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The effects of nicotine on specific eye tracking measures in schizophrenia
The Effects of Nicotine on Specific Eye Tracking Measures in Schizophrenia Jay D. Sherr, Carol Myers, Matthew T. Avila, Amie Elliott, Teresa A. Blaxton, and Gunvant K. Thaker Background: The role of neuronal nicotinic receptors in the etiology and pathophysiology of schizophrenia has been suggested by postmortem findings as well as by linkage analysis implicating chromosome 15q14, the region where the ␣-7 nicotinic receptor gene is located. In addition, drug probe studies show that acute nicotine administration reverses sensory gating and eye-tracking deficits associated with the genetic liability for schizophrenia. The purpose of the current study was to examine the effects of acute administration of nicotine on specific measures of smooth pursuit eye movements and visual attention. Methods: Twenty nine subjects with schizophrenia (15 smokers and 14 nonsmokers), and 26 healthy comparison subjects (15 smokers and 11 nonsmokers) completed testing. The effects of 1 mg of nicotine, administered by nasal spray, on smooth pursuit initiation, pursuit maintenance, and predictive pursuit were examined. Results: Nicotine significantly improved eye acceleration during smooth pursuit initiation in both smoker and nonsmoker patients but had no effects in healthy subjects. The fact that patient initiation eye acceleration in response to nicotine was significantly higher than in healthy subjects suggests that the lack of effect in healthy subjects was not due to ceiling effects. Nicotine significantly improved pursuit gain during maintenance at a target velocity of 18.7 deg/sec. There were no effects of nicotine on visually guided and memory saccades, or visual attention (d⬘ from a continuous performance task). Conclusions: Nicotine showed differential effects in schizophrenic patients compared to healthy subjects. These effects of nicotine were unlikely the result of differences in vigilance or sustained attention, because saccadic peak velocity, a sensitive measure of vigilance, and continuous performance task measures were not affected by nicotine. These findings are not thought to be an artifact of nicotine withdrawal effects at baseline, because the abstinence period was very short, and there were similar effects of nicotine on initiation in nonsmoker From the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Catonsville, Maryland. Address reprint requests to Gunvant Thaker, M.D., Schizophrenia Related Disorders Program, Maryland Psychiatric Research Center, Post Office Box 21247 Baltimore MD 21228. Received September 28, 2001; revised January 8, 2002; accepted January 25, 2002.
© 2002 Society of Biological Psychiatry
patients. These findings suggest an abnormality in neuronal nicotinic system functioning in schizophrenic patients. Biol Psychiatry 2002;52:721–728 © 2002 Society of Biological Psychiatry Key Words: Smooth pursuit eye movements, schizophrenia, nicotine, smoking, predictive pursuit
Introduction
I
n recent years there has been a growing interest in nicotinic neurotransmitter systems in schizophrenia. This interest is stimulated by a body work that has shown decreased ␣-bungarotoxin binding or decreased ␣-7-nicotinic receptor immunoreactivity in postmortem brain tissue, and linkage analysis implicating chromosome 15q14, the site of the ␣-7 nicotinic receptor gene (see Freedman et al 2000 for review). In addition, drug probe studies have shown that acute nicotine administration reverses sensory gating and eye tracking deficits associated with the genetic liability for schizophrenia. The purpose of the current study was to examine the effects of acute administration of nicotine on specific measures of smooth pursuit eye movements and visual attention. Abnormality of smooth pursuit eye movements is one of the most replicated neurophysiological deficits observed in patients with schizophrenia as well as in a proportion of their first-degree relatives (Holzman et al 1984; Thaker et al 1996, 1998). Humans track a small moving object of interest with their eyes using slow movements called smooth pursuit eye movements. Normally, the pursuit system needs motion information to generate a smooth pursuit response. During initiation of smooth pursuit, the slippage of the image of the target on the retina, referred to hereafter as retinal motion, stimulates smooth pursuit (Lisberger et al 1987; Newsome et al 1985, 1988). The processing of retinal motion occurs in the mediotemporal region (Lisberger and Movshon 1999; Newsome et al 1985, 1988). Once eye velocity approximates target velocity, retinal motion is minimal. Continued smooth pursuit (i.e., maintenance pursuit) is based on a complex set of 0006-3223/02/$22.00 PII S0006-3223(02)01342-2
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processes involving predictive smooth pursuit eye movements, and occasional increases in smooth eye velocity or saccades to catch up with the target. Predictive smooth pursuit is driven by potent extraretinal motion inputs, with minor corrections based on retinal velocity and position error information (Barnes and Asselman 1991; Lisberger et al 1987; van den Berg 1988). Investigators have used target masking procedures (brief extinctions of the target along its trajectory) to obtain measures of predictive pursuit independent of retinal information. Medial superior temporal and posterior parietal regions are thought to hold eye velocity and previous retinal velocity information “on-line,” respectively, in the absence of current retinal motion (Assad and Maunsell 1995; Barton et al 1996; Komatsu and Wurtz 1989). The frontal eye fields (FEFs) integrate this extraretinal motion information into a smooth pursuit response (MacAvoy et al 1991). Abnormalities in processing motion information and initiating smooth pursuit (i.e., the initiation phase), as well as abnormalities in predictive pursuit are observed in schizophrenia. Preliminary data in our laboratory suggest that the abnormality in the initiation of smooth pursuit may be marking the liability for the deficit syndrome, whereas predictive pursuit abnormality marks the liability for psychosis in schizophrenia (Hong et al unpublished data; Ross et al 1997; Thaker et al 1998, 1999). In addition to smooth pursuit eye movements, investigators have extensively studied saccadic eye movements in schizophrenia. Visually guided saccades are generally found to be normal in schizophrenia (Thaker et al 2000). Saccadic latency and peak velocity are highly sensitive measures of vigilance (Fafrowicz et al 1995). Because the effects of nicotine on smooth pursuit measures can potentially be mediated by the effects on attention or vigilance, a saccadic task and a visual attentional task were administered in the present study. Visual attention was measured using the identical pairs four-digit numbers version of the continuous performance task (CPT-IP). This is a sensitive measure of attention and discriminates patients with schizophrenia and their relatives from healthy comparison groups (Cornblatt and Keilp 1994). The smooth pursuit abnormalities observed in schizophrenia spectrum disorders provide an important target for drug probes in schizophrenia. These abnormalities represent fundamental neurophysiological deficits associated with the phenotype and are thus likely to be nearer to the genetic effects than the overt symptoms along the pathway from genotype to clinical symptoms. Currently available drug treatments for schizophrenia have minimal therapeutic effect on the more enduring and devastating deficits associated with schizophrenia. Unlike overt psychotic symptoms, which remit frequently during the course of the illness, many of the neurophysiological deficits persist
during fluctuations in psychosis and remain untreated with traditional drugs. Thus, neurophysiological measures, which mark these more enduring and treatment-refractory symptoms, provide a useful target for drug probes. Effective treatments against such neurophysiological deficits also have implications for a much broader group of nonschizophrenic subjects who fall within the phenotype (i.e., individuals with schizophrenia spectrum disorders). Furthermore, such treatments have implications for early treatment and preventive strategies in schizophrenia. Existing antipsychotic drug treatments for schizophrenia have generally been unsuccessful in reversing smooth pursuit abnormalities. Ketamine was shown to disrupt the initiation phase of smooth pursuit in healthy subjects in our laboratory (Weiler et al 2000). The effects of nicotine on smooth pursuit eye movements have been examined by three previous studies in schizophrenic patients (Klein et al 1991; Olincy et al 1998; Thaker et al 1991). The first study examining the effects of nicotine on eye movements in schizophrenia noted an increase in disinhibition of the saccadic system during smooth pursuit marked by an increase in a specific type of saccadic intrusions, called square wave jerks (Thaker et al 1991). Although specific measures of smooth pursuit were not obtained, there was no effect of nicotine on a global measure of eye tracking performance. Olincy et al (1998) showed an improvement in a measure of anticipatory (leading) saccades during smooth pursuit, and a trend toward improvement in a global pursuit measure (Olincy et al 1998); however, it was not clear whether these findings were secondary to a general and nonspecific alerting effect in patients and a ceiling effect in healthy subjects (i.e., the lack of effect in healthy subjects occurred because their tracking was already nearly perfect). Also, it is unclear from previous studies what specific components of the smooth pursuit response are affected by nicotine. Finally, most of the previous studies examined the effects of nicotine in smokers only. The goal of the current study is to test the effects of nicotine on different specific components of the smooth pursuit eye movement system in smoker and nonsmoker schizophrenic patients and healthy subjects.
Methods and Materials Subjects were recruited from the outpatient clinics and an inpatient unit at the Maryland Psychiatric Research Center. Healthy control subjects were recruited by newspaper advertisement. Subjects were excluded if they had a history of substance abuse within the past 6 months or a lifetime diagnosis of substance dependence (DSM-III-R). Individuals with chronic obstructive lung disease and/or pulmonary emphysema or preexisting clinically significant cardiovascular disease, moderate to severe mental retardation, or recent myocardial infarction were excluded. All subjects received clinical evaluations, which in-
Nicotine Effects on Eye Tracking in Schizophrenia
cluded the Structured Clinical Interview for DSM-IV. All subjects gave informed consent in accordance with University of Maryland Institutional Review Board guidelines. Before participating, subjects were interviewed by a noninvestigator clinician (using a standardized form) to assess their ability to understand the procedures and provide valid consent. All subjects received $15/hour for their participation in the study. Subjects abstained from nicotine for 2 hours before the study and participated in two randomly ordered testing sessions: a control state in which no drug was given and after nicotine administration. Nicotine was administered via Nicotrol-Nasal Spray (McNeil, Fort Washington, PA) by the investigator, one puff in each nostril 5 min before eye tracking, for a total dose of 1.0 mg (All participants tested in this experiment also completed a battery of other cognitive tasks described in separate reports and received three separate 1-mg doses of nicotine). One cognitive task, the continuous performance test (CPT) is included in this report. The order of tests was counterbalanced within the nicotine and control conditions to control for number and recency of nicotine administrations.
Subject Description Twenty-nine subjects (18 males and 11 females) with schizophrenia, 15 smokers and 14 nonsmokers, completed testing. Twenty-six healthy comparison subjects (10 males and 16 females), 15 smokers and 11 nonsmokers, completed testing. Schizophrenic and healthy subjects were matched on mean (⫾ SD) age, 40.5 (⫾ 8.5) years and 37.9 (⫾ 12.1) years, respectively. Subjects with schizophrenia differed from healthy comparison subjects on Hollingshead Socioeconomic Scale scores, 4.3 (⫾ 1.0) versus 2.7 (⫾ .8), respectively (Hollingshead and Redlich 1988). All subjects with schizophrenia were taking antipsychotic medications, three (10%) were taking traditional neuroleptics, nine (31%) were taking clozapine, one (3%) was taking risperidone, fourteen (48%) were taking olanzapine, and two (6%) were taking olanzapine and haloperidol. Three subjects each were taking lithium, valproic acid, or a serotonin reuptake inhibitor. The Fagerstrom Test for Nicotine Dependence (FTND) was administered in 27 smokers (14 patients). The FTND collects information about smoking habits and correlates with other proposed measures of nicotine dependence (carbon monoxide, nicotine, and cotinine levels), although it is a weak predictor of withdrawal symptoms during abstinence (Fagerstrom et al 1989; Pomerleau et al 1994). The FTND gives a score from 0 (no dependence) to 10 (high dependence).
Eye Tracking Tasks The testing was carried out in a dark room. Eye movement tasks were presented in a fixed order: 1) visually guided saccade task, and 2) smooth pursuit task. VISUALLY GUIDED SACCADE TASK. Each trial started with the target, a red cross inside a blue box, in the center of a computer monitor (approximately 28⬙ from the eyes). The target remained in the center for a random time of 1.1–2.8 sec, after which it would step to a location 5 or 10 degrees (target
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amplitude) to the left or right of center. The target would remain in this peripheral location for 1.7 sec, at which point the target would disappear and a new trial would begin. Subjects were instructed to look at the target at all times. A total of 16 trials were administered in one session. Latency of response, saccadic accuracy, and peak eye velocity during the saccade were measured. Additionally, the total number of square wave jerks (a dysmetric intrusion) were counted during the 16 trials (Thaker et al 1991). SMOOTH PURSUIT. A fovea-petal step-ramp with unpredictable onset was presented, followed by 3– 4 cycles of (12°) triangular waveform target motion. The excursion of the target at a constant velocity (9.4° or 18.7° per second) from one extreme to the other constituted a ramp. After 4 – 6 ramps the target unpredictably became invisible (mask) for 500 msec. Subjects were instructed to “. . . follow the target as it moves. Occasionally the target will become invisible for very brief periods. During these periods the target will keep moving, so continue moving your eyes to follow the invisible but moving target.” Twenty-five trials were obtained at each ramp velocity. Half of the time the mask was at the beginning of the ramp and half of the time the mask occurred variably sometime in the middle of the ramp. This approach allows examination of both initiation and predictive pursuit. Eye movement data were obtained using an infrared technique (sampling rate of 333 Hz with a time constant of 4 msec) filtered at 75 Hz low-pass filter and converted to digital signals using a 16-bit A-D converter. Smooth pursuit analyses of the eye movement data used interactive software to remove saccades, blinks, and slow compensatory pursuit after leading saccades. Subsequent analyses on the original smooth pursuit data measured leading saccades.
Eye Movement Measures Used in the Study INITIATION PHASE. Latency of the smooth pursuit response and the mean acceleration during the first 100 msec of smooth pursuit were measured (Ross et al 1997; Weiler et al 2000). SMOOTH PURSUIT MAINTENANCE: PREDICTIVE PUR-
Peak predictive pursuit was calculated from responses where the mask occurred at the beginning of a new ramp after the change in direction. In this condition, subjects stop moving in one direction and initiate predictive smooth pursuit in the opposite direction. The latency of the change in direction of eye velocity from the time of the expected change in direction of the target was obtained. Absolute latency values were used, because our interest was mainly in the timing of change, because all nonzero latency values indicate mistiming. Change in direction latency conceptually corresponds to the phase lag. We also measured peak predictive eye velocity within the mask, in the direction of expected ramp. SUIT MEASURES: PEAK PREDICTIVE PURSUIT.
RESIDUAL PREDICTIVE PURSUIT. When the mask occurs during the ramp, the eye continues to move at the same velocity
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Table 1. Smooth Pursuit Measures Target velocity 18.7°/sec
Target velocity 9.4°/sec
Control
Nicotine
Control
Nicotine
87.1 (34.1) 67.82 (19.22) 64.72 (14.57) 66.20 (36.09)
80.3 (14.1) 94.66 (35.39) 63.16 (20.20) 87.48 (24.55)
64.78 (22.13) 61.77 (14.88) 58.61 (21.78) 68.56 (29.34)
66.58 (21.21) 68.69 (24.77) 69.55 (25.38) 90.76 (40.42)
.82 (.16) .68 (.15) .85 (.11) .60 (.17)
.83 (.18) .77 (.12) .87 (.09) .62 (.22)
.87 (.18) .77 (.13) .85 (.11) .66 (.23)
.89 (.15) .82 (.13) .87 (.15) .62 (.24)
a
Initiation–mean acceleration Healthy smoker Schizophrenic smoker Healthy nonsmoker Schizophrenic nonsmoker Closed loop gainb Healthy smoker Schizophrenic smoker Healthy nonsmoker Schizophrenic nonsmoker
Values in the table are mean (⫾ SD). There was a significant effect of velocity on all measures, p ⱕ .01. a Significant drug ⫻ diagnosis interaction, [F(1,47) ⫽ 6.15, p ⫽ .017]. Nicotine increased initiation acceleration in both smoker and nonsmoker patients but not in healthy subjects, [F(1,49) ⫽ 13.26, p ⫽ .001]. Patients after nicotine were superior to healthy subjects on nicotine [F(1,49) ⫽ 4.65, p ⬍ .05]. b There was a significant main effect of drug on closed-loop gain [F(1,48) ⫽ 4.1, p ⬍ .05].
as before the mask for about 130 –170 msec, presumably still influenced by the closed-loop response. After this initial period, there is a 35%–50% reduction in eye velocity, marking the transition from closed-loop to predictive pursuit. Eye velocity during the mask after this transition point was measured to obtain residual predictive gain.
with velocity or target amplitude and drug as within-subjects measures and group (healthy subjects vs. schizophrenic patients) and smoker status (smoker vs. nonsmoker) as two-between subjects factors.
Results SMOOTH PURSUIT MAINTENANCE: OVERALL PER-
Closed loop pursuit gain provides an index of the extent to which eye velocity matches target velocity. This measurement is carried out while the target is visible, thus the eye responses are based on the predictive component as well as retinal information. Closed-loop pursuit gain was calculated by dividing the mean eye-velocity by target velocity.
FORMANCE: CLOSED LOOP PURSUIT GAIN.
Continuous Performance Task The CPT-IP was used. Briefly, this task presents a sequence of four-digit numbers on the computer monitor. Subjects are required to lift their finger from the computer mouse when two identical numbers appear consecutively. Subjects were trained briefly with both flash cards and with on-screen numbers to ensure that they understood the task immediately before testing. Subjects received 1 mg of nicotine nasal spray 5 min before testing. The signal detection analysis (d⬘) was calculated as described by Cornblatt et al (1994).
Smooth Pursuit Eye Movement Measures INITIATION PHASE. There was a significant effect of nicotine on eye acceleration during initiation in schizophrenic patients but not in healthy subjects. This was confirmed by a significant drug ⫻ diagnosis interaction [F(1,47) ⫽ 6.15, p ⫽ .017]. Post hoc analyses collapsing across velocity revealed that nicotine increased initiation acceleration in both smoker and nonsmoker patients but not in healthy subjects [F(1,49) ⫽ 13.26, p ⫽ .001] (see Table 1, Figure 1). After nicotine administration, patients’ performance was significantly superior on this measure compared to healthy subjects on nicotine [F(1,49) ⫽ 4.65, p ⬍ .05]. On average, eye acceleration improved by 19 ⫾ 29 deg/sec/sec in patients versus 0 ⫾ 22 deg/sec/sec in healthy subjects. There was no effect of nicotine on pursuit latency. Current severity of smoking habit did not predict initiation response to nicotine. SMOOTH PURSUIT MAINTENANCE: OVERALL PUR-
Data Analysis For each subject, the data were collapsed across trials to obtain mean values, which were averaged to get the group means. Previous analyses showed no significant effects of ramp direction, number of cycles before the occurrence of the mask and their interactions with group membership. Thus, the data were collapsed across these factors. There were no significant order effects, thus the data were collapsed across order. Repeated measures analyses of variance were used to test each measure
There was a significant main effect of drug on closed-loop gain [F(1,48) ⫽ 4.1, p ⬍ .05]; nicotine improved the average gain from .69 ⫾ .16 to .72 ⫾ .18 in patients and .85 ⫾ .15 to .86 ⫾ .14 in healthy subjects (see Figure 2). There were no significant interactions involving drug, group or smoking status. SUIT.
PREDICTIVE PURSUIT MEASURES. There was a significant velocity ⫻ drug ⫻ smoker status interaction on
Nicotine Effects on Eye Tracking in Schizophrenia
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smoker status ⫻ drug interaction [F(1,49) ⫽ 8.67, p ⬍ .01]. There was significant improvement with nicotine in the nonsmokers (p ⬍ .02), but no significant effect in smokers (see Table 2). There were no significant main effects of drug or interactions involving drug on the other predictive pursuit measures (peak predictive pursuit velocity or change in direction latency).
Visually Guided Saccadic Measures There was no effect of drug, or drug ⫻ group interaction on saccadic latency, saccadic peak velocity, and saccadic gain.
Continuous Performance Test Nicotine had no effect on CPT-IP performance in any group (see Table 3). Figure 1. Effects of nicotine on initiation eye acceleration. Nicotine significantly increased initiation acceleration in both smoker and nonsmoker patients but not in healthy subjects as suggested by drug ⫻ diagnosis interaction [F(1,49) ⫽ 13.26, p ⫽ .001] and post hoc comparisons showing significant improvement in patients (p ⬍ .05). Patients after nicotine were superior to healthy subjects on nicotine [F(1,49) ⫽ 4.65, p ⬍ .05]. Ss, subjects.
residual velocity [F(1,46) ⫽ 6.24, p ⬍ .02]. Probing this interaction at velocity 18.7°revealed a main effect of drug [F(1,49) ⫽ 7.59, p ⬍ .01] with improvement in residual pursuit and a between-subjects effect of smoker status [F(1,49) ⫽ 5.16, p ⬍ .05], smokers having higher residual velocity than nonsmokers. At velocity 9.4° there was a
Figure 2. Effects of nicotine on pursuit maintenance. There was a significant main effect of drug on closed-loop gain in all subjects [F(1,48) ⫽ 4.1, p ⬍ .05]. Ss, subjects.
Smoking Habit and Smooth Pursuit Response to Nicotine Patient smokers smoked on average for 16.9 ⫾ 10.0 years, compared with 19.0 ⫾ 10.4 years in the control smokers (p ⬎ .5). About an equal proportion of healthy subjects and patients were heavy (i.e., ⬎20 cigarettes/day, 23% and 25%, respectively), moderate (i.e., 10 –20 cigarettes/day, 46% and 42%), and light smokers (i.e., ⬍10 cigarettes/ day, 31% and 33%). Despite the similar smoking habits, patients scored significantly higher on the FTND (5.21 ⫾ 2.61) compared to the comparison group [2.77 ⫾ 2.52; F(1,25) ⫽ 6.11, p ⬍ .05]. In healthy subjects, how long the subjects had been smoking predicted the change in eye acceleration with nicotine (r ⫽ .58, n ⫽ 13, p ⬍ .05). The strength of this association did not change after controlling for age and baseline eye acceleration values (patrial r ⫽ .57). In contrast, there was a negative correlation between eye acceleration during initiation in the nicotine condition and years of smoking in patients after controlling for age and baseline eye acceleration values (partial r ⫽ ⫺.54; n ⫽ 14, p ⫽ .069). There were no other significant associations between years of smoking and pursuit measures in response to nicotine. Years of smoking was associated with poor performance in CPT in healthy subjects (r ⫽ ⫺.54, p ⬍ .05), and to a negligible extent in patients (r ⫽ ⫺.11); the findings remained the same if age was covaried. The FTND score significantly predicted the closed-loop gain at baseline in healthy subjects (r ⫽ .58, p ⬍ .05), and the response to nicotine (r ⫽ ⫺.64, p ⬍ .02). There were no significant associations in the patient group; if anything the associations tended to be in the opposite direction (high dependence was associated with poor gain, r ⫽ ⫺.42, p ⫽ .14, and no significant association with response to nicotine, r ⫽ .14).
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Table 2. Predictive Measures Target velocity 18.7°/sec
Residual pursuit–velocity degrees/sec Healthy smoker Schizophrenic smoker Healthy nonsmoker Schizophrenic nonsmoker Peak predictive pursuit–velocity degrees/sec Healthy smoker Schizophrenic smoker Healthy nonsmoker Schizophrenic nonsmoker Change of direction latency (msec) Healthy smoker Schizophrenic smoker Healthy nonsmoker Schizophrenic nonsmoker
Target velocity 9.4°/sec
Control
Nicotine
Control
Nicotine
8.16 (1.98) 7.77 (1.16) 7.39 (1.29) 7.35 (1.58)
8.99 (1.60) 8.86 (2.21) 8.34 (.85) 7.58 (1.29)
5.00 (1.29) 4.93 (1.50) 4.36 (.91) 4.38 (.87)
4.55 (1.22) 5.05 (1.83) 4.82 (1.26) 6.15 (2.66)
10.62 (3.37) 9.35 (3.21) 10.86 (4.44) 9.60 (3.57)
11.01 (3.09) 9.95 (3.30) 10.67 (2.91) 8.81 (2.60)
7.50 (2.96) 6.62 (1.77) 7.20 (2.50) 8.32 (4.12)
7.30 (2.80) 6.76 (2.54) 6.80 (3.62) 6.69 (4.55)
72 (34) 79 (29) 81 (28) 98 (45)
71 (27) 85 (31) 70 (19) 101 (34)
90 (37) 111 (29) 89 (35) 111 (29)
81 (32) 95 (32) 93 (19) 105 (29)
Values in the table are mean (⫾SD). There was a significant velocity ⫻ drug ⫻ smoker status interaction on residual velocity [F(1,46) ⫽ 6.24, p ⬍ .02]. At velocity 18.7° there was a main effect of drug [F(1,49) ⫽ 7.59, p ⬍ .01], and a between-subject effect of smoker status [F(1,49) ⫽ 5.16, p ⬍ .05]. At velocity 9.4° there was a smoking ⫻ drug interaction [F(1,49) ⫽ 8.67, p ⬍ .01]; nicotine significantly improved residual velocity in nonsmokers only (p ⬍ .02). No significant main effects or interactions involving drug on peak predictive pursuit or change in direction latency.
The effects of nicotine on various smooth pursuit and attentional measures reported above remained unchanged after controlling for the years of smoking or FTND score.
Discussion Previous studies have shown an effect of nicotine on smooth pursuit eye movements; however it was unclear what aspect of the smooth pursuit function was affected by the drug. Smooth pursuit is a complex function involving several cognitive and ocular motor processes. These include visual attention, the ability to process motion information, hold motion information “online,” integrate such sensory information to program a motor output, and to generate smooth pursuit eye movements while inhibiting saccades. The results from the current study demonstrate that there is a specific effect of nicotine in schizophrenia, improving eye acceleration during initiation in both smoker and nonsmoker patients but not in smoker or nonsmoker healthy subjects. The lack of effect in healthy subjects cannot be attributed to a ceiling effect, because there was room to improve, and in fact the mean eye Table 3. Continuous Performance Test D⬘ (D prime) Healthy smoker Schizophrenic smoker Healthy nonsmoker Schizophrenic nonsmoker
Control
Nicotine
2.31 (.63) .69 (.77) 2.07 (.69) .85 (.62)
2.26 (.91) .44 (.58) 2.09 (.66) .67 (.80)
Values in the table are mean (⫾ SD). No main effect or interactions involving drug.
acceleration in patients was slightly better than in healthy subjects during the nicotine treatment. This improvement with nicotine during initiation is likely due to better processing of the retinal motion information, and/or the integration of sensory information into a motor command. The improvement in initiation is unlikely due to an alerting effect of the drug, because there was no significant change in the pursuit latency as well as in the saccadic measures from the saccadic task, which are highly sensitive measures of vigilance. Visual attention is critical for the processing of motion information (Tootell et al 1995); however, the beneficial effect on initiation was not thought to be due to an improvement in attention, because nicotine did not improve visual attention as measured by the signal detection analysis (d⬘) of the CPT-IP testing. It may be argued that the initiation benefit was secondary to improved anticipatory or predictive pursuit initiation (Barnes et al 2000). This seems less likely for three reasons: 1) the role of anticipatory or predictive initiation was minimized by making the timing, direction, and the speed of target motion onset unpredictable; 2) a uniform predictive benefit was not observed, as there was no benefit in peak predictive pursuit, only in residual pursuit; and 3) the residual pursuit improvement may be secondary to the overall improvement in smooth pursuit. That is, the effects of nicotine on pursuit velocity were apparent before the mask, resulting in a higher residual pursuit velocity for the same degree of fall-off. This cannot be completely resolved using this paradigm, as the measures may be interdependent. As a result of the improved retinal motion processing, there was an overall
Nicotine Effects on Eye Tracking in Schizophrenia
improvement in smooth pursuit function in patients as indexed by the higher closed-loop gain on nicotine compared to the control condition. This is the first study to demonstrate the effects of nicotine nasal spray on smooth pursuit eye movements. Nicotine nasal spray administers the drug in a pulse that delivers the full dose (1 mg) of the drug within seconds. In contrast, smoking a cigarette or chewing nicotine gum delivers the drug over minutes. The quick delivery of nicotine by spray resulted in more robust effects of nicotine on eye movements than those observed in our previous study with cigarette smoking using a similar dose (⬃1 mg) (Thaker et al 1991). Findings in the current study are consistent with the report by Olincy and colleagues (Olincy et al 1998). Their study examined the effects of 10 min of ad libitum smoking after a 10-hour period of abstinence. It is interesting to note that despite similar smoking habits and the duration of smoking, patients scored higher on nicotine dependence rating than the healthy subjects. The effects of the duration of smoking habit and the FTND dependence scores on smooth pursuit eye movements were opposite in patients and healthy subjects. High dependence scores predicted better closed-loop gain in healthy subjects, and poor performance in patients. Duration of the smoking habit predicted improvement in initiation eye acceleration with nicotine in healthy subjects and worsening in patients. Similar differential effects of smoking have been reported for [3H]nicotine binding in postmortem brain tissue (see below). It is unclear whether the observed effects were mediated by nicotinic ␣42 or ␣-7 receptor subtypes. Based on the low dose of nicotine used in the study and relatively high affinity of ␣42 for nicotine, one may argue that the effects were mediated by the ␣42 subtype. On the other hand, findings of differential effects of nicotine in patients and healthy subjects, and a recent report of reduced numbers of ␣-7 receptors in postmortem brain tissue of schizophrenic patients suggest a role of the ␣-7 receptor subtype (Freedman et al 1995; Leonard et al 2000). In postmortem tissue, there is an increase in [3H]nicotine binding in smokers compared to nonsmokers in hippocampus, cortex, thalamus, and caudate (Breese et al 2000). In schizophrenic patient brain tissues, there was no such increase in [3H]nicotine binding associated with smoker status, other than a slight increase in cortex. Among smokers, [3H]nicotine binding was found to be significantly less in patients than in healthy subjects. Fenster and colleagues have suggested that the upregulation of high affinity nicotinergic receptors is related to desensitization after chronic exposure (Fenster et al 1999). Differences in the rate of resensitization or related mechanisms downstream to nicotinic receptors among schizophrenic and
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healthy smokers can explain the postmortem findings as well as the responses of eye movement measures to nicotinergic challenge (Breese et al 2000; Leonard et al 2000). It is interesting to note that a previous study in our laboratory found that ketamine specifically reduced the initiation eye acceleration in healthy subjects (Weiler et al 2000). Because nicotine specifically increased initiation acceleration, future studies will examine whether nicotine is able to reverse this effect of ketamine in healthy subjects. This work was supported by National Institute of Health grant MH49826 and 40279 and a research contract with Novartis Pharma AG.
References Assad JA, Maunsell JH (1995): Neuronal correlates of inferred motion in primate posterior parietal cortex. Nature 373:518 – 521. Barnes GR, Asselman PT (1991): The mechanism of prediction in human smooth pursuit eye movements. J Physiol 439:439 – 461. Barnes GR, Barnes DM, Chakraborti SR (2000): Ocular pursuit responses to repeated, single-cycle sinusoids reveal behavior compatible with predictive pursuit. J Neurophysiol 84:2340 – 2355. Barton JJ, Simpson T, Kiriakopoulos E, Stewart C, Crawley A, Guthrie B, et al (1996): Functional MRI of lateral occipitotemporal cortex during pursuit and motion perception. Ann Neurol 40:387–398. Breese CR, Lee MJ, Adams CE, Sullivan B, Logel J, Gillen KM, et al (2000): Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia. Neuropsychopharmacology 23:351–364. Cornblatt BA, Keilp JG (1994): Impaired attention, genetics, and the pathophysiology of schizophrenia [published erratum appears in Schizophr Bull 1994;20:248]. Schizophr Bull 20:31– 46. Fafrowicz M, Unrug A, Marek T, van Luijtelaar G, Noworol C, Coenen A (1995): Effects of diazepam and buspirone on reaction time of saccadic eye movements. Neuropsychobiology 32:156 –160. Fagerstrom KO, Schneider NG (1989): Measuring nicotine dependence: A review of the Fagerstrom Tolerance Questionnaire. J Behav Med 12:159 –182. Fenster CP, Hicks JH, Beckman ML, Covernton PJ, Quick MW, Lester RA (1999): Desensitization of nicotinic receptors in the central nervous system. Ann N Y Acad Sci 868:620 – 623. Freedman R, Adams CE, Leonard S (2000): The alpha7-nicotinic acetylcholine receptor and the pathology of hippocampal interneurons in schizophrenia. J Chem Neuroanat 20:299 – 306. Freedman R, Hall M, Adler LE, Leonard S (1995): Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biol Psychiatry 38:22–33.
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Hollingshead A, Redlich S (1988): Social Class and Mental Illness: A Community Study. New York: John Willey & Sons. Holzman PS, Solomon CM, Levin S, Waternaux CS (1984): Pursuit eye movement dysfunctions in schizophrenia. Family evidence for specificity. Arch Gen Psychiatry 41:136 –139. Klein C, Andresen B (1991): On the influence of smoking upon smooth pursuit eye movements of schizophrenics and normal controls. J Psychophysiol 5:361–369. Komatsu H, Wurtz RH (1989): Modulation of pursuit eye movements by stimulation of cortical areas MT and MST. J Neurophysiol 62:31– 47. Leonard S, Breese C, Adams C, Benhammou K, Gault J, Stevens K, et al (2000): Smoking and schizophrenia: Abnormal nicotinic receptor expression. Eur J Pharmacol 393:237–242. Lisberger SG, Morris EJ, Tychsen L (1987): Visual motion processing and sensory-motor integration for smooth pursuit eye movements. Annu Rev Neurosci 10:97–129. Lisberger SG, Movshon JA (1999): Visual motion analysis for pursuit eye movements in area MT of macaque monkeys. J Neurosci 19:2224 –2246. MacAvoy MG, Gottlieb JP, Bruce CJ (1991): Smooth-pursuit eye movement representation in the primate frontal eye field. Cereb Cortex 1:95–102. Newsome WT, Wurtz RH, Dursteler MR, Mikami A (1985): Deficits in visual motion processing following ibotenic acid lesions of the middle temporal visual area of the macaque monkey. J Neurosci 5:825– 840. Newsome WT, Wurtz RH, Komatsu H (1988): Relation of cortical areas MT and MST to pursuit eye movements. II. Differentiation of retinal from extraretinal inputs. J Neurophysiol 60:604 – 620. Olincy A, Ross RG, Young DA, Roath M, Freedman R (1998): Improvement in smooth pursuit eye movements after cigarette smoking in schizophrenic patients. Neuropsychopharmacology 18:175–185. Pomerleau CS, Carton SM, Lutzke ML, Flessland KA, Pomer-
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leau OF (1994): Reliability of the Fagerstrom Tolerance Questionnaire and the Fagerstrom Test for Nicotine Dependence. Addict Behav 19:33–39. Ross RG, Harris J, Olincy A, Radant A, Adler L, Freedman R (1997): Smooth pursuit eye movements in parents of schizophrenic probands: A most likely carrier approach. Schizophr Res 24:244 –245. Thaker GK, Cassady S, Adami H, Moran M, Ross DE (1996): Eye movements in spectrum personality disorders: Comparison of community subjects and relatives of schizophrenic patients. Am J Psychiatry 153:362–368. Thaker GK, Ellsberry R, Moran M, Lahti A, Tamminga CA (1991): Tobacco smoking increases square-wave jerks during pursuit eye movements. Biol Psychiatry 29:82– 88. Thaker GK, Ross DE, Buchanan RW, Adami HM, Medoff DR (1999): Smooth pursuit eye movements to extraretinal motion signals: Deficits in patients with schizophrenia. Psychiatry Res 88:209 –219. Thaker GK, Ross DE, Cassady SL, Adami HM, LaPorte D, Medoff DR, et al (1998): Smooth pursuit eye movements to extraretinal motion signals: Deficits in relatives of patients with schizophrenia. Arch Gen Psychiatry 55:830 – 836. Thaker GK, Ross DE, Cassady SL, Adami HM, Medoff DR, Sherr JD (2000) Saccadic eye movement abnormalities in relatives of patients with schizophrenia. Schizophrenia Res 45:235–244. Tootell RB, Reppas JB, Kwong KK, Malach R, Born RT, Brady TJ, et al (1995): Functional analysis of human MT and related visual cortical areas using magnetic resonance imaging. J Neurosci 15:3215–3230. van den Berg AV (1988): Human smooth pursuit during transient perturbations of predictable and unpredictable target movement. Exp Brain Res 72:95–108. Weiler MA, Thaker GK, Lahti AC, Tamminga CA (2000): Ketamine effects on eye movements. Neuropsychopharmacology 23:645– 653.
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patients. These findings suggest an abnormality in neuronal nicotinic system functioning in schizophrenic patients. Biol Psychiatry 2002;52:721–728 © 2002 Society of Biological Psychiatry Key Words: Smooth pursuit eye movements, schizophrenia, nicotine, smoking, predictive pursuit
Introduction
I
n recent years there has been a growing interest in nicotinic neurotransmitter systems in schizophrenia. This interest is stimulated by a body work that has shown decreased ␣-bungarotoxin binding or decreased ␣-7-nicotinic receptor immunoreactivity in postmortem brain tissue, and linkage analysis implicating chromosome 15q14, the site of the ␣-7 nicotinic receptor gene (see Freedman et al 2000 for review). In addition, drug probe studies have shown that acute nicotine administration reverses sensory gating and eye tracking deficits associated with the genetic liability for schizophrenia. The purpose of the current study was to examine the effects of acute administration of nicotine on specific measures of smooth pursuit eye movements and visual attention. Abnormality of smooth pursuit eye movements is one of the most replicated neurophysiological deficits observed in patients with schizophrenia as well as in a proportion of their first-degree relatives (Holzman et al 1984; Thaker et al 1996, 1998). Humans track a small moving object of interest with their eyes using slow movements called smooth pursuit eye movements. Normally, the pursuit system needs motion information to generate a smooth pursuit response. During initiation of smooth pursuit, the slippage of the image of the target on the retina, referred to hereafter as retinal motion, stimulates smooth pursuit (Lisberger et al 1987; Newsome et al 1985, 1988). The processing of retinal motion occurs in the mediotemporal region (Lisberger and Movshon 1999; Newsome et al 1985, 1988). Once eye velocity approximates target velocity, retinal motion is minimal. Continued smooth pursuit (i.e., maintenance pursuit) is based on a complex set of 0006-3223/02/$22.00 PII S0006-3223(02)01342-2
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processes involving predictive smooth pursuit eye movements, and occasional increases in smooth eye velocity or saccades to catch up with the target. Predictive smooth pursuit is driven by potent extraretinal motion inputs, with minor corrections based on retinal velocity and position error information (Barnes and Asselman 1991; Lisberger et al 1987; van den Berg 1988). Investigators have used target masking procedures (brief extinctions of the target along its trajectory) to obtain measures of predictive pursuit independent of retinal information. Medial superior temporal and posterior parietal regions are thought to hold eye velocity and previous retinal velocity information “on-line,” respectively, in the absence of current retinal motion (Assad and Maunsell 1995; Barton et al 1996; Komatsu and Wurtz 1989). The frontal eye fields (FEFs) integrate this extraretinal motion information into a smooth pursuit response (MacAvoy et al 1991). Abnormalities in processing motion information and initiating smooth pursuit (i.e., the initiation phase), as well as abnormalities in predictive pursuit are observed in schizophrenia. Preliminary data in our laboratory suggest that the abnormality in the initiation of smooth pursuit may be marking the liability for the deficit syndrome, whereas predictive pursuit abnormality marks the liability for psychosis in schizophrenia (Hong et al unpublished data; Ross et al 1997; Thaker et al 1998, 1999). In addition to smooth pursuit eye movements, investigators have extensively studied saccadic eye movements in schizophrenia. Visually guided saccades are generally found to be normal in schizophrenia (Thaker et al 2000). Saccadic latency and peak velocity are highly sensitive measures of vigilance (Fafrowicz et al 1995). Because the effects of nicotine on smooth pursuit measures can potentially be mediated by the effects on attention or vigilance, a saccadic task and a visual attentional task were administered in the present study. Visual attention was measured using the identical pairs four-digit numbers version of the continuous performance task (CPT-IP). This is a sensitive measure of attention and discriminates patients with schizophrenia and their relatives from healthy comparison groups (Cornblatt and Keilp 1994). The smooth pursuit abnormalities observed in schizophrenia spectrum disorders provide an important target for drug probes in schizophrenia. These abnormalities represent fundamental neurophysiological deficits associated with the phenotype and are thus likely to be nearer to the genetic effects than the overt symptoms along the pathway from genotype to clinical symptoms. Currently available drug treatments for schizophrenia have minimal therapeutic effect on the more enduring and devastating deficits associated with schizophrenia. Unlike overt psychotic symptoms, which remit frequently during the course of the illness, many of the neurophysiological deficits persist
during fluctuations in psychosis and remain untreated with traditional drugs. Thus, neurophysiological measures, which mark these more enduring and treatment-refractory symptoms, provide a useful target for drug probes. Effective treatments against such neurophysiological deficits also have implications for a much broader group of nonschizophrenic subjects who fall within the phenotype (i.e., individuals with schizophrenia spectrum disorders). Furthermore, such treatments have implications for early treatment and preventive strategies in schizophrenia. Existing antipsychotic drug treatments for schizophrenia have generally been unsuccessful in reversing smooth pursuit abnormalities. Ketamine was shown to disrupt the initiation phase of smooth pursuit in healthy subjects in our laboratory (Weiler et al 2000). The effects of nicotine on smooth pursuit eye movements have been examined by three previous studies in schizophrenic patients (Klein et al 1991; Olincy et al 1998; Thaker et al 1991). The first study examining the effects of nicotine on eye movements in schizophrenia noted an increase in disinhibition of the saccadic system during smooth pursuit marked by an increase in a specific type of saccadic intrusions, called square wave jerks (Thaker et al 1991). Although specific measures of smooth pursuit were not obtained, there was no effect of nicotine on a global measure of eye tracking performance. Olincy et al (1998) showed an improvement in a measure of anticipatory (leading) saccades during smooth pursuit, and a trend toward improvement in a global pursuit measure (Olincy et al 1998); however, it was not clear whether these findings were secondary to a general and nonspecific alerting effect in patients and a ceiling effect in healthy subjects (i.e., the lack of effect in healthy subjects occurred because their tracking was already nearly perfect). Also, it is unclear from previous studies what specific components of the smooth pursuit response are affected by nicotine. Finally, most of the previous studies examined the effects of nicotine in smokers only. The goal of the current study is to test the effects of nicotine on different specific components of the smooth pursuit eye movement system in smoker and nonsmoker schizophrenic patients and healthy subjects.
Methods and Materials Subjects were recruited from the outpatient clinics and an inpatient unit at the Maryland Psychiatric Research Center. Healthy control subjects were recruited by newspaper advertisement. Subjects were excluded if they had a history of substance abuse within the past 6 months or a lifetime diagnosis of substance dependence (DSM-III-R). Individuals with chronic obstructive lung disease and/or pulmonary emphysema or preexisting clinically significant cardiovascular disease, moderate to severe mental retardation, or recent myocardial infarction were excluded. All subjects received clinical evaluations, which in-
Nicotine Effects on Eye Tracking in Schizophrenia
cluded the Structured Clinical Interview for DSM-IV. All subjects gave informed consent in accordance with University of Maryland Institutional Review Board guidelines. Before participating, subjects were interviewed by a noninvestigator clinician (using a standardized form) to assess their ability to understand the procedures and provide valid consent. All subjects received $15/hour for their participation in the study. Subjects abstained from nicotine for 2 hours before the study and participated in two randomly ordered testing sessions: a control state in which no drug was given and after nicotine administration. Nicotine was administered via Nicotrol-Nasal Spray (McNeil, Fort Washington, PA) by the investigator, one puff in each nostril 5 min before eye tracking, for a total dose of 1.0 mg (All participants tested in this experiment also completed a battery of other cognitive tasks described in separate reports and received three separate 1-mg doses of nicotine). One cognitive task, the continuous performance test (CPT) is included in this report. The order of tests was counterbalanced within the nicotine and control conditions to control for number and recency of nicotine administrations.
Subject Description Twenty-nine subjects (18 males and 11 females) with schizophrenia, 15 smokers and 14 nonsmokers, completed testing. Twenty-six healthy comparison subjects (10 males and 16 females), 15 smokers and 11 nonsmokers, completed testing. Schizophrenic and healthy subjects were matched on mean (⫾ SD) age, 40.5 (⫾ 8.5) years and 37.9 (⫾ 12.1) years, respectively. Subjects with schizophrenia differed from healthy comparison subjects on Hollingshead Socioeconomic Scale scores, 4.3 (⫾ 1.0) versus 2.7 (⫾ .8), respectively (Hollingshead and Redlich 1988). All subjects with schizophrenia were taking antipsychotic medications, three (10%) were taking traditional neuroleptics, nine (31%) were taking clozapine, one (3%) was taking risperidone, fourteen (48%) were taking olanzapine, and two (6%) were taking olanzapine and haloperidol. Three subjects each were taking lithium, valproic acid, or a serotonin reuptake inhibitor. The Fagerstrom Test for Nicotine Dependence (FTND) was administered in 27 smokers (14 patients). The FTND collects information about smoking habits and correlates with other proposed measures of nicotine dependence (carbon monoxide, nicotine, and cotinine levels), although it is a weak predictor of withdrawal symptoms during abstinence (Fagerstrom et al 1989; Pomerleau et al 1994). The FTND gives a score from 0 (no dependence) to 10 (high dependence).
Eye Tracking Tasks The testing was carried out in a dark room. Eye movement tasks were presented in a fixed order: 1) visually guided saccade task, and 2) smooth pursuit task. VISUALLY GUIDED SACCADE TASK. Each trial started with the target, a red cross inside a blue box, in the center of a computer monitor (approximately 28⬙ from the eyes). The target remained in the center for a random time of 1.1–2.8 sec, after which it would step to a location 5 or 10 degrees (target
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amplitude) to the left or right of center. The target would remain in this peripheral location for 1.7 sec, at which point the target would disappear and a new trial would begin. Subjects were instructed to look at the target at all times. A total of 16 trials were administered in one session. Latency of response, saccadic accuracy, and peak eye velocity during the saccade were measured. Additionally, the total number of square wave jerks (a dysmetric intrusion) were counted during the 16 trials (Thaker et al 1991). SMOOTH PURSUIT. A fovea-petal step-ramp with unpredictable onset was presented, followed by 3– 4 cycles of (12°) triangular waveform target motion. The excursion of the target at a constant velocity (9.4° or 18.7° per second) from one extreme to the other constituted a ramp. After 4 – 6 ramps the target unpredictably became invisible (mask) for 500 msec. Subjects were instructed to “. . . follow the target as it moves. Occasionally the target will become invisible for very brief periods. During these periods the target will keep moving, so continue moving your eyes to follow the invisible but moving target.” Twenty-five trials were obtained at each ramp velocity. Half of the time the mask was at the beginning of the ramp and half of the time the mask occurred variably sometime in the middle of the ramp. This approach allows examination of both initiation and predictive pursuit. Eye movement data were obtained using an infrared technique (sampling rate of 333 Hz with a time constant of 4 msec) filtered at 75 Hz low-pass filter and converted to digital signals using a 16-bit A-D converter. Smooth pursuit analyses of the eye movement data used interactive software to remove saccades, blinks, and slow compensatory pursuit after leading saccades. Subsequent analyses on the original smooth pursuit data measured leading saccades.
Eye Movement Measures Used in the Study INITIATION PHASE. Latency of the smooth pursuit response and the mean acceleration during the first 100 msec of smooth pursuit were measured (Ross et al 1997; Weiler et al 2000). SMOOTH PURSUIT MAINTENANCE: PREDICTIVE PUR-
Peak predictive pursuit was calculated from responses where the mask occurred at the beginning of a new ramp after the change in direction. In this condition, subjects stop moving in one direction and initiate predictive smooth pursuit in the opposite direction. The latency of the change in direction of eye velocity from the time of the expected change in direction of the target was obtained. Absolute latency values were used, because our interest was mainly in the timing of change, because all nonzero latency values indicate mistiming. Change in direction latency conceptually corresponds to the phase lag. We also measured peak predictive eye velocity within the mask, in the direction of expected ramp. SUIT MEASURES: PEAK PREDICTIVE PURSUIT.
RESIDUAL PREDICTIVE PURSUIT. When the mask occurs during the ramp, the eye continues to move at the same velocity
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Table 1. Smooth Pursuit Measures Target velocity 18.7°/sec
Target velocity 9.4°/sec
Control
Nicotine
Control
Nicotine
87.1 (34.1) 67.82 (19.22) 64.72 (14.57) 66.20 (36.09)
80.3 (14.1) 94.66 (35.39) 63.16 (20.20) 87.48 (24.55)
64.78 (22.13) 61.77 (14.88) 58.61 (21.78) 68.56 (29.34)
66.58 (21.21) 68.69 (24.77) 69.55 (25.38) 90.76 (40.42)
.82 (.16) .68 (.15) .85 (.11) .60 (.17)
.83 (.18) .77 (.12) .87 (.09) .62 (.22)
.87 (.18) .77 (.13) .85 (.11) .66 (.23)
.89 (.15) .82 (.13) .87 (.15) .62 (.24)
a
Initiation–mean acceleration Healthy smoker Schizophrenic smoker Healthy nonsmoker Schizophrenic nonsmoker Closed loop gainb Healthy smoker Schizophrenic smoker Healthy nonsmoker Schizophrenic nonsmoker
Values in the table are mean (⫾ SD). There was a significant effect of velocity on all measures, p ⱕ .01. a Significant drug ⫻ diagnosis interaction, [F(1,47) ⫽ 6.15, p ⫽ .017]. Nicotine increased initiation acceleration in both smoker and nonsmoker patients but not in healthy subjects, [F(1,49) ⫽ 13.26, p ⫽ .001]. Patients after nicotine were superior to healthy subjects on nicotine [F(1,49) ⫽ 4.65, p ⬍ .05]. b There was a significant main effect of drug on closed-loop gain [F(1,48) ⫽ 4.1, p ⬍ .05].
as before the mask for about 130 –170 msec, presumably still influenced by the closed-loop response. After this initial period, there is a 35%–50% reduction in eye velocity, marking the transition from closed-loop to predictive pursuit. Eye velocity during the mask after this transition point was measured to obtain residual predictive gain.
with velocity or target amplitude and drug as within-subjects measures and group (healthy subjects vs. schizophrenic patients) and smoker status (smoker vs. nonsmoker) as two-between subjects factors.
Results SMOOTH PURSUIT MAINTENANCE: OVERALL PER-
Closed loop pursuit gain provides an index of the extent to which eye velocity matches target velocity. This measurement is carried out while the target is visible, thus the eye responses are based on the predictive component as well as retinal information. Closed-loop pursuit gain was calculated by dividing the mean eye-velocity by target velocity.
FORMANCE: CLOSED LOOP PURSUIT GAIN.
Continuous Performance Task The CPT-IP was used. Briefly, this task presents a sequence of four-digit numbers on the computer monitor. Subjects are required to lift their finger from the computer mouse when two identical numbers appear consecutively. Subjects were trained briefly with both flash cards and with on-screen numbers to ensure that they understood the task immediately before testing. Subjects received 1 mg of nicotine nasal spray 5 min before testing. The signal detection analysis (d⬘) was calculated as described by Cornblatt et al (1994).
Smooth Pursuit Eye Movement Measures INITIATION PHASE. There was a significant effect of nicotine on eye acceleration during initiation in schizophrenic patients but not in healthy subjects. This was confirmed by a significant drug ⫻ diagnosis interaction [F(1,47) ⫽ 6.15, p ⫽ .017]. Post hoc analyses collapsing across velocity revealed that nicotine increased initiation acceleration in both smoker and nonsmoker patients but not in healthy subjects [F(1,49) ⫽ 13.26, p ⫽ .001] (see Table 1, Figure 1). After nicotine administration, patients’ performance was significantly superior on this measure compared to healthy subjects on nicotine [F(1,49) ⫽ 4.65, p ⬍ .05]. On average, eye acceleration improved by 19 ⫾ 29 deg/sec/sec in patients versus 0 ⫾ 22 deg/sec/sec in healthy subjects. There was no effect of nicotine on pursuit latency. Current severity of smoking habit did not predict initiation response to nicotine. SMOOTH PURSUIT MAINTENANCE: OVERALL PUR-
Data Analysis For each subject, the data were collapsed across trials to obtain mean values, which were averaged to get the group means. Previous analyses showed no significant effects of ramp direction, number of cycles before the occurrence of the mask and their interactions with group membership. Thus, the data were collapsed across these factors. There were no significant order effects, thus the data were collapsed across order. Repeated measures analyses of variance were used to test each measure
There was a significant main effect of drug on closed-loop gain [F(1,48) ⫽ 4.1, p ⬍ .05]; nicotine improved the average gain from .69 ⫾ .16 to .72 ⫾ .18 in patients and .85 ⫾ .15 to .86 ⫾ .14 in healthy subjects (see Figure 2). There were no significant interactions involving drug, group or smoking status. SUIT.
PREDICTIVE PURSUIT MEASURES. There was a significant velocity ⫻ drug ⫻ smoker status interaction on
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smoker status ⫻ drug interaction [F(1,49) ⫽ 8.67, p ⬍ .01]. There was significant improvement with nicotine in the nonsmokers (p ⬍ .02), but no significant effect in smokers (see Table 2). There were no significant main effects of drug or interactions involving drug on the other predictive pursuit measures (peak predictive pursuit velocity or change in direction latency).
Visually Guided Saccadic Measures There was no effect of drug, or drug ⫻ group interaction on saccadic latency, saccadic peak velocity, and saccadic gain.
Continuous Performance Test Nicotine had no effect on CPT-IP performance in any group (see Table 3). Figure 1. Effects of nicotine on initiation eye acceleration. Nicotine significantly increased initiation acceleration in both smoker and nonsmoker patients but not in healthy subjects as suggested by drug ⫻ diagnosis interaction [F(1,49) ⫽ 13.26, p ⫽ .001] and post hoc comparisons showing significant improvement in patients (p ⬍ .05). Patients after nicotine were superior to healthy subjects on nicotine [F(1,49) ⫽ 4.65, p ⬍ .05]. Ss, subjects.
residual velocity [F(1,46) ⫽ 6.24, p ⬍ .02]. Probing this interaction at velocity 18.7°revealed a main effect of drug [F(1,49) ⫽ 7.59, p ⬍ .01] with improvement in residual pursuit and a between-subjects effect of smoker status [F(1,49) ⫽ 5.16, p ⬍ .05], smokers having higher residual velocity than nonsmokers. At velocity 9.4° there was a
Figure 2. Effects of nicotine on pursuit maintenance. There was a significant main effect of drug on closed-loop gain in all subjects [F(1,48) ⫽ 4.1, p ⬍ .05]. Ss, subjects.
Smoking Habit and Smooth Pursuit Response to Nicotine Patient smokers smoked on average for 16.9 ⫾ 10.0 years, compared with 19.0 ⫾ 10.4 years in the control smokers (p ⬎ .5). About an equal proportion of healthy subjects and patients were heavy (i.e., ⬎20 cigarettes/day, 23% and 25%, respectively), moderate (i.e., 10 –20 cigarettes/day, 46% and 42%), and light smokers (i.e., ⬍10 cigarettes/ day, 31% and 33%). Despite the similar smoking habits, patients scored significantly higher on the FTND (5.21 ⫾ 2.61) compared to the comparison group [2.77 ⫾ 2.52; F(1,25) ⫽ 6.11, p ⬍ .05]. In healthy subjects, how long the subjects had been smoking predicted the change in eye acceleration with nicotine (r ⫽ .58, n ⫽ 13, p ⬍ .05). The strength of this association did not change after controlling for age and baseline eye acceleration values (patrial r ⫽ .57). In contrast, there was a negative correlation between eye acceleration during initiation in the nicotine condition and years of smoking in patients after controlling for age and baseline eye acceleration values (partial r ⫽ ⫺.54; n ⫽ 14, p ⫽ .069). There were no other significant associations between years of smoking and pursuit measures in response to nicotine. Years of smoking was associated with poor performance in CPT in healthy subjects (r ⫽ ⫺.54, p ⬍ .05), and to a negligible extent in patients (r ⫽ ⫺.11); the findings remained the same if age was covaried. The FTND score significantly predicted the closed-loop gain at baseline in healthy subjects (r ⫽ .58, p ⬍ .05), and the response to nicotine (r ⫽ ⫺.64, p ⬍ .02). There were no significant associations in the patient group; if anything the associations tended to be in the opposite direction (high dependence was associated with poor gain, r ⫽ ⫺.42, p ⫽ .14, and no significant association with response to nicotine, r ⫽ .14).
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Table 2. Predictive Measures Target velocity 18.7°/sec
Residual pursuit–velocity degrees/sec Healthy smoker Schizophrenic smoker Healthy nonsmoker Schizophrenic nonsmoker Peak predictive pursuit–velocity degrees/sec Healthy smoker Schizophrenic smoker Healthy nonsmoker Schizophrenic nonsmoker Change of direction latency (msec) Healthy smoker Schizophrenic smoker Healthy nonsmoker Schizophrenic nonsmoker
Target velocity 9.4°/sec
Control
Nicotine
Control
Nicotine
8.16 (1.98) 7.77 (1.16) 7.39 (1.29) 7.35 (1.58)
8.99 (1.60) 8.86 (2.21) 8.34 (.85) 7.58 (1.29)
5.00 (1.29) 4.93 (1.50) 4.36 (.91) 4.38 (.87)
4.55 (1.22) 5.05 (1.83) 4.82 (1.26) 6.15 (2.66)
10.62 (3.37) 9.35 (3.21) 10.86 (4.44) 9.60 (3.57)
11.01 (3.09) 9.95 (3.30) 10.67 (2.91) 8.81 (2.60)
7.50 (2.96) 6.62 (1.77) 7.20 (2.50) 8.32 (4.12)
7.30 (2.80) 6.76 (2.54) 6.80 (3.62) 6.69 (4.55)
72 (34) 79 (29) 81 (28) 98 (45)
71 (27) 85 (31) 70 (19) 101 (34)
90 (37) 111 (29) 89 (35) 111 (29)
81 (32) 95 (32) 93 (19) 105 (29)
Values in the table are mean (⫾SD). There was a significant velocity ⫻ drug ⫻ smoker status interaction on residual velocity [F(1,46) ⫽ 6.24, p ⬍ .02]. At velocity 18.7° there was a main effect of drug [F(1,49) ⫽ 7.59, p ⬍ .01], and a between-subject effect of smoker status [F(1,49) ⫽ 5.16, p ⬍ .05]. At velocity 9.4° there was a smoking ⫻ drug interaction [F(1,49) ⫽ 8.67, p ⬍ .01]; nicotine significantly improved residual velocity in nonsmokers only (p ⬍ .02). No significant main effects or interactions involving drug on peak predictive pursuit or change in direction latency.
The effects of nicotine on various smooth pursuit and attentional measures reported above remained unchanged after controlling for the years of smoking or FTND score.
Discussion Previous studies have shown an effect of nicotine on smooth pursuit eye movements; however it was unclear what aspect of the smooth pursuit function was affected by the drug. Smooth pursuit is a complex function involving several cognitive and ocular motor processes. These include visual attention, the ability to process motion information, hold motion information “online,” integrate such sensory information to program a motor output, and to generate smooth pursuit eye movements while inhibiting saccades. The results from the current study demonstrate that there is a specific effect of nicotine in schizophrenia, improving eye acceleration during initiation in both smoker and nonsmoker patients but not in smoker or nonsmoker healthy subjects. The lack of effect in healthy subjects cannot be attributed to a ceiling effect, because there was room to improve, and in fact the mean eye Table 3. Continuous Performance Test D⬘ (D prime) Healthy smoker Schizophrenic smoker Healthy nonsmoker Schizophrenic nonsmoker
Control
Nicotine
2.31 (.63) .69 (.77) 2.07 (.69) .85 (.62)
2.26 (.91) .44 (.58) 2.09 (.66) .67 (.80)
Values in the table are mean (⫾ SD). No main effect or interactions involving drug.
acceleration in patients was slightly better than in healthy subjects during the nicotine treatment. This improvement with nicotine during initiation is likely due to better processing of the retinal motion information, and/or the integration of sensory information into a motor command. The improvement in initiation is unlikely due to an alerting effect of the drug, because there was no significant change in the pursuit latency as well as in the saccadic measures from the saccadic task, which are highly sensitive measures of vigilance. Visual attention is critical for the processing of motion information (Tootell et al 1995); however, the beneficial effect on initiation was not thought to be due to an improvement in attention, because nicotine did not improve visual attention as measured by the signal detection analysis (d⬘) of the CPT-IP testing. It may be argued that the initiation benefit was secondary to improved anticipatory or predictive pursuit initiation (Barnes et al 2000). This seems less likely for three reasons: 1) the role of anticipatory or predictive initiation was minimized by making the timing, direction, and the speed of target motion onset unpredictable; 2) a uniform predictive benefit was not observed, as there was no benefit in peak predictive pursuit, only in residual pursuit; and 3) the residual pursuit improvement may be secondary to the overall improvement in smooth pursuit. That is, the effects of nicotine on pursuit velocity were apparent before the mask, resulting in a higher residual pursuit velocity for the same degree of fall-off. This cannot be completely resolved using this paradigm, as the measures may be interdependent. As a result of the improved retinal motion processing, there was an overall
Nicotine Effects on Eye Tracking in Schizophrenia
improvement in smooth pursuit function in patients as indexed by the higher closed-loop gain on nicotine compared to the control condition. This is the first study to demonstrate the effects of nicotine nasal spray on smooth pursuit eye movements. Nicotine nasal spray administers the drug in a pulse that delivers the full dose (1 mg) of the drug within seconds. In contrast, smoking a cigarette or chewing nicotine gum delivers the drug over minutes. The quick delivery of nicotine by spray resulted in more robust effects of nicotine on eye movements than those observed in our previous study with cigarette smoking using a similar dose (⬃1 mg) (Thaker et al 1991). Findings in the current study are consistent with the report by Olincy and colleagues (Olincy et al 1998). Their study examined the effects of 10 min of ad libitum smoking after a 10-hour period of abstinence. It is interesting to note that despite similar smoking habits and the duration of smoking, patients scored higher on nicotine dependence rating than the healthy subjects. The effects of the duration of smoking habit and the FTND dependence scores on smooth pursuit eye movements were opposite in patients and healthy subjects. High dependence scores predicted better closed-loop gain in healthy subjects, and poor performance in patients. Duration of the smoking habit predicted improvement in initiation eye acceleration with nicotine in healthy subjects and worsening in patients. Similar differential effects of smoking have been reported for [3H]nicotine binding in postmortem brain tissue (see below). It is unclear whether the observed effects were mediated by nicotinic ␣42 or ␣-7 receptor subtypes. Based on the low dose of nicotine used in the study and relatively high affinity of ␣42 for nicotine, one may argue that the effects were mediated by the ␣42 subtype. On the other hand, findings of differential effects of nicotine in patients and healthy subjects, and a recent report of reduced numbers of ␣-7 receptors in postmortem brain tissue of schizophrenic patients suggest a role of the ␣-7 receptor subtype (Freedman et al 1995; Leonard et al 2000). In postmortem tissue, there is an increase in [3H]nicotine binding in smokers compared to nonsmokers in hippocampus, cortex, thalamus, and caudate (Breese et al 2000). In schizophrenic patient brain tissues, there was no such increase in [3H]nicotine binding associated with smoker status, other than a slight increase in cortex. Among smokers, [3H]nicotine binding was found to be significantly less in patients than in healthy subjects. Fenster and colleagues have suggested that the upregulation of high affinity nicotinergic receptors is related to desensitization after chronic exposure (Fenster et al 1999). Differences in the rate of resensitization or related mechanisms downstream to nicotinic receptors among schizophrenic and
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healthy smokers can explain the postmortem findings as well as the responses of eye movement measures to nicotinergic challenge (Breese et al 2000; Leonard et al 2000). It is interesting to note that a previous study in our laboratory found that ketamine specifically reduced the initiation eye acceleration in healthy subjects (Weiler et al 2000). Because nicotine specifically increased initiation acceleration, future studies will examine whether nicotine is able to reverse this effect of ketamine in healthy subjects. This work was supported by National Institute of Health grant MH49826 and 40279 and a research contract with Novartis Pharma AG.
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