On the Clinical and Cognitive Meaning of Impaired Sensorimotor Gating in Schizophrenia

Psychiatry Research 96Ž. 2000 187᎐197

On the clinical and cognitive meaning of impaired sensorimotor gating in schizophrenia

Michael E. Dawsona,U, Anne M. Schellb, Erin A. Hazlett c, Keith H. Nuechterleind, Diane L. Filione aDepartment of Psychology, SGM 501, Uniërsity of Southern California, Los Angeles, CA 90089-1061, USA bDepartment of Psychology, Occidental College, 1600 Campus Road, Los Angeles, CA 90041, USA cDepartment of Psychiatry, Box 1505, Mount Sinai School of Medicine, New York, NY 10029, USA dDepartment of Psychiatry and Biobehaïoral Sciences, Uniërsity of California, Los Angeles, CA 90024, USA eDepartment of Psychology, Uniërsity of Missouri, Kansas City, MO, USA

Received 7 February 2000; received in revised form 5 July 2000; accepted 31 July 2000

Abstract

Schizophrenia patients have been shown to have a defective sensorimotor gating process as indexed by impaired prepulse inhibition of the startle eyeblink reflex. Moreover, we have previously reported that schizophrenia patients have dysfunctional attentional modulation of prepulse inhibition. The present experiment combined our previous sample of 14 schizophrenia outpatients and 12 demographically matched control subjects with a new sample of 10 outpatients and 6 control subjects. All participants performed a tone-length judgement task that involved attending to one pitch of toneŽ. the attended prepulse and ignoring another pitch of tone Ž. the ignored prepulse . During this task the acoustic startle eyeblink reflex was electromyographically recorded from the orbicularis oculi muscle. The results replicated the finding of impaired attentional modulation of prepulse inhibition in the new sample of schizophrenia outpatients compared to demographically matched control subjects. Specifically, the new control group exhibited greater startle modification during the attended prepulse, whereas the new patient group failed to show this differential effect. In addition, impaired prepulse inhibition following the attended prepulse was significantly correlated with heightened delusions, conceptual disorganization, and suspiciousness as measured with the expanded Brief Psychiatric Rating Scale. These correlations were significant with prepulse inhibition to the attended prepulse but not with prepulse inhibition to the ignored prepulse. Impaired prepulse inhibition was not correlated with negative symptoms. All in all, the results support the hypothesis that impaired attentional modulation of startle prepulse inhibition reflects basic neurocognitive processes related to thought disorder in schizophrenia. ᮊ 2000 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Attention; Prepulse inhibition; Startle; Positive symptoms; Negative symptoms; Thought disorder

U Corresponding author. Tel.: q1-213-740-2294; fax: q1-213-740-2294. E-mail address: [email protected]Ž. M.E. Dawson .

1. Introduction blink reflex than the normal control subjects at short lead intervalsŽ. 30, 60, 120 ms . Braff et al. Impaired sensory gating is hypothesized to be a Ž.1992 suggested that these results reflected an frequent psychophysiological characteristic of impairment in automatic, preattentive sensorimo- schizophreniaŽ American Psychiatric Association, tor gating relevant to the vulnerability to 1994, p. 280. that could theoretically lead to a schizophrenia. variety of severe dysfunctions in perception, at- More recent research has shown that the atten- tention, and thinkingŽ McGhie and Chapman, tional modulation of PPI and PPF is impaired in 1961. . Specifically, deficits in the ability to selec- medicated schizophrenia patientsŽ Dawson et al., tively filter out irrelevant external and internal 1993. and unmedicated schizophrenia patients stimuli may produce misperceptions, a sense of Ž.Hazlett et al., 1998 . In these studies, schizophre- sensory flooding, increased distractibility, and dis- nia patients and normal control subjects were organized and fragmented thinkingŽ Braff et al., instructed to attend to one type of prepulseŽ e.g. 1992. . high pitch tone.Ž and not attend to another e.g. Prepulse inhibitionŽ. PPI is a psychophysiologi- low pitch tone.Ž . Both short lead intervals 60, 120, cal index of sensorimotor gating that has been and 240 ms in Dawson et al.; 120 and 240 in used with schizophrenia patients. PPI is defined Hazlett et al..Ž and long lead intervals 2000 ms in as the reduction of the amplitude of the startle Dawson et al.; 4500 ms in Hazlett et al.. were reflexŽ usually the eyeblink reflex in human sub- studied. In both studies, normal control subjects jects. when a non-startling ‘prepulse’ precedes showed greater PPI following the attended pre- the startling pulse by an interval of approximately pulse than the ignored prepulse only at the 120-ms 30᎐300 msŽ. see review by Blumenthal, 1999 . The lead interval, and greater PPF following the at- reduction in the startle reflex is thought to be due tended prepulse than the ignored prepulse at the to a momentary inhibitory sensorimotor gating long lead intervals. In contrast to the control process elicited by the prepulse that serves to subjects, the schizophrenia patients failed to show protect the earliest stages of processing of the differential PPI and PPF during the attended and prepulse. In contrast, if a non-startling prepulse ignored prepulses. These results are consistent precedes the startle-eliciting stimulus by a longer with five additional studies of normal participants lead intervalŽ. e.g. 2000 ms , the startle reflex is ŽFilion et al., 1993, 1994; Jennings et al., 1996; often enhancedŽ.Ž prepulse facilitation, PPF see Schell et al., 1995; Schell et al., in press1995. . The review by Putnam and Vanman, 1999. . PPF is finding that attentional modulation of PPI occurs thought to be due to a combination of arousal at the 120-ms lead interval, but not at 60 or 240 and sustained attention elicited by the prepulse. ms, suggests that the ‘attention to prepulse’ Thus, PPI and PPF represent different neurocog- paradigm taps time-locked attentional processes nitive processesŽ Graham, 1975; Filion et al., in normal subjects. The patients, on the other 1998. . Most relevant to the present article, the hand, showed significant overall PPI and PPF but degrees of both PPI and PPF have been shown to failed to respond differentially to the attended be modulated in normal subjects by attention to prepulse and the ignored prepulse at any lead the prepulseŽ for reviews, see Dawson et al., 1997; interval. Dawson et al.Ž. 1993 and Hazlett et al. Filion et al., 1998. . Ž.1998 therefore concluded that schizophrenia Both PPI and PPF have been found to be patients were impaired in controlled attentional impaired in schizophrenia patients. PPI abnor- processes rather than automatic processes in the malities were first demonstrated in schizophrenia ‘attention to prepulse’ paradigm. patients by Braff and his colleaguesŽ Braff et al., The first goal of the present study was to repli- 1978, 1992. . In a passive paradigm in which atten- cate in an independent sample of recent-onset tion to the prepulse was not manipulated, Braff et schizophrenia outpatients the startle modification al.Ž. 1992 found that schizophrenia patients findings in the ‘attention-to-prepulse’ paradigm. showed significantly less PPI of the startle eye- A second broader goal of the present study was to M.E. Dawson et al. rPsychiatry Research 96() 2000 187᎐197 189 determine whether impaired startle modification identified factor structure allowed us to investi- is, as theorized, associated with certain schizo- gate the specific domains of symptoms that might phrenic symptoms. To date, only a few studies be related to a breakdown in sensorimotor gating, have examined this relationship with PPI in a particularly positive symptoms vs. negative symp- passive paradigm, and no study has examined this toms. relationship with PPI of startle blink in the ‘atten- In summary, there were two specific goals of tion to prepulse’ paradigm. the present study. The first goal was to replicate Impaired PPI to a passively attended prepulse the finding of impaired attentional modulation of was recently reported to be significantly corre- PPI and PPF in a new sample of recent-onset lated with positive symptoms rated on the Positive schizophrenia outpatients, relative to demograph- and Negative Syndrome ScaleŽ.Ž PANSS Weike et ically matched normal control subjects. The sec- al., 2000. . No significant correlations were found ond goal was to determine the symptomatic corre- between the amount of PPI and negative symp- lates of impaired startle modification, and its at- toms. In contrast Braff et al.Ž. 1999 reported that tentional modulation, among schizophrenia impaired PPI in a passive paradigm was signifi- patients. It was hypothesized that the original cantly correlated with both positive and negative findings regarding impaired attentional modula- symptoms measured with the Scale for the As- tion of PPI at 120 ms and PPF at 2000 ms in sessment of Positive SymptomsŽ. SAPS and the schizophrenia patients would be replicated, and Scale for the Assessment of Negative Symptoms that the impairments in PPI and its attentional Ž.SANS . Employing a different approach, Perry modulation would be correlated with positive and BraffŽ. 1994 and Perry et al. Ž. 1999 used a symptoms related to thought disturbance. passive paradigm and found correlations between impaired PPI at a 120-ms lead interval in a passive paradigm with thought disorder measured in 2. Methods schizophrenic patients with the Rorschach Inkblot Test. All in all, the results suggest that impaired 2.1. Participants PPI may be related to positive symptomsŽ and possibly negative symptoms. in general, and Data are reported for a total of 24 schizophre- thought disorder in particular in schizophrenic nia patients and 18 demographically matched nor- patients. mal control subjects. Data from an additional 15 In the present study, key psychiatric symptom participantsŽ. 10 patients and 5 control subjects dimensions, particularly those related to thought were discarded because of either failure to blink disorder, were examined in schizophrenic out- on more than 1r3 of the presentations of the patients in relation to PPI and PPF obtained in loud noise Ž.ns3 , experimenter error Ž.ns1, the ‘attention-to-prepulse’ paradigm. Symptoms equipment malfunctions Ž.ns8 , drug abuse Žns were rated with an expanded 24-item version of 1.Ž. , excessive muscle artifact ns 1 or psy- the Brief Psychiatric Rating ScaleŽ. BPRS based chopathology in a control participant Ž.ns1. on information obtained in a brief semi-struc- Of the 24 patients, startle data are reported tured interviewŽ. Lukoff et al., 1986 . The factor separately for 14 ‘old’ participantsŽ i.e. those pre- structure of the expanded BPRS in recent-onset viously reported by Dawson et al., 1993. , and for schizophrenia outpatients, a population from 10 ‘new’ patients added to test the replicability of which the present sample was drawn, has been the earlier findings. Of the 18 control subjects, reported by Ventura et al.Ž. 1999 . There are four startle data are reported separately for 12 ‘old’ factors:Ž. 1 Positive Symptoms Ž e.g. unusual participants and for 6 ‘new’ control subjects. thought content, hallucinations, and conceptual Symptomatic correlates, however, are reported disorganization.Ž. ; 2 Negative Symptoms Ž e.g. for the combined ‘old’ and ‘new’ samples. blunted affect, motor retardation.Ž. ; 3 Depres- The schizophrenia participants were out- sionrAnxiety; andŽ. 4 AgitationrHostility. This patients at the UCLA Aftercare Program taking 190 M.E. Dawson et al. rPsychiatry Research 96() 2000 187᎐197 part in a longitudinal study of the early phases of The BPRS Total Psychopathology scores ranged schizophreniaŽ. Nuechterlein, et al., 1992 . The from 26 to 54, Ms36.2, S.D.s8.9, with a mini- patients were diagnosed as having schizophrenia mum possible rating of 24. Ž.n s 21 or schizoaffective disorder, mainly schizophrenic Ž.ns3 , by Research Diagnostic 2.3.2. Tone-length judgment task CriteriaŽ. Spitzer et al., 1978 . All but one of the Participants were instructed that their task was patients was on a low-to-moderate dose of in- to listen to a series of high and low pitch tones jectable fluphenazine decanoateŽ between 6.25 presented through headphones, to attend to and and 18.75 mg of Prolixin. at the time of the test count silently the number of ‘longer than usual’ sessionŽ see Nuechterlein et al., 1992, for treat- tones of one pitch, and to simply ignore the tones ment details. . of the other pitchŽ the attended pitch was coun- The normal control subjects were also partici- terbalanced across participants. . The standard pants in the longitudinal research project and length was 5 s and the longer than usual duration were recruited primarily through newspaper and was 7 s. Participants also were told that a brief periodical advertisements. They had been inter- loud noise burst would be presented occasionally viewed with an expanded lifetime version of the throughout the tone-counting task, but that it was Present State ExaminationŽ. PSE and family his- unrelated to the task and could be ignored. To tory questions to exclude those with a history of emphasize the importance of the length᎐judg- major psychiatric disorder in self or in their ment task, a monetary reward was offered for a first-degree relatives. The present enlarged sam- correct count of the longer than usual tones of ple of patientsŽ. 21 males and 3 females and the designated pitch. matched control subjectsŽ 14 males and 4 fe- All subjects were first presented samples of the males.Ž did not differ in age patients: Ms27.2, high and low pitch tones and of the loud noise. S.D.s6.3; control subjects: Ms25.7, S.D.s4.1. , The main portion of the test session then con- although the patients did have somewhat fewer sisted of a total of 48 tone trials: 24 high and 24 years of educationŽ patients: Ms12.2, S.D.s1.7; low pitch tones in a mixed, fixed semi-random control subjects: Ms13.6, S.D.s1.7.Ž. , t 40 s order with inter-tone intervals ranging between 2.39, P-0.05. 20 and 30 s. Of the 24 tones of each pitch, 16 were followed by the startle-eliciting noise. Of 2.2. Design these 16 trials, there were four presentations of the startle-eliciting noise at each of four lead-in- The study employed a 2=2=4 mixed factorial tervals: 60 ms, 120 ms, 240 ms, and 2000 ms. The design conducted separately on the ‘old’ sample remaining eight trials without startle-eliciting and ‘new’ sample. The first variable consisted of noises were presented in an intermixed order. two groupsŽ schizophrenia patients vs. normal In addition to presentation of the startle noises control subjects. , the second variable consisted of at critical lead-intervals, startle stimuli were also two types of prepulsesŽ. attended vs. ignored , and presented at pre-selected points during the inter- the third variable consisted of four lead-intervals tone intervals in order to provide a baseline mea- Ž.60, 120, 240, and 2000 ms . sure of startle amplitude with which to compare blink amplitudes elicited during the prepulses. 2.3. Procedure Specifically, startling noises were presented during 75% of the inter-tone intervals, with no more 2.3.1. Symptom measures than one startle stimulus presented during any Symptoms were rated on seven-point scales with inter-tone interval. the expanded 24-item version of the BPRSŽ Lukoff et al., 1986; Ventura et al., 1993. . The BPRS was 2.4. Recording and scoring of startle modification administered an average of 7.7 daysŽ range 1᎐23 days. from the day of the startle modification test. Startle eyeblink amplitude was measured as M.E. Dawson et al. rPsychiatry Research 96() 2000 187᎐197 191 electromyographic activityŽ. EMG from two between stimuli were controlled on-line by a miniature silver᎐silver chloride electrodesŽ 4 mm laboratory computer. in diameter. , filled with TECA electrode paste, placed over the orbicularis oculi muscle of the left eye. One electrode was centered below the 3. Results pupil and the other approximately 10 mm lateral to the first. The EMG signal was fed into a Grass 3.1. Attentional modulation of PPI and PPF 7P3 wide band preamplifierrintegrator and a 7DA driver amplifier. Eyeblinks were recorded at full In order to have a strong test of the indepen- wave rectification and with integration at a time dent replication of the earlier reported attentio- constant of 20 ms. The integrated EMG signal nal modulation effects on PPI and PPF, the ‘old’ was digitized at a rate of 1000 Hz for 200 ms and ‘new’ samples were analyzed independently. preceding and 300 ms following the presentation Thus, a twoŽ schizophrenic group vs. control of each startle-eliciting loud noise. The startle group.Ž=two attended prepulse vs. ignored pre- eyeblink amplitude was then scored off-line with pulse. ANOVA was computed on the percent a modification of the program by Balaban et al. change scores for each of the four lead intervals Ž.1986 . Startle eyeblink amplitude scores were Ž.60, 120, 240, and 2000 ms , separately for the converted to ␮V units, and differences were then ‘old’ and ‘new’ samples. Each lead interval was computed between the mean baseline inter-tone analyzed separately because different cognitive interval eyeblink amplitude and the during-tone processes are hypothesized to be involved at each eye-blink amplitudes separately for each trial interval, with attention effects predicted only at block. Because difference scores in absolute ␮V 120 and 2000 ms and not at 60- and 240-ms lead units were highly correlated with baseline startle intervals. Consistent with the predictions and with blink amplitude, as we have found in previous previous results, the ANOVAs conducted on the studiesŽ. Jennings et al., 1996 , the difference 60- and 240-ms lead intervals revealed neither scores were converted to percent of baseline star- significant Group effects, nor Attention main ef- tle amplitude, which removed the dependence fects, nor Group=Attention interaction effects. upon baseline in the present data. A positive Thus, there were no attentional modulation ef- startle percent change score indicates startle facil- fects at 60 ms and 240 ms for either the patients itation relative to baselineŽ. PPF , whereas a nega- or the control subjects in either the ‘old’ or ‘new’ tive score indicates startle inhibition relative to samples. baselineŽ. PPI . In contrast, as shown in Fig. 1, there was significant attentional modulation of PPI at the 120- 2.5. Experimental stimuli ms lead interval in both the ‘old’ and ‘new’ control samples. The 2=2 ANOVAs revealed sig- The attended and ignored prepulses consisted nificant Attention main effects in both the ‘old’ s - of 800-Hz and 1200-Hz tones, 5 s or 7 s in sample Ž.F1,24 14.34, P 0.001 and the ‘new’ s - duration, presented at an intensity of 70 dBŽ. A . sample Ž.F1,14 5.74, P 0.04 . Most important, The tones were generated using a FordhamŽ FG- significant Group=Attention interaction effects s - 801. signal generator, with 25-ms rise times con- were found in both samples ŽF1,24 6.10, P 0.03, r s - trolled by a Coulbourn S48-04 rise fall gate. The for the ‘old’ sample and F1,14 6.57, P 0.03 for startle stimulus consisted of a 100-dBŽ. A white the ‘new’ sample. . As can be seen in Fig. 1, the noise, 50 ms in duration. The startle noise was interaction effects reflect the finding that the generated by a Grason-Stadler 901B noise gener- control groups showed significantly greater PPI to ator and was gated at a near instantaneous rise the attended prepulse than to the ignored pre- s - time. All of the auditory stimuli were presented pulse Žt11 5.03, P 0.001, for the ‘old’ sample s - binaurally through headphonesŽ Realistic NOVA- and t5 3.35, P 0.03, for the ‘new’ sample. , 40 model. . The onsets, durations, and intervals whereas the patient groups failed to show signifi- 192 M.E. Dawson et al. rPsychiatry Research 96() 2000 187᎐197

ple. , but not in either patient sample. Again, the major difference between patients and control subjects was in their response following the attended prepulse and not in their response following the ignored prepulse.

3.2. Symptomatic correlates of attentional modulation

We predicted that impaired PPI at the 120-ms lead interval following the attended prepulse would be related to the Positive Symptom factor of the BPRS. PPI at 120 ms following the ignored Fig. 1. Mean prepulse inhibition at the 120-ms lead interval in prepulse was also examined for exploratory pur- the ‘old’ and ‘new’ samples of schizophrenia patients and poses. PPF at 2000 ms following the attended matched control subjects.Ž Asterisks indicate a significant dif- prepulse also was abnormal in these patients and ference between the attended and ignored prepulses.. therefore was examined. However, as this abnormality may reflect a sustained attention process separate from sensorimotor gating, we did not cant differential PPI. In fact, 17r18 control sub- hypothesize that PPF would be correlated with jects exhibited greater PPI following the attended thought disturbance. In addition, the relationship prepulse than the ignored prepulse, whereas only of these PPI and PPF measures to other BPRS 12r24 schizophrenia patients showed this direc- factors was examined to determine whether their tion of differential responding. As suggested by influence would extend to symptom severity of all inspection of Fig. 1, the major source of the types. difference between patients and control subjects Table 1 shows the intercorrelations between was in their PPI to the attended prepulse and not the PPI and PPF measures and the four BPRS to the ignored prepulse. Thus there was clear symptom factorsŽ the means for the four factors attentional modulation of PPI in both control were: Positive Symptoms 1.5; Negative Symptoms samples, with enhanced PPI to the attended prepulse relative to the ignored prepulse, whereas such modulation was absent in both patient samples. Similarly at the 2000-ms lead interval, as shown in Fig. 2, there is evidence of significant attentional modulation of PPF in both control groups, but not in either patient group. The 2 =2 ANOVAs revealed significant Attention main ef- s - fects in the ‘old’ sample Ž.F1,24 11.18, P 0.003 , s - and in the ‘new’ sample Ž.F1,14 4.83, P 0.05 . However, a significant Group=Attention interaction effect was found only in the ‘old’ sample, s - F1,24 6.80, P 0.02. Although the interaction effect was not significant in the ‘new’ sample, it can be seen in Fig. 2 that attentional modulation of PPF was significant in both the ‘old’ and ‘new’ Fig. 2. Mean prepulse facilitation at the 2000-ms lead interval s - in the ‘old’ and ‘new’ samples of schizophrenia patients and control samples Žt11 2.99, P 0.02 for the ‘old’ matched control subjects.Ž Asterisks indicate a significant dif- s - sample and t5 2.83, P 0.04 for the ‘new’ sam- ference between the attended and ignored prepulses.. M.E. Dawson et al. rPsychiatry Research 96() 2000 187᎐197 193

Table 1 Correlations between BPRS factors and startle modiﬁcation at 120- and 2000-ms lead intervals for attended and ignored prepulses

Stimulus and lead Positive Negative Agitation- Depressionr interval symptoms symptoms hostility anxiety

U U PPI AttendedŽ. 120 ms 0.41 y0.16 0.37 0.41 PPI IgnoredŽ. 120 ms 0.14 y0.04 0.29 0.13 PPF AttendedŽ. 2000 ms 0.09 y0.13 y0.04 y0.13 PPF IgnoredŽ. 2000 ms y0.06 y0.05 0.04 y0.10

U P-0.05.

2.1; DepressionrAnxiety 1.6; and Agitationr correlations were performedŽ. McNemar, 1962 . Hostility 1.3. . Two of the correlations were statis- The correlation between PPI at 120 ms during the tically significant, and both involve PPI at 120 ms attended prepulse and positive symptoms was sig- to the attended prepulse. As predicted, impaired nificantly larger than that for PPI during the s PPI at 120 ms following the attended prepulse attended prepulse and negative symptoms Žt21 Ž.more positive scores was associated with height- 1.82, P-0.05. , for PPI during the ignored pre- s - ened scores on the Positive Symptom factor. It pulse and positive symptoms Ž.t21 2.66, P 0.01 , was also correlated with higher scores on the and for PPF at 2000 ms during the attended r s - Depression Anxiety factor. Because we had pre- prepulse and positive symptoms Žt21 2.44, P viously hypothesized that the difference between 0.02. . the PPI to attended and ignored prepulses at the To determine the specific items that accounted 120-ms lead interval specifically indexes con- for the significant associations of PPI with the trolled attentional processesŽ. Dawson et al., 1997 , BPRS factors, we next correlated each of the we next correlated this difference score with the items that loaded on the Positive Symptoms fac- two BPRS factors showing significant correlations tor and the DepressionrAnxiety factor with PPI with the attended prepulse. The BPRS correla- to the attended prepulse. With the Positive Symp- tions with the attend᎐ignore difference scores toms factor, two items were significantly corre- revealed the same relationships as did the simple lated Žrs0.52, P-0.01, for unusual thought con- attended PPI scores, although only at the 0.06 tent and rs0.44, P-0.05, for conceptual disor- probability level with the ‘Positive Symptoms’ fac- ganization.Ž , and one approached significance rs tor. Thus, patients who exhibited a more normal 0.38, P-0.06, for suspiciousness. . Thus the most difference scoreŽ PPI during the attended pre- delusional, disorganized, and suspicious patients pulse greater than PPI during the ignored pre- exhibited the least amount of PPI to the attended pulse. also exhibited lower scores on the Depres- prepulse. For the DepressionrAnxiety factor, sionrAnxiety and Positive Symptom factors. None none of the individual items were significantly of the correlations at the 2000-ms lead interval, correlated with PPI, although they all showed nor any of the correlations with PPI during the weak-to-moderate correlations Žr values ranged ignored prepulse, were significant. from 0.30 to 0.36. . We predicted that the strongest correlations with positive symptoms would be with PPI to the 3.3. Task performance data attended prepulse. The obtained correlations in Table 1 are consistent with this prediction. In The participants’ task was to count the longer order to determine if the correlation we predicted than usualŽ. 7 s rather than the usual 5 s occur- to be significant differed from the others not rences of one tone pitch and to simply ignore the predicted to be significant, three specific one- tones of the other pitch. There were 10 longer tailed t-tests for differences between overlapping than usual occurrences of the attended tone pitch. 194 M.E. Dawson et al. rPsychiatry Research 96() 2000 187᎐197

The majority of both groups performed well on but abnormal PPI and PPF to attended prepulses. the task, with 62% of all of the patientsŽ. 15 of 24 , These findings are important because they sug- and 89% of all of the control subjectsŽ. 16 of 18 gest that controlled attentional processes fail to scoring within qry 1 of the correct answer. modulate sensorimotor gating mechanisms fol- However, the patients’ overall average error score lowing the task-significant attended prepulse in was significantly greater than that of the control schizophrenia. Thus, we hypothesize that the nor- subjectsŽ patients, Ms2.08, S.D.s2.4; control mal enhanced protection of processing of the s s s - subjects M 0.67, S.D. 2.3. , t40 2.29, P 0.03. attended stimuli fails to occur in schizophrenia In order to determine whether the impaired star- patients, which could lead to sensory overload at tle modulation simply reflected gross inattention the most critical times. Moreover, sustained fo- to the prepulses, we next analyzed the PPI and cused attention to the attended prepulse at 2000 PPF discrimination between attended and ig- ms also appears to be impaired in schizophrenia nored prepulses for the subgroups of 15 patients patients. These impairments are found even in and 16 control subjects who had performed well the subgroup of patients who perform well on the on the taskŽ the ‘old’ and ‘new’ samples were tone duration judgment task, suggesting that the combined for these analyses in order to have failures to attentionally modulate startle are more sufficiently large subsamples of good performers. . sensitive indexes of the underlying processes than For the good performing control subjects, the is behavioral performance on the counting task. mean discrimination scores between attended and The present findings are also consistent with a ignored prepulses remained significant for PPI at recent report that schizophrenia patients exhibit s 120 ms and for PPF at 2000 ms, ts14 5.97 and impaired attentional modulation of inhibition of 3.26, P-0.01. For the good performers among the R2 component of the electrically elicited eye- patients, the discrimination scores remained blink reflex when attention is focused on the non-significant. Moreover, the difference between reflex-eliciting stimulusŽ. Meincke et al., 1999 . the PPI discrimination scores of the good per- The lack of differences between normal control formers among control subjects and patients was subjects and schizophrenia patients in PPI to the s - significant, t29 2.93, P 0.01, and the PPF dif- ignored prepulse suggests the possibility that the s ference score approached significance, t29 1.97, basic automatic sensorimotor gating mechanism P-0.06. Thus, even for the subgroup that per- is functioning normally in this group of patients. formed the tone-counting task well, schizophrenia This conclusion is consistent with the conclusions patients showed impaired attentional modulation of previous studies that employed the active ‘at- of PPI at 120 ms and PPF at 2000 ms. tention-to-prepulse’ paradigmŽ Dawson et al., 1993; Hazlett et al., 1998. , but is contrary to conclusions reached in studies that employed a 4. Discussion passive attention paradigmŽ. e.g. Braff et al., 1992 . Dawson et al.Ž. 1993 speculated that the differ- The two principal findings of the present study ences between our results and those of Braff and are:Ž. 1 impaired attentional modulation of PPI colleagues could be due to the nature of the and PPF in schizophrenia outpatients was repli- patient sample, the nature of the task, or stimulus cated in a new sample; andŽ. 2 impaired PPI to an parameter differences. For example, the patients attended prepulse was significantly correlated with studied by Braff et al.Ž. 1992 were older, had higher levels of unusual thought content, concep- longer durations of illness, were more sympto- tual disorganization, and suspiciousness. Each of matic, and were more heavily medicated that those these findings is discussed in turn below. studied here. Procedurally, Braff et al.Ž. 1992 did First, the findings of Dawson et al.Ž. 1993 and not require any attention to the prepulse, whereas Hazlett et al.Ž. 1998 were replicated, indicating the tone-length duration task employed here re- that this sample of schizophrenia patients dis- quired at least enough processing of the ignored played normal PPI and PPF to ignored prepulses, prepulse for it to be identified as the task-irrele- M.E. Dawson et al. rPsychiatry Research 96() 2000 187᎐197 195 vant stimulus. Potentially important stimulus specifically with impaired PPI to attended pre- parametric differences also exist between the pulses and not with ignored prepulses? It is hy- laboratories. Braff et al.Ž. 1992 used short Ž 20 ms . pothesized that PPI to attended prepulses reflects increases in a 70-dB background white noise as the ability to selectively protect the processing of the prepulses, whereas we used long duration important sensory information. According to this pure tones presented against an ambient back- view, PPI to the attended prepulses reflects the ground. All in all, Braff et al.Ž. 1992 presented ability to focus on what is important when it is difficult to detect prepulses to older chronic important. Individuals who are less able to pro- symptomatic patients without any instructions to tect information processing when it is most needed attend to the stimuli. We, on the other hand, would presumably show the greatest tendencies presented easy to detect prepulses to relatively toward disconnected speech and perhaps delusio- young and relatively asymptomatic schizophrenic nal thought. In relatively remitted patients who patients with instructions to attend to the stimuli. are required to attend to easily detected prepulse Any of these variables, or combination of vari- stimuli, the deficit in PPI to the attended pre- ables, could conceivably account for the differ- pulse may represent a core dysfunction which ences in results. correlates with residual symptoms of thought dis- The second principal finding of the present order. When patients are more symptomatic, the study was that PPI to the attended prepulse, but PPI abnormality may worsen to the point where it not to the ignored prepulse, was significantly cor- appears even with prepulses in a passive paradigm, related with BPRS measures of disturbances in particularly when the prepulses are brief and both content and form of thought. That is, PPI at difficult to detectŽ e.g. Braff et al., 1992; and in a 120 ms following the attended prepulse was most subsample of patients with more severe positive impaired in patients with higher levels of unusual symptoms studied by Weike et al., 2000. . thought contentŽ. delusions , conceptual disorga- The association of PPI with delusions and sus- nization, and suspiciousness as assessed by the piciousness is not as immediately interpretable as expanded BPRS. Conceptual disorganization is is the correlation with conceptual disorganization. rated high on the expanded BPRS when speech is Delusions are usually considered to be due to confused, disconnected, or disorganizedŽ Ventura faulty inferential thinking. However, an alterna- et al., 1993.Ž . Conceptual disorganization ‘associa- tive view is that delusions, especially paranoid tive disturbance’. was hypothesized by Bleuler delusions of the type exhibited by patients in the Ž.1911 r1950 . to be a fundamental and primary present study, are rationally developed beliefs to dysfunction in schizophrenia, an emphasis that explain abnormal perceptual experiencesŽ Maher, contemporary cognitive neuroscience has contin- 1974. . Maher hypothesized that patients with a ued to supportŽ. Spitzer, 1997 . Patients with poor disorder of sensory gating suffer from intense and sensorimotor gating, as indicated by impaired PPI, confusing perceptual experiences that demand an would be predicted to fail to inhibit irrelevant explanation. The fact that these perceptual expe- intrusions and therefore to display fragmented riences do not seem to be shared by others raises and disorganized speechŽ. Braff et al., 1992 . Peo- the possibility that either other people are lying ple with normal gating are able to inhibit irrele- Ž.which may lead to delusions of persecution or vant intrusions, whereas patients with severely that one is an extraordinary person selected to impaired gating may be less able to do so. Thus, have these experiencesŽ which may lead to delu- the correlation of PPI with conceptual disorgani- sions of grandiosity. . Moreover, because no exter- zation is consistent with the view that PPI reflects nal cause of these unusual perceptual experiences sensorimotor gating and protection of cognitive is obvious, the patient may search for invisible processes, although the fact that this correlation mechanisms found in popular scienceŽ e.g. cosmic is specific to PPI to the attended prepulse is not rays.Ž or religion demonic or divine power . . Thus, directly predictable from these conceptions. the correlation of PPI with delusions and suspi- Why in the present study do correlations occur ciousness is consistent with Maher’s hypothesis 196 M.E. Dawson et al. rPsychiatry Research 96() 2000 187᎐197 that delusions arise from normal cognitive mech- thank Sally Friedlob for help in recruiting the anisms used to explain unusual, intense percep- outpatients, Craig Childress and Rhonda Daily tual experiences resulting from impaired sensory for help in identifying appropriate matched con- gating. The correlation of PPI with the Depres- trol subjects, Bill Troyer for software develop- sionrAnxiety factor may similarly arise from ment, and Jon Wynn for assistance in data prepa- deficit PPI indexing an inability to gate intrusive ration and organization. internal stimuli such as ruminative thoughts of guilt, failure, or loss in depression, or anxiety-pro- References voking thoughts. It is important to note that the absence of American Psychiatric Association, 1994. Diagnostic and Statis- tical Manual of Mental Disorders, 4th ed. APA, Washing- significant PPI correlations with some other BPRS ton, DC. factors and items should be interpreted with cau- Balaban, M.T., Losito, B., Simons, R.F., Graham, F.K., 1986. tion, as the range of some BPRS-rated symptoms Off-line latency and amplitude scoring of the human reflex was restricted in this sample of clinically stable eyeblink with FORTRAN IV. Psychophysiology 23, 612. r outpatients. For instance, one cannot determine Bleuler, E., 1911 1950. Dementia praecox or the group of schizophreniasŽ. Translated by J. Zinkin . International whether disorientation is associated with im- Universities Press, New YorkŽ original work published in paired startle modification because only one of 1911. . the 24 patients had any degree of disorientation Blumenthal, T.D., 1999. Short lead interval startle modifica- symptoms at the time of testing. However, the tion. In: Dawson, M.E., Schell, A.M., Bohmelt,¨ A.H.Ž. Eds. , range of negative symptoms, which was not corre- Startle Modification: Implications for Neuroscience, Cogni- tive Science, and Clinical Science. Cambridge University lated with PPI, was actually greater than the Press, New York, pp. 51᎐71. range of positive symptoms, which were signifi- Braff, D.L., Grillon, C., Geyer, M.A., 1992. Gating and habitu- cantly correlated with PPI. Thus, the absence of ation of the startle reflex in schizophrenic patients. Archives significant correlations with negative symptoms in of General Psychiatry 49, 206᎐215. the present sample was not due to the restricted Braff, D., Stone, C., Callaway, E., Geyer, M., Glick, I., Bali, L., 1978. Prestimulus effects on human startle reflex in nor- range of scores, but rather apparently to these mals and schizophrenics. Psychophysiology 15, 339᎐343. symptoms not arising from the failure of gating Braff, D.L., Swerdlow, N.R., Geyer, M.A., 1999. Symptom processes. correlates of prepulse inhibition deficits in male An important next step is to relate impaired schizophrenic patients. American Journal of Psychiatry 156, ᎐ attentional modulation of PPI to signs and symp- 596 602. Dawson, M.E., Hazlett, E.A., Filion, D.L., Nuechterlein, K.H., toms of schizophrenia in patients who exhibit a Schell, A.M., 1993. Attention and schizophrenia: impaired wider range of symptom severity, and also to modulation of the startle reflex. Journal of Abnormal Psy- relate impaired PPI with a range of laboratory chology 102, 633᎐641. cognitive measures. This step would aid our un- Dawson, M.E., Schell, A.M., Bohmelt,¨ A.H., 1999. Startle derstanding of the clinical and cognitive signifi- modification: introduction and overview. In: Dawson, M.E., Schell, A.M., Bohmelt,¨ A.H.Ž. Eds. , Startle Modification: cance of impaired startle modification in Implications for Neuroscience, Cognitive Science, and Clin- schizophrenia. Such research is a critical next step ical Science. Cambridge University Press, pp. 6᎐18. if the measurement of startle modification is to Dawson, M.E., Schell, A.M., Swerdlow, N.R., Filion, D.L., realize its putative potential as an integrative- 1997. Cognitive, clinical, and neurophysiological implica- bridging paradigm across neuroscience, cognitive tions of startle modification. In: Lang, P.J., Simons, R.F., Ž. Ž.Balaban, M.T. Eds. , Attention and Orienting: Sensory science, and clinical science Dawson et al., 1999 . and Motivational Processes. Erlbaum, Hillsdale, NJ, pp. 257᎐275. Filion, D.L., Dawson, M.E., Schell, A.M., 1993. Modification Acknowledgements of the acoustic startle-reflex eyeblink: a tool for investigat- ing early and late attentional processes. Biological Psy- chology 35, 185᎐200. This research was supported by grants from the Filion, D.L., Dawson, M.E., Schell, A.M., 1994. Probing the National Institute of Mental HealthŽ MH46433, orienting response with startle modification and secondary MH37705, MH30911, and K02 MH01086. . We reaction time. Psychophysiology 31, 68᎐78. M.E. Dawson et al. rPsychiatry Research 96() 2000 187᎐197 197

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