshold level, which is calculated on the moving average of the last 16 trials in a sequence, arriving at the threshold estimate when the standard deviation and least squares slope of the step values reach a stable criterion (S.D. < 0.3%, slope < 0.1%). This procedure converges rapidly to a stable threshold estimate in about 25 trials. For all tasks, Log10 contrast sensitivity was used for statistical analysis. Higher contrast sensitivity values indicated better performance. 2.5. Statistical analysis Analysis of variance (ANOVA) was used to evaluate effects of Groups, Tasks, and interactions among these factors. When a main effect of group occurred in a three-group ANOVA, follow-up ANOVAs were used to isolate which pairs of groups differed. T-tests were to evaluate interactions. Pearson correlation coefficients were used to test for relationships between measures. A p value of < .05 was used for significance testing. With respect to missing data, three subjects did not complete the neuropsychological tests, two did not complete the form coherence task, and two subjects did not complete the SPQ. Subjects with missing data were not used in relevant analyses. 3. Results 3.1. Form and dot discrimination For both tests, control and SPD subjects had comparable thresholds, while SZ patients were impaired as indicated by higher coherence thresholds (Table 2). ANOVA for the motion coherence threshold revealed an effect of Group (F(2,77) = 8.79, p < .001). T-tests indicated that SZ subjects had higher motion coherence thresholds than control (t(62) = 3.85,

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Table 2 Visual test performance by control, unmedicated, and medicated patients Control Coherence thresholds Motion 12.2 (9.1) Form 27.4 (10.2) Contrast sensitivity Static 1.74 (.45) Moving 2.13 (.13) (2.1 Hz) Moving 2.08 (.23) (9.3 Hz) Moving 1.57 (.19) (18.8 Hz)

SPD

Medicated SZ

Unmedicated SZ

14.6 (10.9) 28.9 (7.7)

24.6 (22.8) 42.0 (22.2)

35.7 (28.6) 40.0 (8.7)

1.76 (.46) 2.13 (.11)

1.31 (.53) 2.00 (.28)

1.45 (.42) 1.88 (.56)

2.13 (.18)

1.96 (.40)

1.87 (.71)

1.56 (.13)

1.49 (.24)

1.29 (.78)

Mean values are provided with S.D. in parentheses. SPD: Schizotypal Personality Disorder. SZ: Schizophrenia or schizophrenia or schizoaffective disorder. Coherence thresholds indicate signal percentage required to discriminate a visual feature. Lower coherence thresholds indicate better performance. Contrast sensitivity indicates the log10 contrast sensitivity. Higher contrast sensitivity values indicate better performance.

p < .001) or SPD groups (t(38) = 2.17, p < .04), while SPD and control subjects did not differ. An ANOVA on form coherence also revealed an effect of Group (F(2,75) = 9.41, p < .001). Again, t-tests indicated that SZ subjects had higher coherence thresholds compared to control (t(60) = 3.91, p < .001) and SPD subjects (t(38) = 2.61, p = .01), while SPD and control subjects did not differ. 3.2. Contrast sensitivity for gratings The control and SPD groups had comparable performance on both measures, while the SZ group showed impaired contrast sensitivity (Table 2). ANOVA on log10 contrast sensitivity with the factors of Stimulus (4: static, 2.1 Hz, 9.3 Hz, 18.8 Hz) and Group (3) revealed a main effect of Group (F(2,77) = 6.52, p = .002) and a main effect of Test (F(3,231) = 66.1, p < .001). Follow-up ANOVAs confirmed that the control and SPD groups did not differ (F(1,54) = .14, p = .71), while the SZ group had poorer thresholds compared to the control group (F(1,62) = 9.67, p = .003) as well as the SPD group (F(1,38) = 5.58, p = .02). 3.3. Neuropsychological tests Table 1 provides group means for the three neuropsychological tests and estimated Full Scale IQ. One-way ANOVAs revealed group differences on all

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Table 3 Correlation of visual tests and clinical measures in SZ patients Duration

Positive

Negative

Pic Comp

Simil

Dig Sym

IQ

(N)

(24)

(16)

(16)

(21)

(21)

(21)

(21)

Coherence thresholds Motion Form

.16 −.06

− .04 − .09

−.17 .21

− .25 − .14

− .34 − .22

−.32 −.34

−.40 −.09

Contrast sensitivity Static Moving (2.1 Hz) Moving (9.3 Hz) Moving (18.8 Hz)

−.24 −.23 .00 −.16

− .27 − .36 − .04 .12

.00 −.64 ⁎ .02 −.14

.05 .32 .15 .06

.05 .17 −.25 −.01

.51 ⁎ .53 ⁎ .14 .52 ⁎

.29 .46 ⁎ .02 .26

Duration = illness duration in years; Positive = PANSS Positive Symptom Score; Negative = PANSS Negative Symptom Score; Pic Comp = WAIS-III Picture Completion; Simil = WAIS-III Similarities; Dig Sym = WAIS-III Digit Symbol; IQ = Full Scale Intelligence Quotient. ⁎ p < .05.

measures: Picture Completion (F(2,74) = 12.35, p < .001), Similarities (F(2,74) = 4.91, p = .01), Digit Symbol (F(2,74) = 19.24, p < .001), and IQ (F(2,74) = 21.34, p < .001). For all tests, t-tests indicated that control (t(59) > 3.02, p < .004) and SPD (t(35) > 2.23, p < .04) subjects had higher scores than SZ subjects, while the control and SPD groups did not differ. 3.4. Medication and performance in schizophrenia In order to determine whether medication withdrawal affected visual test performance, control subjects were compared with SZ patients receiving medication (N = 14) and patients who had been withdrawn from medication (N = 10) (Table 2). No SPD subjects were included in this analysis. For motion coherence, ANOVA revealed a main effect of Group (F(2,61) = 8.87, p < .001). Followup t-tests indicated that both medicated SZ (t(52) = 2.87, p = .006) and unmedicated subjects (t(48) = 4.47, p < .001) required higher coherence levels to discriminate motion trajectory. For form coherence, ANOVA showed a main effect of Group (F(2,59) = 7.59, p = .001). Both unmedicated SZ (t(46) = 3.59, p = .001) and medicated SZ subjects (t(50) = 3.25, p = .002) were impaired compared to control subjects. Medicated and unmedicated patients did not differ on either test. For contrast sensitivity, ANOVA with the factors Group (3) and Stimulus (4) revealed a main effect of Group (F(2,61) = 4.97, p = .01) and a main effect of Stimulus (F(3,183) = 43.27, p < .001). Follow-up ANOVAs comparing each pair of groups showed that both the unmedicated patients (F(1,48) = 7.16, p = .01) and the medicated patients (F(1,52) = 8.55, p = .005) were impaired compared to the control group. The medicated and unmedicated patients did not differ.

3.5. SPQ T-tests were used to compare SPQ scale scores between control and SPD subjects (Table 1). As expected, SPD subjects showed higher scores on all three scales (t(53) > 4.2, p < .001). There was only one significant correlation between SPQ scores and thresholds on the visual tests: a correlation between the SPQ positive scale score and contrast sensitivity for the 9.3 Hz modulation rate, r = .30, p = .03. 3.6. Correlations between clinical measures and visual performance in SZ Table 3 lists correlation coefficients between each visual test and clinical measures in SZ patients. Picture Completion was positive correlated with three contrast sensitivity measures, indicating that contrast sensitivity improved with better Picture Completion performance. Full Scale IQ correlated with one of the contrast sensitivity measures. More severe negative symptoms were associated with poorer contrast sensitivity at a 2.1 Hz temporal modulation rate. Positive symptom severity and illness duration were not correlated with visual test performance. 4. Discussion Early stage vision mechanisms were evaluated in patients with schizophrenia, subjects with schizotypal personality disorder and control subjects. Patients with schizophrenia showed impaired perception of motion coherence and form coherence, and poorer contrast sensitivity for static and temporally modulated gratings. Both medicated patients and patients withdrawn from medication showed similar deficits. These findings are

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consistent with pervasive deficits in early stage visual processing. In contrast, subjects with SPD showed performance levels comparable with control subjects on the entire range of tests. These data suggest that early stage visual deficits are associated with the presence of psychosis, rather than schizotypal personality characteristics. Deficits in SPD may appear on more demanding visual perceptual or cognitive tasks, such as backward masking and visual working memory performance (Cadenhead et al., 1999; Farmer et al., 2000; Siever and Davis, 2004). In addition, a larger SPD sample size might detect subtle differences in visual performance. Deficits in trajectory discrimination for coherent dot motion in schizophrenia have been found by several investigators (Brenner et al., 2003; Chen et al., 2003b, 2005; Li, 2002; Stuve et al., 1997). The present data indicated that withdrawal from medication was associated with impaired performance, concordant with another report of impaired motion discrimination in neuroleptic-naive schizophrenia patients (Richardson et al., 1996). However, the present data did not support the hypothesis that impaired global motion perception is a potential endophenotype for schizophrenia spectrum disorders, since SPD subjects with high levels of schizotypal symptoms showed intact motion discrimination, replicating findings in SPD by Farmer et al. (2000). Similarly, with respect to familial risk, Chen et al. (2005) reported that coherent motion thresholds were impaired in schizophrenia, but not in first-degree relatives of schizophrenia patients. Schizophrenia patients showed contrast sensitivity deficits both for the static, high spatial frequency grating, which probed the P or sustained visual pathway and for the drifting, low spatial frequency gratings which probed the M or transient pathway. There was no interaction indicative of a differential disturbance of the temporally modulated compared to the static grating stimuli. Most investigators have reported contrast sensitivity deficits in schizophrenia (Butler et al., 2005; Kéri et al., 2002; Schwartz et al., 1987; Slaghuis, 1998, 2004) but not all (Chen et al., 1999a, 2003b). These divergent findings could be related to factors including medication, symptom characteristics, degree of intellectual impairment, and methodological differences. In the current study, patients treated with novel antipsychotic medication as well as patients withdrawn from medication were impaired on tests of visual function. These findings differ from those of Chen et al. (2003a), who found that patients treated with novel anti-psychotic medication did not show a contrast sensitivity deficits for a low spatial frequency, moving

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grating. In addition, Chen et al. reported that patients withdrawn from medication showed better contrast thresholds than control subjects. A possible difference between studies is the length of time patients were removed from medication, which is not specified in the Chen et al. (2003a) study. Other studies of contrast sensitivity have used medicated patients (Butler et al., 2005; Chen et al., 1999a; Kéri et al., 2002; Slaghuis, 1998, 2004) treated with a wide variety of conventional and novel anti-psychotic medications. Controlled investigations of medication effects would help clarify what types of contrast sensitivity abnormalities are intrinsic to the illness, and which are worsened or improved by specific medications. Cognitive deficits are characteristic of schizophrenia, and may affect performance on psychophysical tests (Brenner et al., 2003; Chapman and Chapman, 2001; Mohamed et al., 1999). In the present data and in Butler et al. (2005), patients with schizophrenia were impaired both on WAIS subtests and tests of contrast sensitivity. In contrast, patients with schizophrenia studied by Chen and colleagues (Chen et al., 2003a, 2005) did not differ in estimated verbal IQ from control groups and also did not differ in contrast sensitivity. Contrast sensitivity performance was most consistently correlated with Picture Completion performance, suggesting that visual perceptual deficits may contribute to problems in higher order visual cognition. It is therefore possible that in patients with higher levels of intellectual function more selective visual deficits would be observed. Slaghuis (1998, 2004) reported that patients with more severe negative symptoms were more likely to show contrast sensitivity deficits than control subjects across a wide range of spatial and temporal frequencies. In the present data, more severe negative symptoms were associated with worse contrast sensitivity on one test. However, the present study did not include a group of patients characterized by severe negative symptoms. Since more severe negative symptoms are often associated with more severe intellectual impairment, as in the Slaghuis (2004) study, this finding is also congruent with a contribution of general cognitive impairment to visual threshold deficits. Methodological differences among studies of contrast sensitivity could also contribute to variations in results. Identification of thresholds have used subjective report (e.g. Schwartz et al., 1987), staircase procedures (e.g. Brenner et al., 2003; Chen et al., 1999a), and method of constant stimuli (e.g. Chen et al., 2005). Spatial frequency, temporal frequency, stimulus duration, and average luminance of the grating stimulus vary among studies. With respect to task demands, subjects

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might be required to make a judgement regarding a single stimulus, as in the present study, or to compare two sequentially presented stimuli, as in Chen et al. (1999a). From a psychometric standpoint, psychophysical methods allow matching for task difficulty and provide high internal reliability (Brenner et al., 2003), but may not match on variance. Consequently, the sensitivity of psychophysical tasks to impairment may differ unless true score variance is equated (Brenner et al., 2003; Chapman and Chapman, 2001). With respect to subjects with SPD, visual tests which posed greater working memory or attentional demands might produce greater discriminating power to detect subtle visual deficits. Abnormalities on psychophysical tests, while often described in terms of the function of specific nuclei or cortical pathways, cannot unambiguously localize abnormalities at the anatomic level. For example, contrast sensitivity deficits can arise from retinal, lateral geniculate nuclei, or cortical dysfunction. Consequently, structural and functional neuroimaging may provide insight into the specific regions affected within the visual pathways. Functional neuroimaging techniques have shown altered visual cortex activation in schizophrenia (Foxe et al., 2001; Braus et al., 2002; Krishnan et al., 2005; Renshaw et al., 1994; Taylor et al., 1997) suggesting a disturbance at early stages of neural processing. At the cellular level, Selemon et al. (1995) reported increased neural density and reduced synaptic connectivity in visual cortex in schizophrenia. Reduced gray matter volumes in schizophrenia have been observed for both the inferior temporal gyrus (Onitsuka et al., 2003) and the fusiform gyrus (Onitsuka et al., 2004), which are important components of the ventral visual pathway involved in face, form and color processing. In aggregate, these findings indicate that visual function is disturbed at early stages of processing in schizophrenia, and may affect processing in both the ventral and dorsal visual pathways of the visual cortex. With respect to cellular mechanisms, it has been proposed that these disturbances may be related to dysregulation of GABAergic or glutamatergic neurotransmission (Butler et al., 2005; Lafargue and Brasic, 2000). A major question is how these disturbances emerge in the development of the illness. Longitudinal studies of high risk individuals prior to symptom onset could clarify this issue. Acknowledgments We are grateful for the support from NIMH 1 RO1 MH62150-01 (BFO), NARSAD (BFO) and the Indiana

University Foundation (BFO). Andrew Koyfman and Nathanael O'Donnell assisted with programming the noise threshold tasks, and Christopher Tyler provided technical guidance on the contrast sensitivity tasks. We thank the participants of the study. References Bodis-Wollner, I., Tagliati, M., 1993. The visual system in Parkinson's disease. Adv. Neurol. 60, 390–394. Braus, D.F., Weber-Fahr, W., Tost, H., Ruf, M., Henn, F.A., 2002. Sensory information processing in neuroleptic-naive first-episode schizophrenic patients: a functional magnetic resonance imaging study. Arch. Gen. Psychiatry 59, 696–701. Brenner, C.A., Lysaker, P.H., Wilt, M.A., O'Donnell, B.F., 2002. Visual processing and neuropsychological function in schizophrenia and schizoaffective disorder. Psychiatry Res. 111, 125–136. Brenner, C.A., Wilt, M.A., Lysaker, P.H., O'Donnell, B.F., 2003. Psychometrically matched tasks of discrimination and recognition performance in schizophrenia spectrum disorders. J. Abnorm. Psychology 112, 28–37. Bunney, W.E., Hetrick, W.P., Bunney, B.G., Patterson, J.V., Jin, Y., Potkin, S.G., Sandman, C.A., 1999. Structured interview for assessing perceptual anomalies (SIAPA). Schizophr. Bull. 25, 577–592. Butler, P.D., Javitt, D.C., 2005. Early-stage visual processing deficits in schizophrenia. Curr. Opin. Psychiatr. 18, 151–157. Butler, P.D., Zemon, V., Schechter, I., Saperstein, A.M., Hoptman, M.J., Lim, K.O., Revheim, N., Siolipo, G., Javitt, D.C., 2005. Early-stage visual processing and cortical amplification deficits in schizophrenia. Arch. Gen. Psychiatry 62, 495–504. Cadenhead, K.S., Pery, W., Shafer, K., Braff, D.L., 1999. Cognitive functions in schizotypal personality disorder. Schizophr. Res. 37, 123–132. Camisa, K.M., Wilt, M.A.B., Lysaker, P.H., Rae, LL., Brenner, C.A., O'Donnell, B.F., 2005. Personality traits in schizophrenia and related personality disorders. Psychiatry Res. 133, 23–33. Chapman, L., Chapman, J., 1973. The measurement of differential deficit. J. Psychiatr. Res. 14, 303–311. Chapman, L., Chapman, J., 2001. Commentary on two articles concerning generalized and specific cognitive deficits. J. Abnorm. Psychology 110, 31–39. Chen, Y., Palafax, G.P., Nakayama, K., Levy, D.L., Matthysse, S., Holzman, P.S., 1999a. Motion perception in schizophrenia. Arch. Gen. Psychiatry 56, 149–154. Chen, Y., Nakayama, K., Levy, D.L., Matthysse, S., Holzman, P.S., 1999b. Psychophysical isolation of a motion-processing deficit in schizophrenics and their relatives and its association with impaired smooth pursuit. Proc. Natl. Acad. Sci. 96, 4724–4729. Chen, Y., Levy, D.L., Sheremata, S., Nakayama, K., Mattysse, S., Holzman, P.S., 2003a. Effects of typical, atypical, and no antipsychotic drugs on visual contrast detection in schizophrenia. Am. J. Psychiatry 160, 1795–1801. Chen, Y., Nakayam, K., Levy, D.L., Matthysse, S.W., Holzman, P.S., 2003b. Processing of global, but not local, direction is deficient in schizophrenia processing. Schizophr. Res. 61, 215–227. Chen, Y., Bidwell, L.C., Holzman, P.S., 2005. Visual motion integration in schizophrenia patients, their first-degree relatives, and patients with bipolar disorder. Schizophr. Res. 74, 271–281.

B.F. OTDonnell et al. / Schizophrenia Research 86 (2006) 89–98 Cutting, J., Dunne, F., 1986. The nature of abnormal perceptual experiences at the onset of schizophrenia. Psychopathology 19, 347–352. Farmer, C.M., O'Donnell, B.F., Niznikiewicz, M.A., Voglmaier, M.M., McCarley, R.W., Shenton, M.E., 2000. Visual perception and working memory in schizotypal personality disorder. Am. J. Psychiatry 57, 781–786. First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W., 1995. Structured Clinical Interview for DSM-IV Axis I Disorders – Patient Edition. New York State Psychiatric Institute, New York. First, M.B., Gibbon, M., Spitzer, R.L., Williams, J.B.W., Benjamin, L.S., 1997. User's Guide for the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II). APA Press, Washington, DC. Foxe, J.J., Doniger, G.M., Javitt, D.C., 2001. Early visual processing deficits in schizophrenia: impaired P1 generation revealed by highdensity electrical mapping. Neuro Report 12, 3815–3820. Green, M.F., Nuechterlein, K.H., Mintz, J., 1994. Backward masking in schizophrenia and mania: II. Specifying the visual channels. Arch. Gen. Psychiatry 51, 945–951. Hooker, C., Park, S., 2000. Trajectory estimation in schizophrenia. Schizophr. Res. 45, 83–92. Kay, S.R., Abraham, F., Opler, L.A., 1987. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr. Bull. 13, 261–275. Kéri, S., Antal, A., Szekeres, G., Benedek, G., Janka, Z., 2002. Spatiotemporal visual processing in schizophrenia. J. Neuropsychiatry Clin. Neurosci. 14, 190–196. Kéri, S., Kelemen, O., Benedek, G., Janka, Z., 2004. Vernier threshold in patients with schizophrenia and in their unaffected siblings. Neuropsychology 18, 537–542. Kety, S.S., Wender, P.H., Jacobsen, F., Ingraham, L.J., Jansson, L., Faber, B., Kinney, D., 1994. Mental Illness in the biological and adoptive relatives of schizophrenic adoptees: replication of the Copenhagen study in the rest of Denmark. Arch. Gen. Psychiatry 51, 442–455. Krishnan, G.P., Vohs, J.L., Carroll, C.A., Hetrick, W.P., Shekhar, A., Bockbrader, M.A., O'Donnell, B.F., 2005. Steady state visual evoked potential abnormalities in schizophrenia. Clin. Neurophysiol. 116, 614–624. Lafargue, T., Brasic, J., 2000. Neurodevelopmental hypothesis of schizophrenia: a central sensory disturbance. Med. Hypotheses 55, 314–318. Legge, G., 1978. Sustained and transient mechanisms in human vision: temporal and spatial properties. Vis. Res. 18, 69–81. Levitt, H., 1970. Transformed up-down methods in psychoacoustics. J. Acoust. Soc. Am. 49, 467–477. Lezak, M.D., 1995. Neuropsychological Assessment, 3rd ed. Oxford University Press, New York. Li, C.-S.R., 2002. Impaired detection of visual motion in schizophrenia patients. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 26, 929–934. Livingstone, M., Hubel, D., 1988. Segregation of form, color, movement and depth: anatomy, physiology and perception. Science 240, 740–749. Merigan, W.H., Maunsell, J.H.R., 1993. How parallel are the primate visual pathways? Annu. Rev. Neurosci. 16, 369–402. Merigan, W., Freeman, A., Meyers, S.P., 1997. Parallel processing streams in the human visual cortex. NeuroReport 18, 3881–3985. Mohamed, S., Paulsen, J.S., O'Leary, D., Arndt, S., Andreasen, N., 1999. Generalized cognitive deficits in schizophrenia: a study of first-episode patients. Arch. Gen. Psychiatry 56, 749–754.

97

Newsome, W.T., Pare, E.B., 1988. A selective impairment of motion perception following lesions of the middle temporal visual area (MT). J. Neurosci. 8, 2201–2211. O'Donnell, B.F., Swearer, J.M., Smith, L.T., Nestor, P.G., Shenton, M. E., McCarley, R.W., 1996. Selective deficits in visual perception and recognition in schizophrenia. Am. J. Psychiatry 153, 687–692. Onitsuka, T., Shenton, M.E., Kasai, K., Nestor, P.G., Toner, S.K., Kikinis, R., Jolesz, F.A., McCarley, R.W., 2003. Fusiform gyrus volume reduction and facial recognition in chronic schizophrenia. Arch. Gen. Psychiatry 60, 349–359. Onitsuka, T., Shenton, M.E., Salisbury, D.F., Dickey, C.C., Kasai, K., Toner, S.K., Frumin, M., Kikinis, R., Jolesz, F.A., McCarley, R.W., 2004. Middle and inferior temporal gyrus gray matter volume abnormalities in chronic schizophrenia: an MRI study. Am. J. Psychiatry 16, 1603–1611. Phillipson, O.T., Harris, J.P., 1985. Perceptual changes in schizophrenia: a questionnaire survey. Psychol. Med. 15, 859–866. Raine, A., 1991. The SPQ: a scale for the assessment of schizotypal personality based on DSM-III-R criteria. Schizophr. Bull. 17, 555–564. Raine, A., Reynolds, C., Lencz, T., Scerbo, A., Triphon, N., Kim, D., 1994. Cognitive–perceptual, interpersonal, and disorganized features of schizotypal personality. Schizophr. Bull. 20, 191–201. Renshaw, P.F., Yurglen-Todd, D.A., Cohen, B.M., 1994. Greater hemodynamic response to photic stimulation in schizophrenic patients: and echo planar MRI study. Am. J. Psychiatry 151, 1493–1495. Richardson, A.J., Gruzlier, J.H., Puri, B.K., 1996. Reduced visual motion sensitivity in unmedicated schizophrenic patients. Eur. Psychiatr. 11, 422S. Schwartz, B.D., McGinn, T., Winstead, D.K., 1987. Disordered spatiotemporal processing in schizophrenics. Biol. Psychiatry 22, 688–698. Selemon, L.D., Rajkowska, G., Goldman-Rakic, P.S., 1995. Abnormally high neuronal density in the schizophrenic cortex. Arch. Gen. Psychiatry 52, 805–818. Sheehan, D.V., Lecrubier, Y., Harnett-Sheehan, K., Amorim, P., Janavs, J., Weiller, E., Hergueta, T., Baker, R., Dunbar, G., 1998. The Mini International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview. J. Clin. Psychiatry 59, 22–33. Siever, L.J., Davis, K.L., 2004. The pathophysiology of schizophrenia disorders: perspectives from the spectrum. Am. J. Psychiatry 161, 398–413. Slaghuis, W.L., 1998. Contrast sensitivity for stationary and drifting spatial frequency gratings in positive- and negative-symptom schizophrenia. J. Abnorm. Psychology 107 (1), 49–62. Slaghuis, W.L., 2004. Spatio-temporal luminance contrast sensitivity and visual backward making in schizophrenia. Exp. Brain Res. 156, 196–211. Stuve, T.A., Friedman, L., Jesberger, J.A., Gilmore, G.C., Strauss, M.E., Meltzer, H.Y., 1997. The relationship between smooth pursuit performance, motion perception and sustained visual attention in patients with schizophrenia and normal controls. Psychol. Med. 27, 143–152. Tagliati, M., Bodis-Wollner, I., Kovanecz, I., Stanzione, P., 1994. Spatial frequency tuning of the monkey pattern ERG depends on D2 receptor-linked action of dopamine. Vis. Res. 34, 2051–2057. Taylor, S.F., Tandon, R., Koeppe, R.A., 1997. PET study of greater visual activation in schizophrenia. Am. J. Psychiatry 154, 1296–1298. Tyler, C.W., 1991. Analysis of normal flicker sensitivity and its variability in the visuogram test. Investig. Ophthalmol. Vis. Sci. 32, 2552–2560.

98

B.F. OTDonnell et al. / Schizophrenia Research 86 (2006) 89–98

Tyler, C.W., McBride, B., 1995. The morphonome image psychophysics software and calibrator for Macintosh Systems. Spat. Vis. 10, 479–484. Ungerleider, L.G., 1985. The corticocortical pathways for object recognition and spatial perception. In: Chagas, C., Gattass, R., Gross, C. (Eds.), Pattern Recognition Mechanisms. InSpringer, Berlin, pp. 21–37.

Van Essen, D.C., Gallant, J.L., 1994. Neural mechanisms of form and motion processing in the primate visual system. Neuron 13, 1–10. Wandell, B.A., 1995. Foundations of Vision. Sinauer, Sunderland, MA. Wechsler, D., 1997. WAIS-III. Administration and Scoring Manual. Psychological Corporation, San Antonio, TX.