Lorazepam impairs perceptual integration of visual forms: a central effect

Transcription

1 Psychopharmacology (1996) 126 : Springer-Verlag 1996 A. Giersch M. Boucart C. Speeg-Schatz F. Muller-Kauffmann J.-M. Danion Lorazepam impairs perceptual integration of visual forms: a central effect Received: 4 January 1996/Final version: 19 March 1996 Abstract Previous studies have shown a lorazepam effect on visual perception. We tested whether this impairment resulted from a peripheral effect induced by benzodiazepines. A first experiment showed that a single dose of lorazepam induces an oculomotor imbalance without impairing visual acuity or accommodation. In a second experiment, we tested whether the impairment induced by lorazepam on visual perception still occurred in monocular vision. Subjects matched incomplete forms controlled on the spacing and alignment of their local contour elements. A reference object was first displayed and followed by two laterally displayed objects, a target and a distractor. The distractor was the mirror-reversed version of the target. Performance was impaired in the lorazepam group when the reference was an incomplete form with a spacing of 10.8' or 22.2' of arc. These results were not correlated with sedation. They confirm that lorazepam has a central deleterious effect on visual perception. A posthoc analysis also suggested that lorazepam-treated subjects used asymmetry in the stimuli as a compensatory strategy. This result is discussed in relation to previous hypotheses about the physiological mechanisms that determine the effects of lorazepam on visual perception. Key words Benzodiazepine - Lorazepam - Human Visual perception - Oculomotor balance - Integration processes Symmetry perception Introduction Previous studies have shown that lorazepam, a benzodiazepine, impairs the identification of Snodgrass et al. A. Giersch ([E~) - M. Boucart - C. Speeg-Schatz F. Muller-Kauffmann. J.-M. Danion Unit6 INSERM 405, D6partement de Psychiatrie. HSpitaux Universitaires, BP 426, F Strasbourg Cedex, France (1987) incomplete pictures (Vidailhet et al. 1994; Legrand et al. 1995) and the matching of Boucart et al. (1994) incomplete pictures (Giersch et al. t995). These studies suggested that lorazepam impairs visuoperceptual processes involved in the processing of contour information (Giersch et al. 1995), The processing of contour information can be affected by either low-level or higher levels of processing. For low-level processes, several authors (Zucker and Davis 1988; Beck et al. 1989; Boucart et al. 1994) have shown that both collinearity and spacing between elements affects the processing of contour information. For high-level processes, Gregory (1972) and Reynolds (1985) reported that semantic cues given prior to the presentation of a fragmented picture improved its identification. Two hypotheses concerning lorazepaminduced impairment were therefore tested in a previous study (Giersch et al. 1995): (1) an impairment of low-level processes involved in the integration of local contour information in a global configuration and (2) the use of stored object representations to help the completion of missing gaps in incomplete pictures. Integration processes were tested by using fragmented pictures controlled on the spacing and alignment of their elements (Boucart et al. 1994). Subjects were required to match a centrally displayed pictm-e (the reference) and two lateral pictures (a target and a distractor) on the basis of their orientation (same versus mirror-reversed images). An impairment of integration processes was suggested by impaired performance in lorazepam-treated subjects, relative to placebo-treated subjects, when the spacing between local elements was greater than 10.8' of arc and when line segments were not collinear. The use of semantic representations was tested by comparing performance in two experimental conditions: (1) when the reference picture was always a complete outline drawing of an object and (2) when the reference picture was either a complete outline drawing or an incomplete and less identifiable picture. The lateral pictures were incomplete forms in both

2 261 conditions. Lorazepam-treated subjects' performance was improved when they started with the condition in which the reference object was always a complete outline drawing. This result suggests that lorazepam impairs low-level integration processes and that this defect can be compensated for by a strategic use of stored object representations to guide the completion of missing parts (Giersch et al. 1995). However, according to clinical experience, lorazepam might also have impaired the oculomotor balance, inducing an ocular convergence and thus blurred vision. Blurred vision could constitute a possible explanation for impaired performance when there were only few local contour elements (i.e. stimuli having a large spacing between elements) or when this information included some incoherence (i.e. stimuli having noncollinear elements). The present study included two sets of measures. Ophthalmologic investigations were designed to examine the peripheral effects of lorazepam on visual performance. Indeed, to our knowledge, only a very few papers have dealt with the peripheral effects of benzodiazepines (see Malone et al for a review), and they point to opposite conclusions. For instance, Turner (1973) found no Iorazepam effect on visual acuity or oculomotor balance, whilst Miller (1962) observed a chlordiazepoxide effect on both oculomotor balance and visual acuity. We thus checked the effects of a single dose of lorazepam on visual acuity, accommodation and oculomotor balance. A second set of measures was designed to explore visuo-perceptual processes by means of a complex pictures matching task, in conditions in which they could not be affected by lorazepam-induced peripheral effects, i.e. with a monocular presentation. Moreover, since lorazepam-treated subjects frequently reported that they had based their response on asymmetries in the stimuli, the use of this strategy was tested in a posthoc analysis. Experiment General methods Subjects Twenty-four paid healthy volunteers (13 women, I1 men) were recruited from the University of Strasbourg. They ranged in age from 20 to 30 years (mean age: 23.6 years) and ranged in weight from 52 to 83 kg (mean weight: 66.8 kg). The protocol was approved by the Faculty Ethics Comittee. All subjects gave their written informed consent. The subjects had no medicat illness or history of alcoholism, drug abuse or tobacco consumption of more than ten cigarettes/day. They were not chronic users of benzodiazepines and had not taken any medication for at least 15 days. They were instructed to abstain from beverages containing caffeine or alcohol for the 24 h prior to the study. All subjects were tested in the morning, after an overnight fast. Experimental design and drugs Subjects were randomly assigned to one of two parallel groups, of 12 subjects each: a placebo group and a lorazepam mg/kg group. The drug tablet was given orally using a double-blind procedure. Ophthalmological investigations were conducted the day before the intake of the drug and subjects were investigated again 2 h 20 rain alter the intake of the drug. All other investigations were carried out between 2 and 3 h after intake. All subjects were tested with optical correction. Ophthalmological measurements of visual acuity, convergence and divergence were conducted separately for the dominant and the non-dominant eye. There was no difference between the two sets of results. The results are thus averaged over dominant and non-dominant eyes. Visual acuity was measured at distances of 33 cm and 5 m. The cover-uncover test and the Maddox rod test were carried out using distances of 60 cm and 5 m. Fusion amplitude was measured at 60 cm, Analyses of the results Analyses of variance were conducted on visual performance for each test with subjects as random variable. There was one betweensubjects variable, the treatment, and one within-subjects variable, the testing session (before or after the intake of the drug). There was no significant difference in performance between the two treatment groups before the intake of the drug. For purposes of clarity, the different sets of measures will be presented separately, with the specific method for each test immediately preceding the results of the test. Ophthalmological investigations Visual acuity Visual acuity at 5 m was measured for each eye separately using the classical Snellen scale. Visual acuity at 33 cm was measured for each eye separately with the Parinaud scale. Results. There was no treatment effect, at either 33 cm or 5 m. Visual acuity was identical before and after the intake of the drug in the placebo and lorazepam groups (20/20 at 5 m and P1.5 at 33 cm, all Fs < 1). COVCY-UFICOVeF test This test was designed to detect heterophoria, small angle strabismus and microstrabismus. Subjects binocularly fixated a non-blinding luminous point (like the central point of the Maddox cross). To ensure that the subject was looking at the fixation point, the examiner checked that the two eyes followed a lateral displacement of the luminous point, and that the interposition of a 4-dioptre prism induced a restitution movement of the eye to restore the fusion. The examiner then occluded one of the eyes with a handled pallet. The restitution movement of the non-occluded eye indicated the presence of a deviation. The present study was con-

3 262 cerned with three cases: (1) if the non-occluded eye did not move, there was no ocular deviation: it was an orthophoria, (2) if the non-occluded eye moved outwards, it indicated an internal deviation: it was an esophoria, and (3) if the non-occluded eye moved inwards, it indicated an external deviation: it was an exophoria. The deviation was quantified using prisms with increasing power. The first prism with which no more restitution movement was observed gave the value of the phoria. By convention, a zero value, positive values and negative values correspond, respectively, to orthophoria, esophoria and exophoria. Results. Performance was drug-affected at 5 m, as indicated by a significant treatment effect [F(1, 22) = 18.8, P < 0.001) and by a significant interaction between treatment groups and testing session [F(1, 22) = 17.8, P < 0.001). An esophoria was observed after the intake of the drug, but only in the lorazepam group [0 dioptre before the intake of the drug and 2.8 dioptres after the intake of the drug, F(1, 23)= 10.3, P < 0.005]. There was no effect in the placebo group (-0.1 dioptre before the intake of the drug and 0.1 dioptre after the intake of the drug, F < 1). There was no treatment effect at 60 cm. Performance was identical in the placebo group before and after the intake of the drug (-0.3 dioptre) and equivalent in the lorazepam group (-0.1 dioptre before the intake of the drug and -0.2 dioptre after the intake of the drug) (F< 1). Maddox rod test The Maddox rod is composed of a set of cylinders which transform a luminous point into a red line. The Maddox rod is held by the examiner in front of one eye so that the subject sees a red line with one eye and a luminous point with the other. To explore for exoor esophoria, the Maddox rod is held in such a way that the red line is vertical. In the case of orthophoria, the luminous point and the red line are superimposed. In the case of esophoria, the red line is seen at the right of the fixation point if the Maddox rod is in front of the right eye. In the case of exophoria, the red line is seen at the left of the fixation point. The red line is brought back to the fixation point by placing a prism in front of the eye. The value of the phoria is given by the power of the prism. Results. The treatment effect was significant at 5 m [F(1, 22)= 11.2, P < 0.005]. The treatment interacted significantly with the testing session (before and after the intake of the drug) [F(1, 11) = 10.6, P < 0.005]. An esophoria was observed in lorazepam treated subjects after the intake of the drug [1.8 dioptres before the intake of the drug and 4.3 dioptres after the intake of the drug, /7(1, 11)= 18.3, P < 0.001]. No effect was found in the placebo group [0.3 dioptre before the intake of the drug and 0.7 dioptre after the intake of the drug, F(1, 11) = 2.6, ns]. Performance at 60 cm was stable across the two sessions in the two groups (F< 1): for the placebo group -0.9 dioptre before the intake of the drug versus dioptre after the intake of the drug (F < 1) and 0.5 dioptre before the intake of the drug versus 0.6 dioptre after the intake of the drug in the lorazepam group (F < 1). Measurement of the Jusion amplitude with the Berens prisms Convergence amplitude. The subject fixated a luminous point. The prism was placed so that the eye had to move inwards to recover the fusion. The power of the prism was increased until the subject was unable to recover the fusion. The convergence amplitude was the highest prism value for which the subject could compensate. Normal convergence amplitude values are between 30 and 40 dioptres. Divergence amplitude. The method was the same as for the convergence amplitude, except that the prism was placed so that subjects had to move their eyes outwards to recover the fixation. Normal values of divergence amplitude values are between 6 and 8 dioptres. Results. There was no significant treatment group effect for convergence omplitude [F(1, 22) = 2.3, ns] but there was a significant interaction between the treatment and the testing session IF(l, 22) = 5.6, P < 0.05]. Performance was stable in the placebo group (t8.8 dioptres before the intake of the treatment and 20 dioptres after the intake of the treatment, F < 1). In contrast, convergence amplitude decreased in the lorazepam group [ 16.4 dioptres before the intake of the treatment and 11.8 dioptres after the intake of the treatment, F(1, 11) = 10.4, P < Divergence amplitude differed significantly between the two treatment groups [F(1, 22) = 6.9, P < 0.05] and there was a significant interaction between the treatment and the testing session [F(1, 22) = 8.2, P < 0.01]. Performance was stable in the placebo group (7.2 dioptres before the intake of the treatment and 7.2 dioptres after the intake of the treatment, F < 1). In contrast, divergence amplitude decreased in the lorazepam group [6.7 dioptres before the intake of the treatment and 3.4 dioptres after the intake of the treatment, F(1, 11) = 15.9, P < 0.005]. Duane scale test The aim of this test is to evaluate the capacities of accommodation and convergence.

4 263 Punctum proximum (near point) of convergence (PPC). The Duane-scale was held in front of the subject, between the two eyes. A moveable rectangle, on which a text was written, was fixated on the scale. The rectangle was gradually moved closer to the subject until the text became blurred. The ptmctum proximum of convergence was given by the shortest distance at which the text was still distinct. A normal PPC is about 6 cm. Punctum proximum (near point) of accommodation (PPA). The Duane scale was held in front of the subject, between the two eyes, as for the punctum proximum of convergence. This time, a point was drawn in the moveable rectangle. The rectangle was moved gradually closer to the subject. The punctum proximum of accommodation is given by the nearest distinct point. It is measured in dioptres, and corresponds to the inverse of the distance in metres between the point and the eye. A normal PPA below the age of 25 is less than 10 cm, that is between 10 and 20 dioptres. Results. Lorazepam induced a change in the PPC, as shown by a trend for a treatment effect [F(1, 22) = 3.6, P = 0.07], and a significant interaction between the treatment and the testing session [F(1,22)=6.5, P < 0.05]. In the placebo group, there was a trend for an increase of the punctum proximum of convergence across the two sessions [7.3 cm before the intake of the drug and 8 cm after the intake of the drug, F(1, 11) = 4.6, P = 0.054]. This effect was larger in the lorazepam group [7 cm before the intake of the drug and 13.3 cm after the intake of the drug, F(1, 11 ) = 8.3, P < 0.05]. Lorazepam did not affect the PPA. Overall, performance decreased slightly between the two test sessions [9.5 dioptres belbre the intake of the drug and 9.2 dioptres after the intake of the drug, F(1, 22)= 4.4, P < 0.05]. However, there was no treatment effect, and no interaction between treatment and the period of the test (F < 1). Performance decreased similarly in the placebo group (9.8 dioptres before the intake of the drug and 9.6 dioptres after the intake of the drug) and in the lorazepam group (9.2 dioptres before the intake of the drug and 8.8 dioptres after the intake of the drug). Complex pictures matching task Materials' and methods Stimuli. The stimuli were 20 outline drawings of objects, including ten animals and ten vehicles, and four incomplete versions of the outline drawings made up of line segments, each with a length of five pixels (one pixel being equal to cm on the screen) : incomplete forms having collinear elements with a spacing of (1) two pixels ($2: 4.2' of arc) between elements, (2) five pixels ($5: 10.8' of arc), or (3) ten pixels (S10: 22.2' of arc) between elements, and (4) forms having non-collinear elements (NC). These lastnamed forms were derived from forms having collinear elements with a spacing of two pixels (4.2' of arc). The line segments were either shifted from one to three pixels or rotated relative to their position or orientation in the collinear version. Examples of the stimuli are presented in Fig. 1. At a viewing distance of 60 cm the mean angular size of the stimuli was 2.5 horizontally and vertically (varying from 1.8 to 3 ). Apparatus. The stimuli were displayed in black on a light grey background on the black and white video monitor of a 486 DX microcomputer equippe d with a VGA (Trident) graphic card. The screen resolution was 640 x 480 pixels. In a dark room the luminance of the stirauli was 0.02 cd/m 2 and the luminance of the background was 31 cd/m 2. Two keys independent of the computer were used for response. Procedure. Subjects viewed the stimuli monocularly with their dominant eye. The sequence of a trial was as follows: a fixation point subtending was centrally displayed for 500 ms. It was followed 500 ms later by a reference picture centrally displayed for 150 ins. After a delay of 500ms during which the fixation point was represented, two pictures (a target and a distractor) were simultaneously presented. The center of the lateral pictures was located 3 left and right of fixation for 150 ms. Two experimental conditions were used: (1) the reference stimulus was always a complete outline drawing of an object, the target being either the same object or one of the four incomplete versions of forms derived from this object (this condition is called the "derived condition" in the remainder of the text) or (2) the reference picture was a complete form or one of the four types of incomplete forms. In this condition, the target was exactly the same as the reference object (this condition is called the "identical condition" in the remainder of the text). In both conditions, the distractor was the mirror-reversed image of the target. Subjects were instructed to decide which of the two lateral pictures was identical to or derived from the reference object. The paradigm and the experimental conditions are presented in Fig. 2. Subjects gave their response by pressing a left or right key according to the spatial location of the target. A practice session in the "derived condition" was given the day before the intake of the drug in order to familiarize the subjects with the task. Practice was pursued until performance reached a criterion of 75% correct responses at the end of 40 trials blocks. On the day of the drug intake, subjects were all tested in both identical and derived conditions. Each condition test consisted of one practice block of 40 trials and a session of 200 experimental trials, in two blocks of 100 trials separated by a short pause. The order of the two sessions, "identical" followed by "derived", or "derived" followed by "identical", was counterbalanced in each treatment group. The 100 pictures, the orientation of the reference picture and the spatial location of the target were randomly and equally represented in each condition. Analogue self-ratings of sedation. As in the previous study, subjects assessed their subjective feelings 1 h 50 min after the intake of the drug, before the two experimental sessions. They used a set of 15 visual analogue scales derived from Bond and Lader (1974). Each scale consisted of a 100 mm horizontal line without gradation, anchored by contrasting states of mind. Subjects were asked to regard each line as a continuum and to rate their feelings at that moment by placing a vertical mark across each line. The scales were scored by measuring in mm from the positive end of each line to the subject's mark. Five of these scales assessed complementary aspects of sedation (alert-drowsy, excited~calm, clear headed-muzzy, energetic-lethargic, fast-slow); the mean score of these five scales was calculated for each subject and was taken as a measure of sedation.

5 264 Fig. 1 Mean correct RTs and error rates with standard errors (averaged across subjects and the session orders) for the two experimental conditions [identical condition (open circles: the reference was one of the five types of form and the target was identical to the reference) and derived condition (filled circles: the reference was always a complete outline drawing of an object and the target was derived from the reference)] as a function of the type of target, as illustrated at the bottom [CC continuous contour, $2 spacing of two pixels (4.2' of arc), $5 spacing of five pixets (10.8' of arc), SIO spacing of ten pixels (22.2' of arc) and NC non-collinear elements], in the two treatment groups: placebo and mg/kg lorazepam ~ fzl Z 2 90o @... Lorazepam: identical condition Placebo - identical condition 700 t I I t I CC S2 S5 Sl0 NC TYPE OF TARGET ' 0 o u~ 40 1 Lorazepam - derived condition ] Placebo - derived condition J '" I / / I I I I CC S2 S5 Sl0 NC TYPE OF TARGET CC $2 $5 S10 NC / k (~ f / -, _ /" Results Two analyses of variance were conducted, one on the mean correct response times (RTs) and one on the mean error rate with both subjects (F1) and pictures (F2) as random variables. There were two between-subject variables: the treatment and the order of the two sessions (derived followed by identical versus identical followed by derived). There were five within-subject variables: the spatial location of the target (left versus right), the semantic category of the reference object (animal versus vehicle), the condition (derived versus identical), and the five types of form used as both targets and distractors. RTs shorter or equal to 150 ms and longer or equal to 3000 ms were discarded. These limits were chosen so that not more than 1% of the data would be eliminated. The mean RT was 906 ms. The mean error rate was 12.9%. Targets located on the right (891 ms and 11.8%) were matched faster and more accurately than targets located on the left (921 ms and 14%) [F1 < 1 and F2(1, 76) = 21.1, P < for RTs and FI(1, 20)=2.6, ns and F2(1, 76) = 7.2, P < 0.01 for errors). Pertbrmance was better for animals (883 ms and t 1.6%) than for vehicles (929ms and 14.1%) [Fl(1,20)= 11, P < 0.005, and F2(1, 76) = 5.8, P < 0.05 for RTs and FI(1, 20) = 7.9, P < 0.05 and F2(1, 76) = 3.3, ns for errors). There was no significant interaction between these variables and the other experimental factors. The results (displayed in Fig. 1) are averaged over target location and semantic category. RTs and the error rate were significantly lower in the placebo group (818 ms and 9%) than in the lorazepam group (994ms and 17%) [F1(1,20)=2.3, ns and F2(1, 76) = 129, P < for RTs and FI(1, 20) = 12.8, P < and F2(1, 76) = 33.5, P < for errors]. There was a main effect of the type of form, both for RTs [Fl(4, 80) = 55.3, P < and F2(4, 304) = 51.6, P < 0.001] and for errors [Fl(4, 80) = 73.2, P < and F2(4, 304) = 54.8, P < 0.001]. RTs and the error rate increased when the spacing between contour elements increased from two to five pixels (4.2' versus 10.8' of arc) (841 ms and 7.5% versus

6 265 (a) (b) ( f Target I Target n j d k t f I ( Reference Reference f ~ "z t -- I j.j k.~ Distraeto r _ / Distractor I / Fig. 2a, b An example of the matching task for the two experimental conditions: a the reference was always a complete outline drawing of an object and the target was derived from the reference and b the reference was one of tile five types of form and the target was identical to the reference 876 ms and 10.3%] [FI(1, 20) = 11.2, P < and F2(1, 76) = 13, P < for RTs and FI(1, 20) = 13.5, P < and F2(1, 76) = 6.8, P < for errors], and when the spacing between elements increased from five to ten pixels (10.8' versus 22.2' of arc) (876 ms and 10.3% versus 962 ms and 20%) [FI(1, 20) = 50.6, P < and F2(1, 76) = 43.2, P < for RTs and FI(1, 20) = 70, P < and F2(1, 76) = 50.7, P < for errors]. RTs, but not errors, increased for incomplete forms with non-collinear elements (NC: 992 ms and 19.5%) [FI(1, 20) = 10.5, P < and F2(1, 76) = 3.3, ns for RTs and F1 < 1 and F2 < 1 for errors). Matching was faster and more accurate when the reference stimulus was always an outline drawing (in the derived condition ms and 10%) than when the reference picture was the same form as the target [ ) 1 (in the identical condition - 920ms and 15.7%) [FI(1, 20)=3.3, P=0.082 and F2(1,76) =18.1, P < for RTs and Ft(1, 20) = 72.5, P < and F2(1, 76) = 71.1, P < for errors]. Subjects were faster when they started with the identical condition (880 ms and 13.5%) than when they started with the derived condition (942 ms and 12.2%) IF1 < 1 and F2(1, 76) = 14.5, P < for RTs and F1 < 1 and F2 < 1 for errors]. Treatment interacted significantly with the order of the two sessions, but only for RTs and only with pictures as the random variable [F1 < 1 and F2(1, 76)= 33.5, P < for RTs and F1 < 1 and F2 < 1 for errors]. In the lorazepam group, RTs were higher when subjects started with the derived condition, with complete objects as the reference (1060 ms and 16.3%) than when they started with the identical condition, with incomplete forms as the reference (928 ms and 17.7%) [F1 < 1 and F2(1, 38) = 42.6, P < for RTs and F1 < 1 and F2 < 1 fbr errors). In contrast, in the placebo group, RTs and the error rate did not differ significantly whether the derived condition was fbllowed by the identical condition (803 ms and 8.2%), or preceded by it (833 ms and 9.2%) [F1 < 1 and F2(1, 38) = 2.1, ns for RTs and F1 < 1 and F2 < 1 for errors]. There was a trend for a significant interaction between the type of form, the treatment and the experimental condition tbr RTs but not for errors, in the analysis with subjects as the random variable [Fl(4, 80) = 2.3, P = and F2(4, 272) = 1.8, ns fbr RTs and F1 < 1 and F2 < 1 for errors). The interaction between the experimental condition and the type of form was significant in the lorazepam group [Fl(4, 40)= 3.9, P < 0.01] but not in the placebo group (F1 < 1). There was a significant difference in the lorazepam group between performance in the identical and in the derived condition, but only for some types of forms. RTs were significantly higher when the reference, the target and the distractor had a spacing of five pixels (10.8' of arc) or ten pixels (22.2' of arc) between elements, in the identical condition, as compared to the condition in which the target and the distractor had a similar spacing between elements but the reference was always complete [FI(1, 10) = 6.5, P < 0.05]: 986 (reference fragmented) versus 933 ms (reference complete) for incomplete forms having a spacing of five pixels between elements [FI(1, 10) = 5.3, P < 0.05) and 1106 (reference fragmented) versus 1003 ms (reference complete) for incomplete forms having a spacing of ten pixels between elements [FI(1, 10)= 4.2, P = 0.067] (see Fig. 1). There was no significant difference in terms of RTs between the two experimental conditions for other types of forms (Fs < 1) and in the placebo group [FI(1, 10)= 1.6, ns]. Analogue self-ratings of sedation. There was a trend for a significant main treatment effect on self-ratings of sedation [F(1, 22) = 3.8, P = 0.064]. Sedation scores

7 266 were higher in the lorazepam group (59 _+ 7) than in the placebo group (43 + 4). Pearson measures of correlation were carried out between RTs and error rates and self-rated sedation for each type of form. Neither measure of correlation was significant (Ps > 0.10). Discussion The results of the ophtalmologic investigations can. be summarized as follows. (1) Lorazepam had no effect on visual acuity. This result confirms previous work (Turner 1973). (2) Lorazepam did not affect accommodation. An effect on accommodation is generally attributed to cholinergic effects and lorazepam has a negligeable impact on the cholinergic system (Hommer et al. 1987). (3) Lorazepam impaired the oculomotor balance: (3a) the Maddox rod test and the coveruncover test consistently showed that lorazepam induced esophoria at 5 m. (3b) The convergence amplitude was significantly reduced by lorazepam. (3c) The divergence amplitude was also significantly reduced. (3d) Lorazepam induced an increase in the PPC. The results confirm the clinical observation that lorazepam induces an oculomotor imbalance without impairing visual acuity or accommodation. Concerning the visuo-perceptual processes tested in the complex pictures matching task, performance in the lorazepam group differed from performance in the placebo group in three main respects: (1) RTs and the error rate were higher in the lorazepam group than in the placebo group. This result can be explained by a non-specific sedative effect. (2) In the lorazepam group, performance was impaired in the identical condition (when the reference picture was either complete or fragmented), as compared to the derived condition (when the reference picture was always a complete object), when the spacing between elements was five and ten pixels (10.8' and 22.2' of arc, respectively). There was no significant difference in performance between the two conditions in the placebo group. (3) Subjects in the lorazepam group were slower when they started with the derived condition (with complete objects as reference) than when they started with the identical condition (with incomplete forms as reference). Performance in the placebo group was the same, whichever order was used. The difference in performance observed in the lorazepam group between the identical and derived conditions for incomplete forms having a spacing of five or ten pixels (10.8' or 22.2' of arc) between elements indicates that lorazepam impaired performance when there was a large spacing between elements. The results replicate those found with binocular vision (Giersch et al. 1995). This impairment cannot be explained by an ocular divergence. This effect there- fore confirms that the lorazepam effect is a central effect. Three arguments suggest that sedation cannot account for this effect. First, there was no correlation between performance and sedation. Second, the longer RTs observed in the placebo group for incomplete forms with non-cotlinear elements, as compared to the other types of form, indicate that this type of form is the most difficult to match. If the results were due to sedation, the largest difference in RTs between the identical and derived conditions should have been observed fbr this version of incomplete forms. This was not the case. Third, if sedation was responsible for the longer RTs found with the identical condition, RTs should have been longer for subjects starting the experimental sessions with the identical condition than for subjects for whom the identical condition followed the derived condition. We found the opposite. The results therefore suggest a specific impairment of binding processes responsible for the integration of local contour information into a global configuration. As in the previous study (Giersch et al. 1995), performance differed significantly in the lorazepam group, depending on whether subjects started with the identical condition or the derived condition, suggesting different strategies according to the order of the sessions. However, in contrast to the previous study, subjects were faster when they started with the identical condition, in which the reference was either complete or fragmented, than when they started with the derived condition, in which the reference was always complete. Subjects starting with the identical condition in the present study were thus considerably faster than in the previous study (928 ins and 17.7% in the present study versus 1224 ms and 23.3% in the previous one). When subjects started with the derived condition, with complete forms as reference, they were also faster in the present study than in the previous one but the difference was smaller (1060ms and t6.3% in the present study versus 1180 msec and 14.3% in the previous one). This result suggests that when subjects started with the identical condition, they used compensatory strategies that were not used in the previous study due to an oculomotor imbalance. When subjects started with the derived condition, they probably used semantic information in both studies. They could, for instance, identify a part of the first picture, code its orientation (oriented to the left or to the right) and use this in formation to match the reference and the target. The use of semantic information requires additional processing, and typically slows down RTs in form matching tasks (Posner and Mitchell 1967; Bartram 1976; Boucart and Humphreys 1992; Boucart et al. 1994). Subjects in the lorazepam group frequently reported that they used stimulus asymmetries to determine their response. This aspect was examined in a post-hoc analysis of the data.

8 267 Post.hoc-analysis Evaluation of the stimulus asymmetries It has been argued that both global and local information are involved in the processing of symmetry (see Wagemans 1993 for a review). Asymmetry in pictures was therefore measured along the vertical axis with an objective parameter varying with surface difference (global information) and also with the quantity of local irregularities in the contour (local information). The degree of asymmetry in pictures was determined by superimposing one half of a picture on the other. This procedure defines an internal perimeter and an external perimeter in the asymmetric zones (Fig. 3). The symmetry parameter was then computed by subtracting the internal from the external perimeter. Less than half of the objects were largely asymmetrical so the 20 objects were divided into two groups as followed: seven asymmetrical, with a perimeter difference greater than 50 pixels (mean: 72 pixels), and 13 termed 'symmetrical' in the remainder of the text, with a perimeter difference less than 50 pixels (mean: 24 pixels). Results There was a symmetry main effect for errors [FI(t, 20) = tl.8, P < and F2(1, 72) = 4, P < 0.05 for errors] but not for RTs (both F< 1). Accuracy was higher for asymmetrical pictures (901 ms and 11%) than for symmetrical pictures (864 ms and 13.9%) Symmetry interacted significantly with treatment and experimental condition for RTs but not for errors [F1(1,20)=8.6, P<0.01 and F2(1,72)=9.6, P< for RTs and FI<I and F2<l for errors]. Subsequent analyses showed that this effect was mainly due to an interaction between symmetry and experimental condition for RTs in the lorazepam group [FI(1, 10) = 10.3, P < 0.01 and F2(1, 36) = 12.1, P < 0.001) but not in the placebo group (F1 and F2 < 1). In the lorazepam group, there was a larger difference in performance between the derived and the identical conditions for asymmetrical pictures than for symmetrical pictures. Asymmetrical figures were matched faster (by 89 ms) when the reference was always complete than when it was either complete or fragmented [FI(1, t0) = 10.3, P< 0.01 and F2(1, 12) = 35.1, P < 0.001]. No effect was found for symmetrical pictures (F1 and F2 < 1) (Fig. 4). Treatment interacted significantly with symmetry, the type of form and the order of the sessions, but only for errors [Fl(4, 80) = 1.4, ns and F2(4, 288) = 1.3, ns for RTs and Fl(4, 80) = 3.6, P < 0.01 and F2(4, 288) = 2.5, P < 0.05 for errors]. This effect resulted from an improvement in accuracy for asymmetrical figures (19% errors and 961 ms), as compared to symmetrical figures (28% errors and 995 ms), in the lorazepam group, when the spacing between elements was ten pixels (22.2' of arc) and when the first session was in the identical condition [FI(t, 5) = 9.2, P < 0.05 and F2(1, 18) = 2.4, ns]. There was no such improvement when the first session was in the derived condition (26% errors and 1198 ms for asymmetrical figures versus 23.7% errors and 1105 ms for symmetrical figures) (F1 and F2 < 1). It should be noted that the treatment effects observed in the complex pictures matching task remained significant in this analysis. There was still a significant interaction between the treatment and the order of the sessions [F1 < 1 and F2(1, 72) = 30.5, P < for RTs and F1 < 1 and F2 < 1 for errors] and a significant interaction between the type of form, the treatment and the experimental condition [Fl(4, 80) = 3.4, P < 0.05 and F2(4, 88) = 1.8, ns for RTs and F1 < 1 and F2 < 1 for errors). Symmetry did not interact with these factors (Fs < 1). Discussion The results of the post-hoc analysis showed that: (1) the difference in RTs between the derived condition (with complete objects as reference) and the identical condition (with incomplete forms as reference) increased as the objects became more asymmetrical in the lorazepam group, but not in the placebo group; (2) for forms having a large spacing between elements (22.2' of arc), there was an improvement in accuracy in the lorazepam group for asymmetrical forms as compared to symmetrical forms, but only when subjects started in the identical condition. We propose that, in the present study, lorazepam treated subjects used asymmetry when they started in the identical condition. This hypothesis is supported by the symmetry effect observed in lorazepam-treated subjects but not in placebo-treated subjects. First, the use of asymmetry should be more difficult with incomplete pictures, because they contain less information (a) Fig. 3a, b An example of the asymmetry measure used in the posthoc analysis, a Each picture was divided in two halves, b These two halves were superimposed, defining an internal perimeter (clashed line) and an external perimeter (complete line). The asymmetry parameter was given by the difference between the internal and the external perimeter (b) /

9 268 Fig. 4 Mean correct RTs and error rates with standard errors (averaged across subjects and the sessions order) for the two types of figure, symmetrical or asymmetrical, as a function of the experimental condition [identical condition (in grey: the reference was one of the five types of form and the target was identical to the reference) and derived condition (in white: the reference was always a complete outline drawing of an object and the target was derived from the reference)], in the two treatment groups: placebo and mg/kg lorazepam PLACEBO 1200, E o 900- o Asymmetrical Type of figure ~N Symmetrical Asymmetrical Type of figure Symmetrical LORAZEPAM " 11(D- 20- g o I:: 15- [" o to t Asymmetrical i Symmemcal 0- Asymmetrical Symmetrical Type of figure Type of figure with which to perceive the asymmetry. There was indeed a large difference in RTs in the lorazepam group between the identical condition (with incomplete objects as reference) and the derived condition (with complete objects as reference) when the stimuli were asymmetrical. This difference was larger than when the stimuli were symmetrical. This effect supports the hypothesis that lorazepam treated subjects used asymmetry as a response criterion. Second, when subjects started with the identical condition (irrespective of the experimental condition), accuracy was better for asymmetrical targets with a spacing of ten pixels (22.2' of arc) between elements than for symmetrical targets with the same spacing between elements. The previous study (Giersch et al. 1995) and the complex pictures matching task in the present study have shown that stimuli with a spacing of 22.2' of arc between elements are the forms in which lorazepam-induced impairment was the largest. This effect therefore suggests that asymmetry was used as a compensatory strategy, and that this compensation occurred only when the first experimental session was in the identical condition. It supports the proposition that lorazepam-treated subjects used assymetry when the order of the sessions was identical-derived, but another strategy which might be the use of semantic information, when the order of the sessions was derived-identical. It is generally accepted that symmetry is easily detected and can help object recognition (Bruce and Morgan 1975; Royer 1981). However, the mechanisms involved in the processing of symmetry are more controversial. For instance, some proposals have stressed an early processing of global symmetry, without any organizational process being necessary (Julesz 1971; Barlow and Reeves 1979). In contrast, other authors have suggested that spatial grouping is involved in the detection of symmetry (Royer 1981; Jenkins 1983; Itoffman and Richards 1984; Pashler 1990; Locher and Wagemans 1993; Quinlan and Humphreys 1993; Baylis and Driver 1994; Dakin and Watt 1994; Watt 1994). Our results do not permit any firm conclusion on the type of symmetry processing used by lorazepam treated

10 269 subjects. It could be based for instance on raw global information conveyed by low" spatial frequencies on each side of the vertical axis of the picture. Though recent results (Harris and Phillipson 1995) suggest that lorazepam induces a loss in contrast sensitivity at lower spatial frequencies, this loss could be insufficient to prevent the integration of low spatial frequencies, particularly above contrast threshold, as it is the case in the present study. Our results suggest that a decrease in sensitivity to low spatial frequencies at contrast threshold does not account fbr the impairment observed in the complex pictures matching task. Lorazepam affected performance both for symmetrical and asymmetrical pictures when the spacing between elements was five and ten pixels (10.8' and 22.2' of arc, respectively), as indicated by the lack of any interference of the symmetry factor with this effect. Indeed, the difference in RTs between the identical condition and the derived condition increases with the same magnitude for symmetrical pictures (+ 73 ms) and for asymmetrical pictures (+ 80 ms) having a spacing of five or ten pixels (10.8' or 22.2' of arc) between elements. This equivalent effect for the two types of forms eliminates the loss in low spatial frequencies as a possible cause to explain our results. Indeed, subjects could hardly base their response on low spatial frequency for symmetrical pictures, given that they differed on a small amount of details conveyed by high spatial frequencies. An alternative explanation for the use of asymmetries in lorazepam treated subjects could be that subjects compared nonlinearities such as curvatures or edges on each side of the form. According to numerous electrophysiological or computational studies, nonlinearities are coded by end-stopped cells (Hubel and Wiesel 1965; Dobbins 1989; Peterhans and von der Heydt 1989; Versavel et al. 1990; Heidtger et al. 1992). Since we suggested in the previous study (Giersch et al. 1995) that lorazepam might enhance end-stopped cells responses through its GABA-A agonistic effect, it is tempting to propose that the resulting enhancement of segmentation processes led to the use of asymmetries in lorazepam treated subjects. Conclusion The present results confirm the clinical knowledge that lorazepam impairs the oculomotor balance but not visual acuity or accommodation. The results observed in the complex pictures matching task suggest that lorazepam also impairs central visuo-perceptual integration processes, irrespective of the peripheral effects. 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