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Scotopic sensitivity in schizophrenia
Schizophrenia Research 84 (2006) 378 – 385 www.elsevier.com/locate/schres
Scotopic sensitivity in schizophrenia Audrey H. Gutherie 1, Jennifer E. McDowell, Billy R. Hammond Jr. * Psychology Department, University of Georgia, Athens, GA. 30602, USA Received 7 December 2005; received in revised form 23 February 2006; accepted 28 February 2006 Available online 19 April 2006
Abstract Among participants with schizophrenia there is evidence for early-stage visual processing deficits, which may arise in the rod pathways. Input to the earliest level of this pathway, however, has not been tested in this population. It has been widely hypothesized that schizophrenia participants have magnocellular deficits that occur at the pre-cortical level. To address this hypothesis, we studied absolute scotopic (dark-adapted) sensitivity in fifteen schizophrenia and fifteen matched control participants. Scotopic thresholds were assessed using a 1.85-deg, 510-nm circular test stimulus located at 108 eccentricity in the left visual field and presented in Maxwellian-view. Thresholds were obtained using a two-alternative forced-choice paradigm (an average of 200 trials per participant was obtained). Threshold estimates were derived using probit analysis. In this procedure the transformed binomial data (the inverse of the normal probability integral) is fit with a weighted linear regression. Noise was defined as the average deviation from this line. Lens optical density was also assessed by comparing absolute scotopic thresholds to the extinction spectrum of rhodopsin. Scotopic thresholds and lens density values of the two groups were evaluated using independent samples t-tests. The scotopic thresholds, and associated noise, did not differ between the schizophrenia and control participants. Lens density was also nearly identical between groups. These results suggest that magnocellular deficits in schizophrenia may not be due to problems at the level of the rods but are more likely to occur later in the visual pathway. D 2006 Elsevier B.V. All rights reserved. Keywords: Schizophrenia; Scotopic sensitivity; Intrinsic noise; Lens optical density
1. Introduction Past studies have found that schizophrenia participants exhibit specific deficits in lower-level visual * Corresponding author. Tel.: +1 706 542 4812; fax: +1 706 542 3275. E-mail address: [email protected] (B.R. Hammond). 1 Permanent Address: 775 Nature Court, Bethlehem, GA. 30620, USA. 0920-9964/$ - see front matter D 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2006.02.024
functioning. For example, schizophrenia participants have exhibited impairments in contrast sensitivity (e.g., Ke´ri et al., 2002), temporal vision (e.g., Slaghuis and Bishop, 2001), spatio-temporal vision (e.g., Ke´ri et al., 2002; Schwartz et al., 1987), and backward masking (e.g., Butler et al., 1996; Cadenhead et al., 1998; Slaghuis and Bakker, 1995) when compared to controls. The findings of many of these studies suggest a magnocellular (M) pathway deficit in schizophrenia (e.g., Slaghuis and Bishop, 2001;
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Cadenhead et al., 1998; Butler et al., 2001; Cadenhead et al., 1998). The localization of this deficit, however, is unclear. The M pathway receives its primary input from rod (and to a lesser extent, cone) photoreceptors, which synapse with parasol ganglion cells. This pathway continues through the ventral layers of the lateral geniculate portion of the thalamus and extends through the visual cortex to the parietal cortex (via the dorsal stream). The deficit found in schizophrenia could occur at any stage along this pathway. Since the primary symptoms of schizophrenia are cognitive (e.g. hallucinations, delusions, impoverished speech, etc.), the majority of the research on the etiology and treatment of the disorder has focused on higher-order processing and has adopted a top-down view of the origin of the symptoms. From a top-down point of view, cortical dysfunction causes disruption of primary sensory processes. From a bottom-up perspective, however, it may be the case that lowerlevel dysfunction contributes to the cognitive disturbances common to schizophrenia. Recent results by Kim et al. (2005) are an example of the latter perspective. These authors measured the steady state visual evoked potentials of schizophrenia participants to determine whether alterations in these potentials suggested neurophysiological changes early in the visual pathway. Based on their results, they concluded that early sensory deficits were primarily responsible for subsequent visual impairment in the M pathway. Psychophysical and electrophysical evidence has indicated that the M pathway plays a dominant role in scotopic vision (e.g., Benedek et al., 2003). As originally shown by Wald (1945), absolute scotopic thresholds appear to be largely mediated by the kinetics of rod photopigment. Thus, the shape of the spectral scotopic sensitivity curve is nearly identical to the extinction spectrum of rhodopsin (as shown in Fig. 1). If schizophrenia participants have deficits in the input portion of their magnocellular pathway, it is probable that this would be manifested either as deficits in absolute sensitivity and/or the noise associated with these thresholds. A certain level of noise is inherent in all visual thresholds, and performance at threshold is heavily limited by this noise (e.g., Donner, 1992). Although intrinsic noise can arise at numerous levels of the visual system,
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Fig. 1. Rod extinction curve (solid line) with human scotopic sensitivity curve superimposed (dotted) (from Dartnall, 1953; CIE, 1951). Deviation at the shortwave end is due to the pre-retinal optical media (i.e., crystalline lens).
noise associated with scotopic thresholds is thought to originate at the input stage, i.e., at the level of the retina (e.g., Van Rossum and Smith, 1998). When in a fully dark-adapted state, the visual system is maximally sensitive, and the effects of noise are evident. In this study, we therefore tested whether schizophrenia participants had deficits in rod photoreceptor functioning by testing absolute scotopic thresholds and the noise associated with such thresholds. Although the scotopic sensitivity of this population has never been reported, there is some basis in the literature for suspecting scotopic deficits. Granger (1957), for instance, originally reported that participants with psychiatric disorders (neuroses and psychoses) had significantly higher scotopic thresholds compared to matched controls. Other past studies have found that schizophrenia patients have altered electroretinogram waveforms (a-wave amplitudes) (e.g., Warner et al., 1999). In addition, there is evidence to suggest that medicated and drug-naı¨ve schizophrenia patients have reduced levels of docosahexaenoic acid (DHA) (e.g., Khan et al., 2002), which is the most abundant essential polyunsaturated fatty acid in the phospholipids of the rod outer segment membranes. Reduced retinal DHA alters the optical density of rhodopsin and rod function in rat models (e.g., Bush et al., 1994). If schizophrenia patients have reduced DHA levels and DHA alters rod-mediated functions such as scotopic function, it is possible that schizophrenia participants may also have scotopic deficits.
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Taken together, the available evidence suggests that a deficit in early rod-mediated vision in schizophrenia is possible. Moreover, past data suggests that if such deficits exist, they may arise at the level of the retina. Such conclusions, however, must be tentative. For example, decreased scotopic sensitivity could also be produced by preretinal optical changes such as increased optical density of the crystalline lens (due to less light being transmitted by the lens). Some evidence suggests that common antipsychotic drugs (e.g. chlorpromazine) are associated with increased lens density (see Shahzad et al., 2002 for review). To assess these possibilities, we also measured lens optical density. Thus, the current study was designed to determine whether schizophrenia participants suffer from earlystage visual dysfunction by psychophysical assessment of absolute scotopic thresholds, scotopic noise, and lens optical density.
2. Method 2.1. Participants Fifteen participants diagnosed with DSM-IV schizophrenia (8 males and 7 females, mean age = 41.5 years, range = 26–55) and 15 control participants (8 males and 7 females, mean age = 41.13 years, range = 23–57) were studied. All participants with schizophrenia were chronic, stable outpatients recruited from regional mental health centers. Diagnoses were confirmed by two psychologists using the Structured Clinical Interview for the DSM-IV (SCIDIV; First et al., 1997). The Scales for the Assessment of Negative (SANS) and Positive (SAPS) Symptoms (Andreasen, 1984) were used to quantify symptom data (zero indicating the symptom was absent to 5 indicating the symptom was severe). Global ratings for negative symptoms were the average of summary scores for alogia, affective flattening, anhedonia/ asociality and avolition/apathy (M = 1.6, SD = 0.5). Global ratings for the positive symptoms were the average of summary scores for hallucinations, delusions, bizarre behavior and thought disorder (M = 2.0, SD = 1.0). Fourteen of the schizophrenia subjects were on atypical antipsychotic medication (M CPZ equivalent dose = 318 mg; using the conversion factors for
atypical antipsychotics provided by Woods, 2003), eleven of who were taking a single antipsychotic (olanzapine (N = 4), risperidone (N = 2), quetiapine (N = 2), ziprasidone (N = 2), and clozapine (N = 1)). Two schizophrenia subjects were taking two or more antipsychotic medications and two were not taking any antipsychotic medications but both were prescribed stimulants. From the entire group of fifteen, eight subjects were taking medications from classes other than the atypical antipsychotics, of which antidepressants were the most common (N = 7). Control participants were recruited from the local Athens area and surrounding environs based on local advertisements and had no personal or family history of schizophrenia or any other Axis I disorder (as determined by selfreport). Participants were matched on gender, age, ethnicity and smoking history (see Table 1), and participants were excluded if they reported any ocular or systemic diseases that would be expected to influence the outcome of this study (e.g. macular degeneration). We tested the Snellen acuity of each subject and used refractive correction when a participant had visual acuity less than 20/30. Furthermore, participants were matched on average number of servings of fruits and vegetables per week (via self-report; one participant elected not to provide this information). Dietary information was obtained in order to determine whether any visual deficits we might find in our subjects was related to dietary behavior. Table 1 Demographic characteristics of participants: schizophrenia vs. control participants
Age
Sex Ethnicity Smoking history
Diet (mean number of servings of fruits and vegetables per week)
Schizophrenia group
Control group
M = 41.5 years, SD = 8.2, range = 26–55 years 8 men 7 women 10 Caucasians 4 African-Americans 7 current smokers 3 past smokers 5 non-smokers M = 8.25 (SD = 3.9)
M = 41.1 years, SD = 10.4, range = 23–57 years 8 men 7 women 10 Caucasians 4 African-Americans 10 current smokers 1 past smoker 4 non-smokers M = 12.23 (SD = 8.5)
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2.2. Apparatus A Maxwellian-view optical system with a FiberLite PL-900 DC Regulated Illuminator light source (Dolan-Jenner Industries: Lawrence, MA.) was used. Maxwellian-view allows the stimuli to be directly projected onto the retina and therefore controls for any variations in pupil size. Two infrared cameras allowed constant viewing of the participant’s iris and pupil and were used to assure that the stimuli were precisely aligned. Precise alignment was facilitated by a chinand forehead-rest assembly that controlled for head movements. Scotopic sensitivity was measured using three 1.85-deg test stimuli located at 108 eccentricity. The main wavelength tested was 510 nm, which falls near the peak of the human scotopic sensitivity curve (i.e., approximately 507 nm) and rod spectral sensitivity curve (see Fig. 1). Since our scotopic sensitivity measures were relative to the actual stimulus and experimental parameters employed in the present study, they will be hereafter referred to as log relative scotopic sensitivity values. A 410 nm stimulus and a 565 nm stimulus were also tested in order to derive an estimate of lens optical density. Since the lens absorbs a small amount of light at 510 nm (e.g., see Wyszecki and Stiles, 1982), measurements of lens density allowed an analysis of the effect of lens absorption on the thresholds obtained for each participant. Light at 565 nm is not absorbed by the lens, but light at 410 nm is heavily absorbed. Consequently, these two wavelengths were used to obtain lens density values based on the classic scotopic threshold method (for a review see Snodderly and Hammond, 1999). 2.3. Method and procedures The nature of the task was explained to each participant before testing began. They were instructed to fixate on a red dot that was located in their right visual field throughout the entire experiment. Participants were then aligned along the optical axis of the optical system and shown suprathreshold samples of the stimuli or blank presentations. Participants were instructed to respond byesQ if a stimulus was detected and bnoQ if a stimulus was not detected. Once the experimenter was convinced the participants understood the nature of the task, the participants were
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dark-adapted for a total of 40 min. After this period, the subjects were aligned (using the infrared cameras), and the stimuli were presented. Stimuli were presented for 1000 ms separated by a short interval. Log relative scotopic sensitivity for the 410 and 565 nm stimuli was assessed using the method of limits to obtain an approximate threshold. This was done by presenting the stimuli in ascending and descending order (the intensity of the test stimulus was varied progressively by approximately 0.05 log increments over a range of about 1 log unit) until an approximate threshold was determined. Once the approximate threshold was determined, stimulus intensity was varied randomly around that point (i.e., the method of constant stimuli) until enough determinations were available to generate a psychometric function. The precise threshold for each wavelength was defined as that intensity where the subject responded that they saw the stimulus 75% of the time. Lens optical density was calculated by subtracting the threshold value at 410 nm (where there is high lens absorbance) from the threshold value at 565 nm (where there is minimal lens absorbance) (e.g., see Wyszecki and Stiles, 1982). This method is referred to as the balancedrhodopsin method; see Snodderly and Hammond (1999) or Van Norren and Vos (1974) for a discussion of the rationale behind using this technique for obtaining lens optical density. More extensive testing was conducted at 510 nm (compared to the 410 and 565 nm thresholds used for calculating lens density) in order to obtain both more exact threshold values and an estimate of intrinsic noise. For this wavelength, we used a temporal twoalternative forced-choice (2-AFC) paradigm similar to the one employed by Sturr et al. (1997). This procedure consists of two alternating trials where the stimulus is either present or absent and the subject must make a forced choice regarding whether the stimulus appeared in the first or in the second presentation. The presentations are signaled by two different auditory tones. The 510 nm stimulus was presented randomly after one of the two auditory tones. All correct and incorrect responses were recorded. Approximately 12 evenly spaced intensities (all intervals consisted of about 0.05 log units) below or above the estimated threshold were used. Each of these stimuli were presented a total of 8 times. Random performance (i.e., about 50% correct) was
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interpreted as the stimulus being below threshold. Threshold was defined as the intensity that produced 75% correct responses. A probit regression analysis was conducted on the data from the 510 nm test stimulus. In this procedure the transformed binomial data (the inverse of the normal probability integral) is fit with a weighted linear regression. Noise was defined as the average deviation from this line. Based on this procedure, individuals with larger deviation values would be interpreted as having higher amounts of noise, and individuals with smaller deviation values would be interpreted as having smaller amounts of intrinsic noise. In order to assess the reliability of this procedure, we assessed two control participants (1 woman and 1 man, ages 20 and 27) on two separate occasions. The average deviation values of the two participants from time one were 0.49 and 0.83, and the average deviation values of the participants from time two were 0.47 and 0.85, respectively. The similarity across sessions suggested our method of measuring noise was reliable.
value of 0.60, which fell 4.6 standard deviation units away from the mean of the distribution of all of the log relative scotopic sensitivity scores (3.01) and could have significantly skewed the results. We therefore decided to exclude these two participants for a final N = 28. The schizophrenia and control participants were highly similar on all the dependent measures; log relative scotopic sensitivity, lens density, and intrinsic noise (see Table 2). Mean log relative scotopic sensitivity (schizophrenia participants, M = 3.14; controls, M = 3.07) only differed by about 2% ( p b 0.21). Average lens optical density (schizophrenia participants, M = 0.96, controls, M = 0.94) only differed by about 2% ( p = 0.85). Intrinsic noise associated with the scotopic thresholds (schizophrenia participants, M = 0.76, Controls M = 0.77) also only varied by about 1% ( p b 0.46). Lens OD was not correlated with either scotopic thresholds (r = 0.24) or variations in sensory noise (r = 0.03).
4. Discussion 3. Results Non-directional independent samples t-tests were conducted on the age and diet data. The groups did not significantly differ on either age or consumption of fruits and vegetables. As shown in Table 1, the groups were also well-matched with respect to ethnicity, smoking, and sex. Independent samples t-tests were also used to compare the mean values of the schizophrenia and control participants on LRSS (at 510 nm) and lens density. Data was unusable for two schizophrenia participants. The first could not be properly aligned with the Maxwellian-view system due to an extremely small pupil; even after 40 min of dark adaptation the participant’s pupil was still approximately 2–3 mm. The second had a log relative scotopic sensitivity
The main finding of our study was that the schizophrenia and control participants were highly similar on the dependent measures assessing rod functioning. Notably, these results are based on a rigorous criterion-free psychophysical procedure. For example, all participants were tested in Maxwellianview using infrared cameras to ensure exact alignment of the stimulus at all times. The scotopic measures used to derive the threshold and noise values were obtained using a 2-AFC paradigm with an average of 200 trials per measure. The two groups did not differ on measures of LRSS, lens OD, or intrinsic noise. Our data are, therefore, inconsistent with an early origin (i.e., retinal) of some of the M-pathway deficits seen in schizophrenia. These results must be considered in light of two caveats. The first caveat is that the sample size was
Table 2 Descriptive statistics for the schizophrenia and control participants on noise, LRSS (at 510 nm)
Intrinsic noise LRSS (at 510 nm) Lens OD
Schizophrenia group
Control group
M = 0.76 (SD = 0.14) range = 0.58–1.12 M = 3.14 (SD = 0.17) range = 2.8–3.88 M = 0.96 (SD = 0.24) range = 0.34–1.49
M = 0.77 (SD = 0.14) range = 0.54–1.01 M = 3.07 (SD = 0.26) range = 2.56–3.44 M = 0.94 (SD = 0.17) range = 0.72–1.32
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small. Scotopic thresholds, however, tend to have low variability as can be seen in this sample and past data (e.g., Hammond et al., 1998). It is unlikely, therefore, that the sample was too small to obtain a reasonable estimate of the average log relative scotopic sensitivity of schizophrenia participants (e.g., the data were relatively normally distributed). Assuming our estimate is reasonable, an extremely large sample would be necessary for the small difference that we found (2%) to be statistically significant. It is doubtful that such a small magnitude of difference is clinically meaningful. The second caveat is that of medication use. The majority of the schizophrenia participants were on atypical antipsychotic medications (e.g. risperidone, olanzapine, etc.). It appears that the majority of the schizophrenia participants assessed in past studies showing M pathway deficits (e.g., Ke´ri et al., 2002; Cadenhead et al., 1998; Slaghuis and Bishop, 2001) were taking typical antipsychotic medications. Therefore, it is possible that one reason past studies have found M pathway deficits in schizophrenia is that their schizophrenia patients were taking typical antipsychotic medications. The question of whether patients taking atypical antipsychotics also display M pathway deficits is open. Antal et al. (1999), for instance, found that schizophrenia patients taking atypical medications did not exhibit contrast sensitivity deficits. In contrast, Butler et al. (2005) did find contrast sensitivity deficits in patients taking atypical medications when using stimuli that were biased to reflect magnocellular processing. Clearly some psychotropic medications appear to influence magnocellular activity. It is unlikely, however, that M pathway deficits are due simply to medication use. For example, relatives of schizophrenia participants are not medicated and still show M pathway deficits (e.g., Bedwell et al., 2003; Green et al., 1997), and differences in brain activity (Bedwell et al., 2004) when compared with normal control subjects. If schizophrenia patients on atypical medications have M pathway deficits (like those on typical medications; e.g., Ke´ri et al., 2002; Slaghuis and Bishop, 2001; Cadenhead et al., 1998), the finding of normal scotopic and noise values in such patients has important implications. If, for instance, schizophrenia patients have M pathway deficits but normal rod
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function, the loci of their deficits must be either postreceptoral and/or reflect the relatively small cone input to the M pathway. The former interpretation is consistent with the finding that schizophrenia participants have significantly reduced CFF thresholds compared to controls (e.g., Black et al., 1975). CFF is considered to be determined by cortical processing at the level of the visual cortex (e.g., Curran, 1990; Wells et al., 2001) but is also thought to be mediated by the M pathway (e.g., Merigan and Maunsell, 1990). Much like schizophrenia, it has been widely concluded through psychophysical, physiological, and anatomical data that some dyslexics display M pathway deficits (e.g., Demb et al., 1998; Livingstone et al., 1991; Stein, 2001; Stein and Walsh, 1997). For example, Livingstone et al. (1991) found that the cells of the M layers of the lateral geniculate nucleus of 5 dyslexic brains were on average 27% smaller than those of control brains, and there were no differences in cell sizes in the P layers. Furthermore, it was widely assumed that dyslexics would also have scotopic impairments. For example, DHA supplementation for dyslexia has been suggested as a mean of addressing M pathway deficits based on the idea that altered rod function could be corrected by increased omega-fatty acids in the outer-segments of rods (e.g., Stordy, 1995, 2000). Careful testing, however, has shown that dyslexics do not have scotopic deficits (e.g., Greatrex et al., 2000), which parallels the findings of this study. The anatomical findings with respect to dyslexia (i.e., smaller M cells in the lateral geniculate nucleus of some dyslexics) may provide a clue to the location of the M pathway deficits observed in schizophrenia. Kim et al. (2005) concluded that the visual deficits seen in schizophrenia originate early in the visual processing stream. Our data suggest this level is not retinal. Like dyslexia, the defects may therefore arise within the thalamus, primary visual cortex, or in the connections between the two areas. This interpretation is consistent with imaging studies that have found that schizophrenia participants have decreased white matter integrity in occipital white matter (Agartz et al., 2001; Ardekani et al., 2003) and thalamocortical radiations (Butler et al., 2005). Ultimately, our results strongly suggest that rod functioning is normal in schizophrenia participants. Our results are, of course, specific to our sample (e.g.,
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chronic, stable outpatients). This conclusion must therefore be confirmed by studies designed to test log relative scotopic sensitivity and magnocellular activity in a) schizophrenia subjects who have not been medicated, b) schizophrenia subjects who are selected based on symptom profiles of predominantly negative or predominantly positive symptoms, and c) the biological relatives of schizophrenia subjects. If the conclusion stands, however, it begs the question of why the retina, which depends strongly on dopaminergic systems, is relatively immune to alteration.
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Scotopic sensitivity in schizophrenia Audrey H. Gutherie 1, Jennifer E. McDowell, Billy R. Hammond Jr. * Psychology Department, University of Georgia, Athens, GA. 30602, USA Received 7 December 2005; received in revised form 23 February 2006; accepted 28 February 2006 Available online 19 April 2006
Abstract Among participants with schizophrenia there is evidence for early-stage visual processing deficits, which may arise in the rod pathways. Input to the earliest level of this pathway, however, has not been tested in this population. It has been widely hypothesized that schizophrenia participants have magnocellular deficits that occur at the pre-cortical level. To address this hypothesis, we studied absolute scotopic (dark-adapted) sensitivity in fifteen schizophrenia and fifteen matched control participants. Scotopic thresholds were assessed using a 1.85-deg, 510-nm circular test stimulus located at 108 eccentricity in the left visual field and presented in Maxwellian-view. Thresholds were obtained using a two-alternative forced-choice paradigm (an average of 200 trials per participant was obtained). Threshold estimates were derived using probit analysis. In this procedure the transformed binomial data (the inverse of the normal probability integral) is fit with a weighted linear regression. Noise was defined as the average deviation from this line. Lens optical density was also assessed by comparing absolute scotopic thresholds to the extinction spectrum of rhodopsin. Scotopic thresholds and lens density values of the two groups were evaluated using independent samples t-tests. The scotopic thresholds, and associated noise, did not differ between the schizophrenia and control participants. Lens density was also nearly identical between groups. These results suggest that magnocellular deficits in schizophrenia may not be due to problems at the level of the rods but are more likely to occur later in the visual pathway. D 2006 Elsevier B.V. All rights reserved. Keywords: Schizophrenia; Scotopic sensitivity; Intrinsic noise; Lens optical density
1. Introduction Past studies have found that schizophrenia participants exhibit specific deficits in lower-level visual * Corresponding author. Tel.: +1 706 542 4812; fax: +1 706 542 3275. E-mail address: [email protected] (B.R. Hammond). 1 Permanent Address: 775 Nature Court, Bethlehem, GA. 30620, USA. 0920-9964/$ - see front matter D 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2006.02.024
functioning. For example, schizophrenia participants have exhibited impairments in contrast sensitivity (e.g., Ke´ri et al., 2002), temporal vision (e.g., Slaghuis and Bishop, 2001), spatio-temporal vision (e.g., Ke´ri et al., 2002; Schwartz et al., 1987), and backward masking (e.g., Butler et al., 1996; Cadenhead et al., 1998; Slaghuis and Bakker, 1995) when compared to controls. The findings of many of these studies suggest a magnocellular (M) pathway deficit in schizophrenia (e.g., Slaghuis and Bishop, 2001;
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Cadenhead et al., 1998; Butler et al., 2001; Cadenhead et al., 1998). The localization of this deficit, however, is unclear. The M pathway receives its primary input from rod (and to a lesser extent, cone) photoreceptors, which synapse with parasol ganglion cells. This pathway continues through the ventral layers of the lateral geniculate portion of the thalamus and extends through the visual cortex to the parietal cortex (via the dorsal stream). The deficit found in schizophrenia could occur at any stage along this pathway. Since the primary symptoms of schizophrenia are cognitive (e.g. hallucinations, delusions, impoverished speech, etc.), the majority of the research on the etiology and treatment of the disorder has focused on higher-order processing and has adopted a top-down view of the origin of the symptoms. From a top-down point of view, cortical dysfunction causes disruption of primary sensory processes. From a bottom-up perspective, however, it may be the case that lowerlevel dysfunction contributes to the cognitive disturbances common to schizophrenia. Recent results by Kim et al. (2005) are an example of the latter perspective. These authors measured the steady state visual evoked potentials of schizophrenia participants to determine whether alterations in these potentials suggested neurophysiological changes early in the visual pathway. Based on their results, they concluded that early sensory deficits were primarily responsible for subsequent visual impairment in the M pathway. Psychophysical and electrophysical evidence has indicated that the M pathway plays a dominant role in scotopic vision (e.g., Benedek et al., 2003). As originally shown by Wald (1945), absolute scotopic thresholds appear to be largely mediated by the kinetics of rod photopigment. Thus, the shape of the spectral scotopic sensitivity curve is nearly identical to the extinction spectrum of rhodopsin (as shown in Fig. 1). If schizophrenia participants have deficits in the input portion of their magnocellular pathway, it is probable that this would be manifested either as deficits in absolute sensitivity and/or the noise associated with these thresholds. A certain level of noise is inherent in all visual thresholds, and performance at threshold is heavily limited by this noise (e.g., Donner, 1992). Although intrinsic noise can arise at numerous levels of the visual system,
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Fig. 1. Rod extinction curve (solid line) with human scotopic sensitivity curve superimposed (dotted) (from Dartnall, 1953; CIE, 1951). Deviation at the shortwave end is due to the pre-retinal optical media (i.e., crystalline lens).
noise associated with scotopic thresholds is thought to originate at the input stage, i.e., at the level of the retina (e.g., Van Rossum and Smith, 1998). When in a fully dark-adapted state, the visual system is maximally sensitive, and the effects of noise are evident. In this study, we therefore tested whether schizophrenia participants had deficits in rod photoreceptor functioning by testing absolute scotopic thresholds and the noise associated with such thresholds. Although the scotopic sensitivity of this population has never been reported, there is some basis in the literature for suspecting scotopic deficits. Granger (1957), for instance, originally reported that participants with psychiatric disorders (neuroses and psychoses) had significantly higher scotopic thresholds compared to matched controls. Other past studies have found that schizophrenia patients have altered electroretinogram waveforms (a-wave amplitudes) (e.g., Warner et al., 1999). In addition, there is evidence to suggest that medicated and drug-naı¨ve schizophrenia patients have reduced levels of docosahexaenoic acid (DHA) (e.g., Khan et al., 2002), which is the most abundant essential polyunsaturated fatty acid in the phospholipids of the rod outer segment membranes. Reduced retinal DHA alters the optical density of rhodopsin and rod function in rat models (e.g., Bush et al., 1994). If schizophrenia patients have reduced DHA levels and DHA alters rod-mediated functions such as scotopic function, it is possible that schizophrenia participants may also have scotopic deficits.
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Taken together, the available evidence suggests that a deficit in early rod-mediated vision in schizophrenia is possible. Moreover, past data suggests that if such deficits exist, they may arise at the level of the retina. Such conclusions, however, must be tentative. For example, decreased scotopic sensitivity could also be produced by preretinal optical changes such as increased optical density of the crystalline lens (due to less light being transmitted by the lens). Some evidence suggests that common antipsychotic drugs (e.g. chlorpromazine) are associated with increased lens density (see Shahzad et al., 2002 for review). To assess these possibilities, we also measured lens optical density. Thus, the current study was designed to determine whether schizophrenia participants suffer from earlystage visual dysfunction by psychophysical assessment of absolute scotopic thresholds, scotopic noise, and lens optical density.
2. Method 2.1. Participants Fifteen participants diagnosed with DSM-IV schizophrenia (8 males and 7 females, mean age = 41.5 years, range = 26–55) and 15 control participants (8 males and 7 females, mean age = 41.13 years, range = 23–57) were studied. All participants with schizophrenia were chronic, stable outpatients recruited from regional mental health centers. Diagnoses were confirmed by two psychologists using the Structured Clinical Interview for the DSM-IV (SCIDIV; First et al., 1997). The Scales for the Assessment of Negative (SANS) and Positive (SAPS) Symptoms (Andreasen, 1984) were used to quantify symptom data (zero indicating the symptom was absent to 5 indicating the symptom was severe). Global ratings for negative symptoms were the average of summary scores for alogia, affective flattening, anhedonia/ asociality and avolition/apathy (M = 1.6, SD = 0.5). Global ratings for the positive symptoms were the average of summary scores for hallucinations, delusions, bizarre behavior and thought disorder (M = 2.0, SD = 1.0). Fourteen of the schizophrenia subjects were on atypical antipsychotic medication (M CPZ equivalent dose = 318 mg; using the conversion factors for
atypical antipsychotics provided by Woods, 2003), eleven of who were taking a single antipsychotic (olanzapine (N = 4), risperidone (N = 2), quetiapine (N = 2), ziprasidone (N = 2), and clozapine (N = 1)). Two schizophrenia subjects were taking two or more antipsychotic medications and two were not taking any antipsychotic medications but both were prescribed stimulants. From the entire group of fifteen, eight subjects were taking medications from classes other than the atypical antipsychotics, of which antidepressants were the most common (N = 7). Control participants were recruited from the local Athens area and surrounding environs based on local advertisements and had no personal or family history of schizophrenia or any other Axis I disorder (as determined by selfreport). Participants were matched on gender, age, ethnicity and smoking history (see Table 1), and participants were excluded if they reported any ocular or systemic diseases that would be expected to influence the outcome of this study (e.g. macular degeneration). We tested the Snellen acuity of each subject and used refractive correction when a participant had visual acuity less than 20/30. Furthermore, participants were matched on average number of servings of fruits and vegetables per week (via self-report; one participant elected not to provide this information). Dietary information was obtained in order to determine whether any visual deficits we might find in our subjects was related to dietary behavior. Table 1 Demographic characteristics of participants: schizophrenia vs. control participants
Age
Sex Ethnicity Smoking history
Diet (mean number of servings of fruits and vegetables per week)
Schizophrenia group
Control group
M = 41.5 years, SD = 8.2, range = 26–55 years 8 men 7 women 10 Caucasians 4 African-Americans 7 current smokers 3 past smokers 5 non-smokers M = 8.25 (SD = 3.9)
M = 41.1 years, SD = 10.4, range = 23–57 years 8 men 7 women 10 Caucasians 4 African-Americans 10 current smokers 1 past smoker 4 non-smokers M = 12.23 (SD = 8.5)
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2.2. Apparatus A Maxwellian-view optical system with a FiberLite PL-900 DC Regulated Illuminator light source (Dolan-Jenner Industries: Lawrence, MA.) was used. Maxwellian-view allows the stimuli to be directly projected onto the retina and therefore controls for any variations in pupil size. Two infrared cameras allowed constant viewing of the participant’s iris and pupil and were used to assure that the stimuli were precisely aligned. Precise alignment was facilitated by a chinand forehead-rest assembly that controlled for head movements. Scotopic sensitivity was measured using three 1.85-deg test stimuli located at 108 eccentricity. The main wavelength tested was 510 nm, which falls near the peak of the human scotopic sensitivity curve (i.e., approximately 507 nm) and rod spectral sensitivity curve (see Fig. 1). Since our scotopic sensitivity measures were relative to the actual stimulus and experimental parameters employed in the present study, they will be hereafter referred to as log relative scotopic sensitivity values. A 410 nm stimulus and a 565 nm stimulus were also tested in order to derive an estimate of lens optical density. Since the lens absorbs a small amount of light at 510 nm (e.g., see Wyszecki and Stiles, 1982), measurements of lens density allowed an analysis of the effect of lens absorption on the thresholds obtained for each participant. Light at 565 nm is not absorbed by the lens, but light at 410 nm is heavily absorbed. Consequently, these two wavelengths were used to obtain lens density values based on the classic scotopic threshold method (for a review see Snodderly and Hammond, 1999). 2.3. Method and procedures The nature of the task was explained to each participant before testing began. They were instructed to fixate on a red dot that was located in their right visual field throughout the entire experiment. Participants were then aligned along the optical axis of the optical system and shown suprathreshold samples of the stimuli or blank presentations. Participants were instructed to respond byesQ if a stimulus was detected and bnoQ if a stimulus was not detected. Once the experimenter was convinced the participants understood the nature of the task, the participants were
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dark-adapted for a total of 40 min. After this period, the subjects were aligned (using the infrared cameras), and the stimuli were presented. Stimuli were presented for 1000 ms separated by a short interval. Log relative scotopic sensitivity for the 410 and 565 nm stimuli was assessed using the method of limits to obtain an approximate threshold. This was done by presenting the stimuli in ascending and descending order (the intensity of the test stimulus was varied progressively by approximately 0.05 log increments over a range of about 1 log unit) until an approximate threshold was determined. Once the approximate threshold was determined, stimulus intensity was varied randomly around that point (i.e., the method of constant stimuli) until enough determinations were available to generate a psychometric function. The precise threshold for each wavelength was defined as that intensity where the subject responded that they saw the stimulus 75% of the time. Lens optical density was calculated by subtracting the threshold value at 410 nm (where there is high lens absorbance) from the threshold value at 565 nm (where there is minimal lens absorbance) (e.g., see Wyszecki and Stiles, 1982). This method is referred to as the balancedrhodopsin method; see Snodderly and Hammond (1999) or Van Norren and Vos (1974) for a discussion of the rationale behind using this technique for obtaining lens optical density. More extensive testing was conducted at 510 nm (compared to the 410 and 565 nm thresholds used for calculating lens density) in order to obtain both more exact threshold values and an estimate of intrinsic noise. For this wavelength, we used a temporal twoalternative forced-choice (2-AFC) paradigm similar to the one employed by Sturr et al. (1997). This procedure consists of two alternating trials where the stimulus is either present or absent and the subject must make a forced choice regarding whether the stimulus appeared in the first or in the second presentation. The presentations are signaled by two different auditory tones. The 510 nm stimulus was presented randomly after one of the two auditory tones. All correct and incorrect responses were recorded. Approximately 12 evenly spaced intensities (all intervals consisted of about 0.05 log units) below or above the estimated threshold were used. Each of these stimuli were presented a total of 8 times. Random performance (i.e., about 50% correct) was
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interpreted as the stimulus being below threshold. Threshold was defined as the intensity that produced 75% correct responses. A probit regression analysis was conducted on the data from the 510 nm test stimulus. In this procedure the transformed binomial data (the inverse of the normal probability integral) is fit with a weighted linear regression. Noise was defined as the average deviation from this line. Based on this procedure, individuals with larger deviation values would be interpreted as having higher amounts of noise, and individuals with smaller deviation values would be interpreted as having smaller amounts of intrinsic noise. In order to assess the reliability of this procedure, we assessed two control participants (1 woman and 1 man, ages 20 and 27) on two separate occasions. The average deviation values of the two participants from time one were 0.49 and 0.83, and the average deviation values of the participants from time two were 0.47 and 0.85, respectively. The similarity across sessions suggested our method of measuring noise was reliable.
value of 0.60, which fell 4.6 standard deviation units away from the mean of the distribution of all of the log relative scotopic sensitivity scores (3.01) and could have significantly skewed the results. We therefore decided to exclude these two participants for a final N = 28. The schizophrenia and control participants were highly similar on all the dependent measures; log relative scotopic sensitivity, lens density, and intrinsic noise (see Table 2). Mean log relative scotopic sensitivity (schizophrenia participants, M = 3.14; controls, M = 3.07) only differed by about 2% ( p b 0.21). Average lens optical density (schizophrenia participants, M = 0.96, controls, M = 0.94) only differed by about 2% ( p = 0.85). Intrinsic noise associated with the scotopic thresholds (schizophrenia participants, M = 0.76, Controls M = 0.77) also only varied by about 1% ( p b 0.46). Lens OD was not correlated with either scotopic thresholds (r = 0.24) or variations in sensory noise (r = 0.03).
4. Discussion 3. Results Non-directional independent samples t-tests were conducted on the age and diet data. The groups did not significantly differ on either age or consumption of fruits and vegetables. As shown in Table 1, the groups were also well-matched with respect to ethnicity, smoking, and sex. Independent samples t-tests were also used to compare the mean values of the schizophrenia and control participants on LRSS (at 510 nm) and lens density. Data was unusable for two schizophrenia participants. The first could not be properly aligned with the Maxwellian-view system due to an extremely small pupil; even after 40 min of dark adaptation the participant’s pupil was still approximately 2–3 mm. The second had a log relative scotopic sensitivity
The main finding of our study was that the schizophrenia and control participants were highly similar on the dependent measures assessing rod functioning. Notably, these results are based on a rigorous criterion-free psychophysical procedure. For example, all participants were tested in Maxwellianview using infrared cameras to ensure exact alignment of the stimulus at all times. The scotopic measures used to derive the threshold and noise values were obtained using a 2-AFC paradigm with an average of 200 trials per measure. The two groups did not differ on measures of LRSS, lens OD, or intrinsic noise. Our data are, therefore, inconsistent with an early origin (i.e., retinal) of some of the M-pathway deficits seen in schizophrenia. These results must be considered in light of two caveats. The first caveat is that the sample size was
Table 2 Descriptive statistics for the schizophrenia and control participants on noise, LRSS (at 510 nm)
Intrinsic noise LRSS (at 510 nm) Lens OD
Schizophrenia group
Control group
M = 0.76 (SD = 0.14) range = 0.58–1.12 M = 3.14 (SD = 0.17) range = 2.8–3.88 M = 0.96 (SD = 0.24) range = 0.34–1.49
M = 0.77 (SD = 0.14) range = 0.54–1.01 M = 3.07 (SD = 0.26) range = 2.56–3.44 M = 0.94 (SD = 0.17) range = 0.72–1.32
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small. Scotopic thresholds, however, tend to have low variability as can be seen in this sample and past data (e.g., Hammond et al., 1998). It is unlikely, therefore, that the sample was too small to obtain a reasonable estimate of the average log relative scotopic sensitivity of schizophrenia participants (e.g., the data were relatively normally distributed). Assuming our estimate is reasonable, an extremely large sample would be necessary for the small difference that we found (2%) to be statistically significant. It is doubtful that such a small magnitude of difference is clinically meaningful. The second caveat is that of medication use. The majority of the schizophrenia participants were on atypical antipsychotic medications (e.g. risperidone, olanzapine, etc.). It appears that the majority of the schizophrenia participants assessed in past studies showing M pathway deficits (e.g., Ke´ri et al., 2002; Cadenhead et al., 1998; Slaghuis and Bishop, 2001) were taking typical antipsychotic medications. Therefore, it is possible that one reason past studies have found M pathway deficits in schizophrenia is that their schizophrenia patients were taking typical antipsychotic medications. The question of whether patients taking atypical antipsychotics also display M pathway deficits is open. Antal et al. (1999), for instance, found that schizophrenia patients taking atypical medications did not exhibit contrast sensitivity deficits. In contrast, Butler et al. (2005) did find contrast sensitivity deficits in patients taking atypical medications when using stimuli that were biased to reflect magnocellular processing. Clearly some psychotropic medications appear to influence magnocellular activity. It is unlikely, however, that M pathway deficits are due simply to medication use. For example, relatives of schizophrenia participants are not medicated and still show M pathway deficits (e.g., Bedwell et al., 2003; Green et al., 1997), and differences in brain activity (Bedwell et al., 2004) when compared with normal control subjects. If schizophrenia patients on atypical medications have M pathway deficits (like those on typical medications; e.g., Ke´ri et al., 2002; Slaghuis and Bishop, 2001; Cadenhead et al., 1998), the finding of normal scotopic and noise values in such patients has important implications. If, for instance, schizophrenia patients have M pathway deficits but normal rod
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function, the loci of their deficits must be either postreceptoral and/or reflect the relatively small cone input to the M pathway. The former interpretation is consistent with the finding that schizophrenia participants have significantly reduced CFF thresholds compared to controls (e.g., Black et al., 1975). CFF is considered to be determined by cortical processing at the level of the visual cortex (e.g., Curran, 1990; Wells et al., 2001) but is also thought to be mediated by the M pathway (e.g., Merigan and Maunsell, 1990). Much like schizophrenia, it has been widely concluded through psychophysical, physiological, and anatomical data that some dyslexics display M pathway deficits (e.g., Demb et al., 1998; Livingstone et al., 1991; Stein, 2001; Stein and Walsh, 1997). For example, Livingstone et al. (1991) found that the cells of the M layers of the lateral geniculate nucleus of 5 dyslexic brains were on average 27% smaller than those of control brains, and there were no differences in cell sizes in the P layers. Furthermore, it was widely assumed that dyslexics would also have scotopic impairments. For example, DHA supplementation for dyslexia has been suggested as a mean of addressing M pathway deficits based on the idea that altered rod function could be corrected by increased omega-fatty acids in the outer-segments of rods (e.g., Stordy, 1995, 2000). Careful testing, however, has shown that dyslexics do not have scotopic deficits (e.g., Greatrex et al., 2000), which parallels the findings of this study. The anatomical findings with respect to dyslexia (i.e., smaller M cells in the lateral geniculate nucleus of some dyslexics) may provide a clue to the location of the M pathway deficits observed in schizophrenia. Kim et al. (2005) concluded that the visual deficits seen in schizophrenia originate early in the visual processing stream. Our data suggest this level is not retinal. Like dyslexia, the defects may therefore arise within the thalamus, primary visual cortex, or in the connections between the two areas. This interpretation is consistent with imaging studies that have found that schizophrenia participants have decreased white matter integrity in occipital white matter (Agartz et al., 2001; Ardekani et al., 2003) and thalamocortical radiations (Butler et al., 2005). Ultimately, our results strongly suggest that rod functioning is normal in schizophrenia participants. Our results are, of course, specific to our sample (e.g.,
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chronic, stable outpatients). This conclusion must therefore be confirmed by studies designed to test log relative scotopic sensitivity and magnocellular activity in a) schizophrenia subjects who have not been medicated, b) schizophrenia subjects who are selected based on symptom profiles of predominantly negative or predominantly positive symptoms, and c) the biological relatives of schizophrenia subjects. If the conclusion stands, however, it begs the question of why the retina, which depends strongly on dopaminergic systems, is relatively immune to alteration.
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