Neural Anomalies During Sustained Attention in First-Degree Biological Relatives of Schizophrenia Patients

Neural Anomalies During Sustained Attention in First-Degree Biological Relatives of Schizophrenia Patients Scott R. Sponheim, Kathryn A. McGuire, and John J. Stanwyck Background: A deficit in sustained attention might serve as an endophenotype for schizophrenia and therefore be a useful tool in understanding the genetic underpinnings of the disorder. We sought to detail functional brain abnormalities associated with sustained attention (i.e., vigilance) in individuals with genetic liability for schizophrenia. Methods: We gathered electrophysiological data from 23 schizophrenia patients, 28 first-degree biological relatives of schizophrenia patients, and 23 nonpsychiatric control subjects while they performed a degraded-stimulus continuous performance task. Inclusion of sensory control trials allowed separation of target detection and vigilance effects on brain potentials. Results: Schizophrenia patients, but not relatives, showed a behavioral deficit in sustained attention. During target detection, relatives exhibited diminished late positive amplitudes (P3b, i.e., P300) over parietal brain regions and augmented early posterior (P1) and right frontal (anterior N1) potentials. Electrophysiological anomalies were still evident after the exclusion of three relatives with histories of psychosis. Conclusions: Genetic liability for schizophrenia is associated with augmented early and diminished late brain potentials during sustained attention. Electrophysiological anomalies suggestive of right frontal–posterior parietal dysfunction might represent neural expression of genetic liability for schizophrenia. Electrophysiological indices also seem to be more sensitive than behavioral measures in assessing genetic liability for schizophrenia. Key Words: Schizophrenia, sustained attention, vigilance, electrophysiology, genetic liability, evoked potential

E

vidence suggests that a deficit in visual sustained attention might serve as an alternative phenotype (i.e., endophenotype [Gottesman and Gould 2003]) for studying genetic vulnerability for schizophrenia. Remitted schizophrenia patients and biological relatives of individuals with schizophrenia exhibit impaired detection of behaviorally relevant “targets” during sustained attention, whereas individuals with other mental disorders generally fail to exhibit a similar trait-based dysfunction (Cornblatt and Keilp 1994; Liu et al 2002). Researchers have described poor target detection during sustained attention as a “vigilance deficit,” with vigilance defined as “a state of readiness to detect and respond to certain small changes occurring at random time intervals in the environment” (Mackworth 1957). Although simpler and more specific than the clinical phenotype of schizophrenia, poor performance on a vigilance task is less likely to directly map onto effects of gene expression than a biological index of brain function. Therefore, it might be advantageous to delineate specific neural processes that contribute to vigilance deficits, to detail how genes predisposing for schizophrenia affect brain function. To determine neural phenomena associated with vigilance deficits in schizophrenia and genetic liability for the disorder, we studied electrophysiological characteristics of schizophrenia patients and first-degree biological relatives of schizophrenia patients during a continuous performance task.

From the Veterans Affairs Medical Center (SRS, KAM, JJS); and the Departments of Psychiatry and Psychology (SRS), University of Minnesota, Minneapolis, Minnesota. Address reprint requests to Scott R. Sponheim, Ph.D., Veterans Affairs Medical Center (116B), One Veterans Drive, Minneapolis, MN 55417; E-mail: [email protected]. Received June 13, 2005; revised September 9, 2005; accepted November 18, 2005.

0006-3223/06/$32.00 doi:10.1016/j.biopsych.2005.11.017

Among the variety of continuous performance tasks used to study schizophrenia, a desirable test for revealing the neural underpinnings of impaired vigilance is one that specifically assesses attention and visual perception (Chen and Faraone 2000). The degraded-stimulus continuous performance task (DS-CPT) places sizable demands on the visual perception system (Nuechterlein et al 1983). The task reveals poor vigilance in schizophrenia if stimuli are brief (⬍70 msec), substantially degraded, and occur at high event rates (Maier et al 1992). Given these characteristics, CPTs with degraded stimuli have reliably revealed schizophrenia patients to exhibit vigilance deficits that are not the result of medications (Liu et al 2000; Nuechterlein 1991). Seven studies in which the DS-CPT was used have demonstrated vigilance deficits in adult first-degree relatives of schizophrenia patients (Asarnow et al 2002; Chen et al 1998; Condray and Steinhauer 1992; Grove et al 1991; Laurent et al 2000; Maier et al 1992; Saoud et al 2000), and one study yielded low d= scores (i.e., poor target detection during vigilance) in children of mothers with schizophrenia (Nuechterlein 1983). Consequently, investigators have viewed vigilance deficits as potentially valuable in characterizing genetic vulnerability for schizophrenia (Chen and Faraone 2000; Nuechterlein 1991). The two published studies that failed to show diminished DS-CPT performance in schizophrenia patients or their relatives enrolled control subjects who were older than the relatives studied, thus failing to consider age effects on vigilance (Jones et al 2001), or strictly examined adolescents with schizophrenia, suggesting that variation in brain maturation during adolescence might make vigilance deficits more difficult to detect (Rund et al 1998). A stable impairment in vigilance might be specific to schizophrenia (Liu et al 2002). Schizophrenia patients in symptom remission produce low d= scores on the DS-CPT (Nuechterlein 1991; Nuechterlein et al 1994), whereas unipolar (Liu et al 2002; Suslow and Arolt 1997) and obsessive-compulsive (Milliery et al 2000) patients fail to exhibit stable deficits. Studies using DS-CPTs have shown bipolar patients to have improved vigilance with symptom reduction (Liu et al 2002; Sax et al 1998), and stable bipolar outpatients fail to show persistent vigilance deficits that are BIOL PSYCHIATRY 2006;60:242–252 © 2006 Society of Biological Psychiatry

BIOL PSYCHIATRY 2006;60:242–252 243

S.R. Sponheim et al

Table 1. Characteristics of Participants (Schizophrenia Patients, First-Degree Relatives of Schizophrenia Patients, and Nonpsychiatric Control Subjects) Variable Age (y) % Female Education (y) Estimated IQ BPRS Total Score SPQ Total Score

Patients (n ⫽ 23)

Relatives (n ⫽ 28)

Control Subjects (n ⫽ 23)

Statistic

p (ANOVA)

45.0 (9.6) 13a,b 14.2 (2.2) 99.6 (11.9)a,b 42.6 (10.8) NA

47.5 (8.7) 57 14.9 (2.5) 108.7 (10.3) NA 12.9 (6.8)

46.0 (9.1) 48 15.4 (1.8) 110.7 (10.6) NA 9.7 (6.4)

F(2,71) ⫽ .50 ␹2(2) ⫽ 10.92 F(2,71) ⫽ 1.72 F(2,71) ⫽ 6.87 NA t(46) ⫽ 1.6

ns .004c ns ⬍.002 ns ns

Data are presented as mean (SD). Estimated IQ was derived from the formula of Brooker and Cyr (1986) with Vocabulary and Block Design subtests. ANOVA, analysis of variance; IQ, intelligence quotient; BPRS, Brief Psychiatric Rating Scale (Lukoff et al 1986); NA, not applicable; SPQ, Schizotypal Personality Questionnaire (Raine 1991). a Different from control group mean (p ⬍ .05). b Different from relatives of schizophrenia group mean (p ⬍ .05). c Significance level for ␹2 test.

significantly worse than in normal control subjects (Liu et al 2002; Wilder-Willis et al 2001). Recent findings of euthymic bipolar subjects exhibiting sustained attention deficits on nondegraded CPTs that involve working memory (Clark et al 2005) highlight how degraded and perceptually challenging stimuli reveal vigilance deficits specific to schizophrenia. Evidence suggests that aberrant frontal and temporal lobe processes underlie vigilance dysfunction in schizophrenia. A set of positron emission tomography studies carried out more than a decade ago revealed hypometabolism in frontal and medial temporal cortices in individuals with schizophrenia performing the DS-CPT (Buchsbaum et al 1992; Siegel et al 1993). Both of these studies failed to include a condition controlling for aspects of the task unrelated to vigilance (e.g., visual processing), thereby leaving open the possibility that findings are not specific to target detection in the DS-CPT. Although no magnetic resonance imaging studies of brain function in schizophrenia during the DS-CPT appear in the literature, a more recent positron emission tomography study points to temporal and dorsolateral prefrontal metabolic anomalies during the task (Potkin et al 2002). Abnormal frontal activation during sustained attention is consistent with anterior anomalies in a lateral prefrontal–posterior parietal system subserving sustained attention (Pardo et al 1991; Posner and Petersen 1990). Only a single published report describes electrophysiological abnormalities associated with DS-CPT performance in schizophrenia (Knott et al 1999). In 14 chronic medicated schizophrenia outpatients, Knott et al found diminished positive potentials (P3b) over parietal brain regions at 400 msec after stimulus onset, perhaps suggesting poor updating of the posterior aspect of the frontal–parietal sustained attention system (Pardo et al 1991). To our knowledge, no published studies have implemented the DS-CPT to characterize neural anomalies during sustained attention in relatives of schizophrenia patients presumed to carry genes predisposing the disorder. To examine neural correlates of impaired vigilance and genetic liability for schizophrenia, we used the DS-CPT to study electrophysiological characteristics of first-degree biological relatives of schizophrenia patients and chronic schizophrenia outpatients. The work was specifically designed to address whether 1) relatives of schizophrenia patients exhibit diminished P3b (i.e., P300) amplitudes in response to target stimuli during the DS-CPT; 2) schizophrenia patients exhibit diminished P3b amplitudes during a single-stimulus DS-CPT; 3) schizophrenia patients and relatives exhibit early processing abnormalities evident

in early evoked potentials; and 4) electrophysiological anomalies in relatives are dependent on the presence of schizophrenia spectrum symptomatology. With inclusion of sensory control trials, we sought to determine separate effects of target identification and vigilance on early and late event-related brain activity during sustained attention.

Methods and Materials Participants Table 1 presents the characteristics of participants. We recruited stable outpatient schizophrenia participants from the clinics of the Minneapolis Veterans Affairs (VA) Medical Center, community support programs for the mentally ill, and a county mental health clinic. First-degree biological relatives were identified through interviews with schizophrenia participants and were invited by letter and telephone to participate. We identified potential nonpsychiatric control subjects through posting announcements at community libraries, fitness centers, the Minneapolis VA Medical Center, and in newsletters for veterans and fraternal organizations. Staff excluded potential control subjects for personal or family histories of psychotic symptoms or affective disorder as defined by the DSM-IV (American Psychiatric Association 1994). Patients and control subjects were excluded for histories of substance dependence but were not excluded for past alcohol dependence, as long as they had not abused alcohol in the past month. Because we sought to maximally describe electrophysiological characteristics of families from which the schizophrenia probands came, we did not exclude family members with histories of substance dependence. All participants completed an informed consent process, and the Minneapolis VA Medical Center and University of Minnesota Institutional Review Boards approved the study protocol and performed annual reviews of the study consent procedures. To obtain diagnostic information, a trained doctoral-level clinical psychologist completed the Diagnostic Interview for Genetic Studies (DIGS; Nurnberger et al 1994) with each patient. From the DIGS and supplemental questions, the interviewer made symptom ratings of patients, using the Scale for the Assessment of Negative Symptoms (Andreasen 1983), the Scale for the Assessment of Positive Symptoms (Andreasen 1984), and the 24-item version of the Brief Psychiatric Rating Scale (Lukoff et al 1986). Relatives and control subjects completed the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I; First et al 1996), the Structured Interview for Schizotypy (SIS; Kendler et al www.sobp.org/journal

244 BIOL PSYCHIATRY 2006;60:242–252

S.R. Sponheim et al

1989), and the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II; First et al 1997), where indicated by the SCID-II Personality Questionnaire (Ekselius et al 1994). Lifetime Axis I and II diagnoses for subjects were determined by doctoral-level psychologists and trained advanced graduate students through a consensus process consistent with published guidelines (Leckman et al 1982), which involved review of DIGS, SCID-I, SCID-II, SIS, medical history, and family informant material. Please see Supplement 1 for additional information on clinical procedures, prevalence of lifetime diagnoses, and medication status. Vigilance Assessment Participants with normal or corrected-to-normal visual acuity completed a vigilance assessment that consisted of sensory control trials, instructions, practice trials, and DS-CPT test trials (Continuous Performance Test Program for IBM-Compatible Microcomputers, Version 7.10 for the Degraded Stimulus CPT, K.H. Nuechterlein and R.F. Asarnow, 1996). Each trial was composed of a single-digit numeral (4.3° ⫻ 3.4° visual angle in size) presented for 29 msec followed by a 971-msec white display. The numbers and background were degraded, with 40% of the white numeral pixels switched to black and 40% of the black background pixels switched to white. The sensory control trials consisted of instructing the participant to “just look” at 80 stimuli, the experimenter pausing the task, and then instructing the subject to “press to every” stimulus for 80 trials. After completing control trials, subjects were instructed to press the button only when they thought they saw the numeral “0.” Twenty-five percent of the stimuli were targets (“0”), and 75% were nontargets (numerals “1” to “9”). After 160 practice trials, subjects were given a rest and then presented 480 continuous test trials in a fixed-pseudorandom order. We characterized subject performance by computing standard signal detection indices of d= (target detection/perceptual sensitivity) and ln(␤) (response threshold reflecting overall tendency to respond).

Electrophysiological Data Collection and Analyses Electroencephalograms (EEG) were recorded with a 16-bit analogue-to-digital amplifier and 27 tin electrodes embedded in an elastic cap (Electrode Cap International [ECI, Eaton, Ohio]). Electrodes were placed on the head to conform to 10-20 nomenclature and referenced to the left earlobe. Electrodes were filled with ECI gel, and sites were abraded to yield impedances below 5 K⍀. Electroencephalogram signals were digitized at a rate of 500 Hz with .05-Hz low-frequency and 100-Hz high-frequency filters and a 60-Hz notch filter. After data collection, EEG recordings were divided into epochs extending from 100 msec before stimulus to 1000 msec after stimulus. Vertical electrooculograms recorded from above and below the right eye were used to remove ocular artifact (Semlitsch et al 1986). Data were baseline corrected to the 100 msec preceding the onset of the stimulus, digitally filtered with a high-frequency cutoff of 30 Hz (48 dB/octave roll-off) and a low-frequency cutoff of .1 Hz (48 dB/octave roll-off), and re-referenced to linked earlobes. Epochs with EEG or horizontal electrooculogram (HEOG) exceeding ⫾100 ␮V were automatically rejected. In addition, all epochs were visually inspected and excluded if artifacts of ⬍100 ␮V were identified. For each subject, only trials containing correct responses were averaged for sensory (just look, button press), target, and nontarget trials. The average number of trials composing target waveforms was 77 (minimum 27) for schizophrenia patients, 91 (minimum 35) for relatives of schizophrenia patients, and 91 (minimum 51) for nonpsychiatric control subjects. Sensory control waveforms were composed at a minimum of 25 trials but averaged above 50 trials for all groups. For those components for which individuals exhibited a clear peak, we measured peak amplitude (P1, N1 [150 –180 msec], P2, P3b); however, for components that were either broad or less peaked, we used mean amplitude measures (anterior N1, N2, P3a). Statistical Analyses of Electrophysiological Variables To examine group differences in electrophysiological components associated with target detection during vigilance, we

Table 2. Degraded-Stimulus Continuous Performance Task Performance for Schizophrenia Patients, First-Degree Relatives of Schizophrenia Patients, and Nonpsychiatric Control Groups Task Target Detection (d=) Block 1 Block 2 Block 3 Total Response Threshold [ln(␤)] Block 1 Block 2 Block 3 Total Reaction Time for Targets (msec) Total

Patients (n ⫽ 23)

Relatives (n ⫽ 28)

Control Subjects (n ⫽ 23)

Test Value

2.54 (.79)b,c 2.07 (.78)b,c 1.97 (.86)b,c 2.14 (.72)b,c

2.99 (.74) 2.63 (.77) 2.57 (.81) 2.69 (.76)

3.04 (.76) 2.91 (.95) 2.46 (.72) 2.74 (.75)

F(2,71) ⫽ 3.06 F(2,71) ⫽ 5.95 F(2,71) ⫽ 3.86 F(2,71) ⫽ 4.93

.50 (1.08) .90 (.70) 1.01 (.87) .87 (.75)

.33 (1.22) .57 (1.06) 1.02 (1.35) .73 (1.19)

.66 (.79) .83 (.96) .85 (.93) .72 (.80)

F(2,71) ⫽ .62 F(2,71) ⫽ .91 F(2,71) ⫽ .18 F(2,71) ⫽ .18

548 (99)b,c

483 (47)

464 (41)

pa

.05 .004 .03 .01 ns ns ns ns

F(2,71) ⫽ 10.14 ⬍.0005

Data are presented as mean (SD). There was no break between blocks, and participants experienced the trials as if they were in a single block of 480 trials. A two-way analysis of variance (ANOVA) of d= with group (patients, relatives, and control subjects) and trial block (block 1: first 160 trials; block 2: second 160 trials; block 3: third 160 trials) revealed main effects for group [F(2,71) ⫽ 4.98, p ⬍ .01] and block [Pillai’s Trace ⫽ .43, F(2,70) ⫽ 26.12, p ⬍ .0005] but no group ⫻ block interaction. A similar two-way ANOVA of ln(␤) yielded a main effect of block [Pillai’s Trace ⫽ .26, F(2,70) ⫽ 12.02, p ⬍ .0005] but no group or group ⫻ block interaction. a Significance level of one-way ANOVA for specified set of trials. b Schizophrenia patients ⬍ nonpsychiatric control subjects. c Schizophrenia patients ⬍ relatives of schizophrenia patients.

www.sobp.org/journal

S.R. Sponheim et al conducted multivariate analyses of variance (MANOVAs) with one between-subjects factor (group: schizophrenia, relatives, control subjects) and three within-subjects factors (target: target, nontarget; hemisphere: left, right; and region: e.g., occipital, parietal). We included scalp regions in analyses in which electrophysiological components were most evident. Because there were only three female schizophrenia patients, gender was not specified as a between-subjects factor. To also examine the effect of vigilance on electrophysiological differences between groups, we carried out MANOVAs of data from both sensory control and DS-CPT trials, specifying task (sensory control, DS-CPT) as an additional within-subjects factor. Significant effects involving task or group were further evaluated with analyses of variance and t tests.

Results Behavioral Performance Behavioral results are presented in Table 2. The block effect reported in Table 2 indicated that all groups exhibited a decline in perceptual sensitivity for targets (d=) during the DS-CPT. This is consistent with the task tapping vigilance. Schizophrenia participants exhibited worse overall target detection (d=) than other groups but similar response thresholds as measured by ln(␤). Schizophrenia patients exhibited slower reaction times for correct target responses compared with first-degree relatives and nonpsychiatric control subjects. First-degree biological relatives failed to exhibit worse target detection than control subjects. Correlations with age indicated that older relatives tended to have lower response thresholds [ln(␤)] [r(28) ⫽ ⫺.44, p ⬍ .05] and produce more false alarms to nontargets that were perceptually similar to targets (“6”, “8”, and “9” but not other numerals from 1 to 9) [r(27) ⫽ .49, p ⫽ .01]. Control subjects with more years of education tended to have better target detection (d=) [r(23) ⫽ .43, p ⬍ .05]. There were no other significant correlations between performance measures and demographic characteristics. Patients failed to exhibit any associations between DS-CPT performance and measures of symptomatology. Electrophysiological Components Because our main goal was to detail effects of genetic liability on electrophysiological processes related to target detection during sustained attention, we primarily focused on group effects for target and nontarget waveforms from DS-CPT trials. Table 3 presents means, SDs, and results of statistical tests for electrophysiological components amplitudes evident during the DSCPT. Figure 1 depicts DS-CPT target waveforms for schizophrenia subjects, relatives, and control subjects. Figure 2 contrasts electrophysiological components from sensory control and DS-CPT trials for each group by depicting button press, just look, target, and nontarget waveforms at select scalp sites (P7, F8). Posterior Early Evoked Potentials Target Detection. We first examined group and target detection effects on sensory-based evoked potentials P1, N1, and P2. Compared with control subjects and relatives, schizophrenia subjects exhibited diminished posterior P2 potentials. Interactions of group with region, target, and hemisphere reflected the greatest P2 amplitude decrements in schizophrenia patients being over left occipital and parietal brain regions (see Table 3 for mean values and significant mean differences between groups). Specifically, in response to target stimuli, schizophre-

BIOL PSYCHIATRY 2006;60:242–252 245 nia patients had lower P2 amplitudes than control subjects at sites Pz [t (44) ⫽ ⫺2.63, p ⫽ .01], P3 [t (44) ⫽ ⫺2.32, p ⫽ .02], and O1 [t (44) ⫽ ⫺2.34, p ⫽ .02]. Analyses of P1 and N1 amplitudes for DS-CPT trials failed to yield any effect involving group. Target main effects were evident for N1 [F (1,70) ⫽ 7.01, p ⫽ .01] and P2 potentials, indicating that target stimuli generally elicited greater early negativity than nontargets. Vigilance. Contrasts of sensory control and DS-CPT trials yielded task effects indicating that P1 [F (1,67) ⫽ 13.32, p ⫽ .001] and N1 [F (1,67) ⫽ 54.52, p ⬍ .0005] amplitudes were augmented and P2 amplitudes [F (1,67) ⫽ 26.87, p ⬍ .0005] were diminished during DS-CPT trials compared with sensory control trials. P1 amplitude also exhibited an interaction of task with group and target. This task ⫻ group ⫻ target interaction resulted from relatives of schizophrenia patients having larger P1 amplitudes than control subjects at right parietal and occipital scalp sites. Specifically, in response to target stimuli, relatives exhibited P1 amplitudes that were larger than those of controls subjects at sites P4 [t (49) ⫽ 2.01, p ⫽ .04] and P8 [t (49) ⫽ 1.97, p ⫽ .05]. Schizophrenia patients and relatives failed to significantly augment P1 amplitudes for target as compared with nontarget DS-CPT stimuli (as noted by the absence of underlined mean target amplitude values in Table 3). Hence, all early posterior evoked potentials were augmented by the vigilance demands of the DS-CPT, and relatives showed greater augmentation of the P1 amplitude than the other two groups. Later posterior evoked potentials (i.e., posterior N1 and P2) showed modulation in response to DS-CPT target stimuli. Posterior Late Potentials Target Detection. We next tested late posterior event-related potentials for group and target effects. Analyses of P3b amplitude revealed a group main effect and a group ⫻ target interaction. Both schizophrenia patients and relatives of schizophrenia patients exhibited diminished P3b potentials to target stimuli compared with control subjects. Reduced P3b amplitude to target stimuli was evident at all parietal and occipital sites for patients and at right parietal– occipital (P8) and occipital (O1, O2) sites for relatives (see Table 3) and Figure 1 for means and effects). The MANOVA of N2 amplitude yielded a group effect. Group comparisons revealed that, in response to nontarget stimuli, schizophrenia patients generated smaller N2 amplitudes than control subjects at parietal– occipital and occipital sites [P7: t (44) ⫽ 1.99, p ⫽ .05; P8: t (44) ⫽ 2.63, p ⫽ .01; O1: t (44) ⫽ 2.15, p ⫽ .04; O2: t (44) ⫽ 2.46, p ⫽ .02]. Compared with control subjects, relatives exhibited augmented N2 amplitudes over the left parietal and occipital regions for target stimuli [P3: t (49) ⫽ ⫺2.02, p ⫽ .05; P7: t (49) ⫽ ⫺2.62, p ⫽ .01; O1: t (49) ⫽ ⫺2.06, p ⫽ .04]. Both N2 and P3b amplitudes showed strong target effects indicative of target stimuli eliciting larger potentials than nontargets. Vigilance. Consistent with the observation that N2 and P3b components were largely absent in sensory control trials, MANOVAs revealed significant task effects for both N2 [F (1,67) ⫽ 36.34, p ⬍ .0005] and P3b [F (1,67) ⫽ 92.53, p ⬍ .0005] amplitudes. A task ⫻ group effect was also evident for N2. The interaction reflected DS-CPT target trials eliciting augmented N2 amplitudes in control subjects and relatives but not in schizophrenia patients (see Figure 2). Patients with diminished target N2 amplitudes over parietal– occipital regions tended to have lower response thresholds [ln(␤)] (site P8: r ⫽ ⫺.41, p ⬍ .05; site O1: r ⫽ ⫺.48, p ⬍ .05; site O2: r ⫽ ⫺.48, p ⬍ .05) and less formal thought disorder (site P8: r ⫽ ⫺.47, p ⬍ .05). www.sobp.org/journal

Component Amplitudes (␮V) Group Schizophrenia Component

Window (msec)

Posterior Early Evoked Potentials P1 110–140

P2

190–260

Significant Group and Target Effectsa Task ⫻ Tg ⫻ Gp

3.61b (2,66)

Gp ⫻ Rg Gp ⫻ Tg ⫻ Rg Gp ⫻ Tg ⫻ Hm ⫻ Rg

2.91b (2.3,45.3)e 2.49b (1.8,125.1)e 2.52b (3.9,135.2)e

Tg Tg ⫻ Rg Posterior Late Potentials N2 320–360

P3b

360–700

Gp Task ⫻ Gp Tg Tg ⫻ Rg Tg ⫻ Hm Tg ⫻ Hm ⫻ Rg Gp Tg ⫻ Gp Tg Tg ⫻ Rg

Anterior Potentials Anterior N1

160–240

Gp ⫻ Hm Gp ⫻ Tg ⫻ Hm

260–320

Gp ⫻ Tg ⫻ Hm Tg

7.80g (1,70) 43.88h (1.79,125.1)

3.45b (2,70) 4.98b (2,67) 11.99g (1,70) 39.55h (2,69) 45.59h (1,70) 8.02g (2,69) 4.69b (2,70) 3.55b (2,70) 172.86 (1,70) 76.71 (1.8,131.6)

4.21b (2,68) 5.65g (2,68) 59.34h (1,68) 27.78h (2,136) 4.68h (1,68) 4.15b (2,57) 109.69h (1,57)

Site

Target Stimulus

Control Subjects

Nontarget Stimulus

Target Stimulus

Nontarget Stimulus

Target Stimulus

Nontarget Stimulus

O1 P7 P3 Pz P4 P8 O2 O1 P7 P3 Pz P4 P8 O2

5.3 (4.4) 3.5 (3.1) 3.7 (4.4) 3.4 (5.3) 4.5 (5.4) 4.8 (3.9) 4.6d (5.0) 7.9f (6.0) 2.8 (3.1) 2.6f (3.1) 2.5f (3.4) 2.5 (3.4) 2.4 (3.3) 8.7 (6.8)

5.5 (4.3) 3.9 (2.6) 3.9 (3.9) 3.6 (4.6) 4.6 (4.9) 4.7 (3.4) 4.7 (4.7) 8.4d,f (5.4) 3.0 (2.4) 2.4 (2.5) 2.0 (3.2) 2.4 (3.1) 2.8 (2.9) 9.2d (6.4)

7.3 (5.2) 5.5 (3.9) 5.7 (5.1) 5.2 (5.4) 6.4c (5.1) 6.2c (3.6) 8.4 (7.1) 10.0 (6.5) 2.6 (2.6) 3.8 (3.7) 4.3 (4.0) 3.5 (4.1) 2.4 (3.3) 11.5 (7.2)

7.1 (5.5) 5.4 (4.1) 5.3 (5.2) 5.1c (5.5) 6.2c (5.1) 6.1c (3.7) 8.2 (7.2) 11.7 (6.7) 3.5 (2.7) 4.1 (4.1) 4.2 (4.7) 3.8 (4.6) 3.0 (3.5) 13.1 (7.6)

6.6 (6.8) 4.2 (3.4) 3.6 (4.1) 2.5 (4.3) 3.7 (4.2) 4.3 (3.2) 5.8 (6.6) 12.4 (7.0) 3.7 (3.4) 4.9 (3.6) 5.1 (3.6) 4.7 (3.6) 3.5 (2.7) 12.2 (5.3)

5.9 (6.9) 3.8 (3.3) 3.2 (3.7) 2.0 (3.7) 3.1 (3.6) 3.8 (3.2) 5.2 (6.6) 13.1 (6.8) 4.0 (3.1) 4.3 (3.1) 4.1 (3.1) 4.1 (3.0) 3.6 (2.5) 13.0 (5.4)

O1 P7 P3 Pz P4 P8 O2 O1 P7 P3 Pz P4 P8 O2

.2d (4.0) .2d (2.7) 1.3d (3.7) 2.2 (4.0) 2.2 (3.8) 1.0 (3.6) .5 (4.2) 6.4f (3.7) 5.6f (2.9) 8.5f (3.6) 9.8f (3.9) 8.6f (3.2) 6.0f (2.7) 6.4f (3.7)

1.9f (2.4) 1.6d,f (1.9) 1.6 (2.9) 1.4 (3.3) 1.7 (2.9) 1.8d,f (2.2) 1.8f (2.5) 2.8 (1.8) 2.4 (1.4) 3.0f (1.6) 3.2 (1.9) 3.1 (1.8) 2.7 (1.7) 2.8 (2.2)

⫺2.5c (3.7) ⫺2.5c (2.7) ⫺.6c (3.2) .5 (3.2) .5 (3.3) ⫺.6 (2.9) ⫺1.6 (3.8) 7.9c (4.9) 6.9 (4.0) 10.1 (5.4) 11.1 (5.9) 10.1 (5.6) 6.9c (4.2) 7.8c (4.7)

0.3 (3.7) 0.1 (2.1) 1.0 (2.7) 1.0 (2.7) 1.0 (2.9) 0.5 (2.4) 0.4 (3.7) 3.2 (2.2) 2.3 (1.4) 3.4 (1.8) 3.6 (2.0) 3.3 (2.1) 2.3 (1.7) 3.3 (2.6)

⫺.6 (3.0) ⫺.7 (2.3) 1.0 (2.5) 1.8 (2.9) 1.6 (2.8) .3 (2.4) ⫺.3 (2.6) 10.3 (3.3) 8.5 (2.6) 12.0 (3.4) 12.7 (3.9) 12.1 (3.6) 8.8 (2.6) 10.0 (2.8)

0.4 (2.3) 0.7 (1.3) 1.0 (1.4) 0.7 (1.6) 0.7 (1.4) 0.4 (1.1) 0.2 (1.8) 3.3 (1.4) 2.9 (1.1) 4.0 (1.7) 4.1 (2.0) 4.0 (1.7) 3.0 (1.4) 3.2 (1.2)

FT7 F7 F3 Fz F4 F8 FT8 FT7 F7 F3

⫺1.6 (1.6) ⫺1.4 (1.9) ⫺1.8 (1.9) ⫺2.3 (2.0) ⫺2.3 (2.1) ⫺2.0f (2.0) ⫺2.2 (1.9) .7 (2.3) 1.0 (2.7) 1.1 (3.0)

⫺1.3 (2.3) ⫺1.0 (2.5) ⫺1.9 (3.1) ⫺2.1 (3.4) ⫺2.2 (3.1) ⫺1.7c (2.6) ⫺1.8 (2.3) 2.0 (2.2) 2.9 (2.3) 2.5 (3.1)

⫺2.4 (2.1) ⫺2.4 (2.3) ⫺3.4 (2.7) ⫺3.7 (2.8) ⫺3.4 (2.6) ⫺2.6 (2.1) ⫺2.5 (1.9) ⫺0.1 (1.7) ⫺0.2 (2.0) ⫺0.2 (2.4)

⫺.9 (2.0) ⫺.9 (2.1) ⫺1.2 (2.4) ⫺1.1 (2.6) ⫺.9 (2.4) ⫺.4 (1.8) ⫺.7 (1.8) 1.8 (2.2) 2.3 (2.7) 2.2 (3.3)

⫺2.0 (1.7) ⫺2.2 (1.6) ⫺2.7 (2.2) ⫺2.7 (2.4) ⫺2.5 (2.2) ⫺2.0 (1.5) ⫺1.9 (1.6) 0.0 (1.6) ⫺0.2 (2.0) ⫺0.2 (2.3)

⫺2.2 (1.8) ⫺2.3 (1.9) ⫺3.0 (2.2) ⫺3.2 (2.4) ⫺3.0 (2.5) ⫺2.4 (2.3) ⫺2.3 (2.2) ⫺0.7 (2.1) ⫺0.7 (2.3) ⫺0.9 (2.6)

S.R. Sponheim et al

Tg Tg ⫻ Rg Tg ⫻ Hm P3a

Statistic (df)

Relatives

246 BIOL PSYCHIATRY 2006;60:242–252

www.sobp.org/journal

Table 3. Mean Electrophysiological Component Amplitudesa from DS-CPT Trials for Schizophrenia Patients, First-Degree Relatives of Schizophrenia Patients, and Control Subjects

BIOL PSYCHIATRY 2006;60:242–252 247 Amplitude data are presented as mean (SD). Midline sites (Fz, Cz, Pz) were excluded from omnibus test but included in follow-up test when significant effects involving group or target occurred. All amplitude values reflect peak amplitudes, with the exception of anterior N1, N2, and P3a, which are mean amplitudes for the specified window. DS-CPT, degraded-stimulus continuous performance task; Gg, group effect; Tg, target effect; Hm, hemisphere effect; Rg, region effect; Task, task effect. Underlined target stimulus amplitude values indicate that the target amplitude is significantly different from the nontarget amplitude value for the subject group. a Electrophysiological components are included in the table only if they show an effect of group. b p ⬍ .05. c First-degree relatives of schizophrenia patients significantly different from nonpsychiatric control participants. d Schizophrenia patients significantly different from first-degree relatives of schizophrenia patients. e Greenhouse-Geiser correction. f Schizophrenia patients significantly different from nonpsychiatric control participants. g p ⬍ .01. h p ⱕ .001.

⫺0.4 (2.1) ⫺0.4 (2.1) ⫺0.2 (2.6) ⫺0.1 (2.1) ⫺0.1 (1.8) 3.0 (2.8) 3.5 (2.9) 2.6 (3.5) 2.9 (2.5) 2.2 (2.3) Tg ⫻ Rg

31.30h (2.27,129.6)

Fp1 Fp2 F4 F8 FT8

1.4 (3.7) 1.1 (3.7) .9 (3.3) 1.0 (3.1) .5 (2.8)

⫺0.9 (2.8) ⫺0.8 (2.8) ⫺0.8 (2.7) ⫺0.5 (2.2) ⫺0.5 (2.1)

3.5 (2.7) 3.4 (2.8) 2.5 (3.2) 2.7 (2.4) 2.0 (2.1)

⫺0.3 (2.3) ⫺0.2 (2.3) ⫺0.2 (2.5) ⫺0.1 (1.9) ⫺0.1 (1.7)

Nontarget Stimulus Target Stimulus Nontarget Stimulus Target Stimulus Nontarget Stimulus Window (msec) Component

Table 3. (continued)

Significant Group and Target Effectsa

Statistic (df)

Site

Target Stimulus

Group

Relatives Schizophrenia

Component Amplitudes (␮V)

Control Subjects

S.R. Sponheim et al

Hence, late posterior potentials (N2 and P3b) were only evident in response to DS-CPT target stimuli. Late potentials reflective of target detection were diminished in schizophrenia and partially diminished (i.e., P3b only) in relatives of schizophrenia patients. Anterior Potentials Target Detection. We also examined components evident over frontal brain regions to determine whether schizophrenia subjects and relatives exhibited anterior electrophysiological anomalies and whether component amplitudes were affected by target detection. Analyses yielded group ⫻ hemisphere and group ⫻ target ⫻ hemisphere interactions for anterior N1 amplitude. These effects reflected schizophrenia patients and relatives exhibiting larger anterior N1 potentials than control subjects over the right lateral frontal brain regions. Specifically, at site F8, schizophrenia patients and relatives had larger anterior N1 amplitudes to target stimuli than control subjects [t (44) ⫽ ⫺1.97, p ⫽ .05; t (48) ⫽ ⫺1.98, p ⫽ .05, respectively]. For P3a, analyses yielded a group ⫻ target ⫻ hemisphere interaction. Follow-up comparisons revealed that compared with control subjects, schizophrenia patients exhibited a trend toward diminished anterior P3a potentials to target stimuli over the right frontal pole [Fp2: t (36) ⫽ ⫺1.72, p ⫽ .09]. P3a amplitudes showed strong target effects, indicating that the potential was augmented for target stimuli as compared with nontarget stimuli (see Figure 2). Vigilance. A MANOVA of anterior N1 amplitudes yielded a task main effect [F (1,64) ⫽ 49.14, p ⬍ .0005]. Anterior N1 amplitudes were generally smaller during control trials, and this effect was maximal over right frontal lateral regions (see Figure 2). Analyses contrasting P3a mean amplitude in DS-CPT and sensory control trials yielded task ⫻ region [F(2.1,109.7) ⫽ 22.78, p ⬍ .0005] (Greenhouse-Geiser correction), task ⫻ region ⫻ condition [F (2.3,123.5) ⫽ 17.14, p ⬍ .0005] (GreenhouseGeiser correction), and task ⫻ condition [F (1,53) ⫽ 6.19, p ⬍ .05] effects. Inspection of means revealed that P3a amplitudes over prefrontal (Fp1, Fp2) and right frontal lateral (F8) sites were augmented for DS-CPT target trials compared with sensory control trials (see Figure 2). Hence, like posterior evoked potentials, the early anterior potentials (anterior N1) were augmented by vigilance demands of the DS-CPT and differentiated target and nontarget stimuli. Late anterior potentials (i.e., P3a) were only evident in response to target stimuli of the DS-CPT and showed a trend toward being diminished in schizophrenia patients. Effect of Schizophrenia Spectrum Symptoms in Relatives We carried out analyses to determine the effect of histories of psychosis and schizophrenia spectrum symptoms on electrophysiological anomalies in relatives. Exclusion of three affected relatives failed to alter any of the effects described above, and inspection of means revealed that the three relatives tended to have less deviant P1, anterior N1, N2, and P3b amplitudes than unaffected relatives. Although only three of the remaining unaffected relatives had more than one symptom of schizotypal, schizoid, or paranoid personality disorder (one relative with three symptoms and two relatives with two), and relatives as a group failed to differ from control subjects on self-rated schizotypy as assessed by the SPQ, we computed correlations between Schizotypal Personality Questionnaire (SPQ) scores and behavioral and electrophysiological indices to determine whether anomalies were associated with self-reported schizotypal characwww.sobp.org/journal

248 BIOL PSYCHIATRY 2006;60:242–252

S.R. Sponheim et al

Figure 1. Average event-related potentials from schizophrenia patients, first-degree biological relatives of schizophrenia patients, and nonpsychiatric control participants for target trials during the degraded-stimulus continuous performance task.

teristics. Relatives with higher SPQ scores tended to have lower response thresholds for indicating a stimulus was a target [ln(␤)] [r(25) ⫽ ⫺.40, p ⬍ .05] and showed a trend toward smaller P3b amplitudes [r(25) ⫽ ⫺.34, p ⫽ .10] at site P8.

Discussion In using the DS-CPT to study neural correlates of impaired vigilance in schizophrenia, we found several electrophysiological abnormalities in schizophrenia patients and first-degree biological relatives of schizophrenia patients. Abnormalities Shared by Schizophrenia Patients and First-Degree Biological Relatives of Schizophrenia Patients Schizophrenia patients and their first-degree biological relatives exhibited diminished late amplitudes (P3b) over posterior parietal regions and augmented early amplitudes (anterior N1) over right frontal regions during target detection. Abnormalities Unique to Schizophrenia Patients. In response to target stimuli, schizophrenia patients showed decreased N2 potentials over parietal and occipital brain regions and a trend toward decreased P3a potentials over right frontal www.sobp.org/journal

regions. Schizophrenia patients also showed decreased P2 amplitudes over parietal and occipital brain regions; however, P2 potentials were smaller in schizophrenia patients regardless of stimulus (i.e., evident in target and nontarget trials) and vigilance state (i.e., in both sensory control and DS-CPT trials). Abnormalities Unique to Relatives of Schizophrenia Patients. We also found relatives to exhibit augmented P1 and N2 amplitudes over posterior parietal brain regions. Augmented P1 amplitudes were evident in relatives in response to both target and nontarget stimuli, whereas N2 amplitudes were only augmented during target trials. Diminished P3b and augmented P1, N2, and anterior N1 potentials were present in relatives regardless of history of psychosis or schizophrenia spectrum disorders, raising the possibility that the abnormalities sensitively measure neural expression of genetic liability for schizophrenia. Other Findings. Early evoked potentials were evident during sensory control trials but were generally augmented during vigilance. Later event-related potentials (N2, P3a, and P3b) were only evident during DS-CPT trials and were larger for target stimuli than nontarget stimuli. Although schizophrenia patients showed impaired perfor-

S.R. Sponheim et al

BIOL PSYCHIATRY 2006;60:242–252 249

Figure 2. Average event-related potentials at select electrode sites from schizophrenia patients, first-degree biological relatives of schizophrenia patients, and nonpsychiatric control participants for target (solid line) and nontarget (dashed line) trials during the degraded-stimulus continuous performance task, and “button press” (dotted line) and “just look” (dash-dot line) control trials.

mance on the DS-CPT, the relatives as a group failed to have deficient performance on the task. Diminished Late Potentials During Target Detection in Relatives and Patients To our knowledge, this is the first report of diminished P3 amplitude in first-degree relatives of schizophrenia patients during a visual sustained attention task. For more than a decade, researchers have documented P3 decrement in relatives of schizophrenia patients during simple auditory target detection tasks (Blackwood et al 1991; Frangou et al 1997; Kidogami et al 1991; Turetsky et al 2000; Weisbrod et al 1999). Recent work has shown the auditory P3 decrement to be concordant in large samples of sibling pairs of schizophrenia patients (Winterer et al 2003) and to be associated with translocation at chromosome 1q42 in unaffected relatives in a schizophrenia pedigree (Blackwood et al 2001). Our finding of decremented P3 amplitude in relatives during target detection in a visual sustained attention task suggests the presence of a target detection anomaly that is evident across modalities but in particular task conditions, and is associated with genetic liability for schizophrenia. Perhaps this target detection anomaly is most evident in people with genetic liability for schizophrenia when tasks challenge the visual system with sustained attention demands (Posner and Petersen 1990). Electrophysiological studies using nondegraded versions of the visual CPT have revealed diminished P3 amplitudes to single-stimulus targets in adults (Pass et al 1980) and children (Friedman et al

1986) with schizophrenia. The one published study that failed to reveal diminished P3 in schizophrenia patients during a visual CPT examined the potential over central brain regions rather than over the parietal region (Wagner et al 1989). Because similar visual target detection (“oddball”) tasks have been shown to activate dorsolateral prefrontal cortex and parietal cortex (Kirino et al 2000; McCarthy et al 1997), vigilance deficits and diminished P3b might be manifestations of dysfunction in a right frontal–posterior parietal target detection network that is active during vigilance. In this regard, we found associations of smaller P3a with more false alarms in schizophrenia subjects (site F7: r ⫽ ⫺.43, p ⫽ .05) and relatives (site F7: r ⫽ ⫺.39, p ⬍ .05; site Fp1: r ⫽ ⫺.47, p ⬍ .05; site Fp2: r ⫽ ⫺.42, p ⬍ .05), perhaps indicating that both early and late frontal anomalies contribute to deficient target detection. There were no significant associations between task performance and P3b amplitude, indicating that whereas anterior brain regions might be most important to target detection, posterior P3 components probably reflect updating of target information and context in working memory. P3 abnormalities are unlikely to be due to motor preparation, given that the “button press” sensory control trial (see Figure 2) shows no P3b potential, thus indicating that although the P3b potential occurs around the time of the button press, it fails to reflect the motor component of pressing the button. Also, decremented P3b amplitudes in schizophrenia patients and relatives were not the result of histories of www.sobp.org/journal

250 BIOL PSYCHIATRY 2006;60:242–252 substance and alcohol dependence in a handful of individuals. When individuals with histories of alcohol or substance dependence were excluded, schizophrenia patients continued to exhibit diminished P3b amplitudes (Pz: t ⫽ ⫺1.96, p ⫽ .05; P3: t ⫽ ⫺2.64, p ⫽ .01; P4: t ⫽ ⫺3.09, p ⫽ .004; P7: t ⫽ ⫺2.82, p ⫽ .007; P8: t ⫽ ⫺3.21, p ⫽ .003; O1: t ⫽ ⫺2.95, p ⫽ .005; O2: t ⫽ ⫺3.22, p ⫽ .003), and relatives showed nearly significant diminished P3b amplitudes (P8: t ⫽ ⫺1.66, p ⫽ .10; O1: t ⫽ ⫺1.62, p ⫽ .11; O2: t ⫽ ⫺1.79, p ⫽ .08). When we carried out tests for the remaining potentials (P1, anterior N1, P2, P3a, and N2) after excluding individuals with histories of alcohol or substance dependence, only P3a no longer showed a significant effect involving group. Diminished N2 potentials in schizophrenia are generally consistent with other studies of visual attention in schizophrenia. Strandburg et al (1990, 1994, 1999) used nondegraded single-stimulus and successive-stimulus targets accompanied by distractor stimuli and found children and adults with schizophrenia to exhibit performance deficits and to have smaller negative potentials over posterior brain regions. More recent investigations have added to evidence of diminished N2 in schizophrenia patients during visual discrimination (Egan et al 1994; Ford et al 1994) by showing that schizophrenia patients exhibited diminished posterior N2 potentials during visual target detection, with a ventral shift in the potential for object-defined targets (Potts et al 2002). Additionally, one study revealed a diminished posterior Ncl component, of similar topography and time course as the posterior N2, that was associated with defective recognition of degraded objects by schizophrenia patients (Doniger et al 2002).

Augmented Early Visual Evoked Potentials in Relatives and Patients Early evoked potentials were evident during sensory control trials and were generally augmented during vigilance. Electrophysiological studies of visual attention that have shown frontal negativities of similar latency to the anterior N1 provide evidence that these potentials reflect response-related preparatory processes (Vogel and Luck 2000) and perhaps top-down attention to local elements of stimuli (Han et al 2001). Thus, augmented anterior N1 in schizophrenia patients and relatives might indicate that individuals who carry genes for schizophrenia use attentional resources for analysis of local stimulus elements rather than relying on a gestalt template to identify target stimuli. One study depicted augmented anterior N1 activity in schizophrenia patients during an object recognition task (Doniger et al 2002). Although the potential was not formally analyzed, anterior N1 seemed to increase in schizophrenia patients during greater image degradation, suggesting that with sparse visual information, schizophrenia patients increasingly rely on local element analysis and might fail to apply a gestalt in appraising stimuli. Similarly, we found that control subjects who had larger anterior N1 potentials for nontargets tended to perform worse on the DS-CPT (Pearson correlations with d=: [site F3] r ⫽ .42, p ⬍ .05; [site F7] r ⫽ .45, p ⬍ .05), perhaps reflecting an over-reliance on local element characteristics. There were no other significant correlations between DS-CPT performance and N1 amplitude in any group. During the DS-CPT, relatives also had larger P1 amplitudes than other groups, whereas schizophrenia patients failed to augment the potential under demands of the vigilance task. www.sobp.org/journal

S.R. Sponheim et al Investigators have shown P1 amplitude to be modulated by attention and perceptual load (Handy and Mangun 2000; Handy et al 2001; Hillyard and Munte 1984). Augmented P1 in relatives of schizophrenia patients is consistent with degraded stimuli creating greater perceptual load and attentional demands for relatives than control subjects. Schizophrenia patients’ failure to augment the P1 during vigilance demands of DS-CPT trials suggests aberrant early processing of stimuli in patients. P1 amplitude failed to be associated with task performance in patients, relatives, and control subjects. In studying the neural expression of genetic liability for schizophrenia, we identified early and late functional brain abnormalities in first-degree biological relatives of schizophrenia patients during a sustained attention task. Relatives of schizophrenia patients exhibited diminished late positive potentials (P3b) over parietal regions and early processing abnormalities over parietal– occipital (P1) and frontal (anterior N1) brain regions. Regardless of history of psychosis or schizophrenia spectrum disorders, relatives exhibited electrophysiological abnormalities. Findings are consistent with dysfunction in a right frontal–posterior parietal network mediating target detection during sustained attention. The right frontal–posterior parietal abnormality might represent a neural manifestation of genetic liability for schizophrenia.

This work was supported by grants from the Department of Veterans Affairs Medical Research Service (to SPS) and the Minnesota Medical Foundation (SMF-2075-99) (to SPS); and by the Mental Health Patient Service Line at the Veterans Affairs Medical Center, Minneapolis Minnesota. Presented in part at the Annual Meeting for the Cognitive Neuroscience Society, San Francisco, April 2002. We thank Keith H. Nuechterlein for provision of the DS-CPT computer program and consultation during paradigm implementation. We also thank Sarah M. Sass, Sarah Burt, and Robb Hunter for assistance with data collection. Supplementary material cited in this article is available online. American Psychiatric Association (1994): Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: American Psychiatric Association. Andreasen NC (1983): Scale for the Assessment of Negative Symptoms (SANS). Iowa City: University of Iowa. Andreasen NC (1984): Scale for the Assessment of Positive Symptoms (SAPS). Iowa City: University of Iowa. Asarnow RF, Nuechterlein KH, Subotnik KL, Fogelson DL, Torquato RD, Payne DL, et al (2002): Neurocognitive impairments in nonpsychotic parents of children with schizophrenia and attention-deficit/hyperactivity disorder: The University of California, Los Angeles Family Study. Arch Gen Psychiatry 59:1053–1060. Blackwood DH, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ (2001): Schizophrenia and affective disorders— cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: Clinical and P300 findings in a family. Am J Hum Genet 69:428 – 433. Blackwood DH, St Clair DM, Muir WJ, Duffy JC (1991): Auditory P300 and eye tracking dysfunction in schizophrenic pedigrees. Arch Gen Psychiatry 48:899 –909. Brooker BH, Cyr JJ (1986): Tables for clinicians to use to convert WAIS-R short forms. J Clin Psych 42:983. Buchsbaum MS, Haier RJ, Potkin SG, Neuchterlein K, Bracha HS, Katz M, et al (1992): Frontostriatal disorder of cerebral metabolism in never-medicated schizophrenics. Arch Gen Psychiatry 49:935–942. Chen WJ, Faraone SV (2000): Sustained attention deficits as markers of genetic susceptibility to schizophrenia. Am J Med Genet 97:52–57.

S.R. Sponheim et al Chen WJ, Liu SK, Chang CJ, Lien YJ, Chang YH, Hwu HG (1998): Sustained attention deficit and schizotypal personality features in nonpsychotic relatives of schizophrenic patients. Am J Psychiatry 155:1214 –1220. Clark L, Kempton MJ, Scarna A, Grasby PM, Goodwin GM (2005): Sustained attention-deficit confirmed in euthymic bipolar disorder but not in firstdegree relatives of bipolar patients or euthymic unipolar depression. Biol Psychiatry 57:183–187. Condray R, Steinhauer SR (1992): Schizotypal personality disorder in individuals with and without schizophrenic relatives: Similarities and contrasts in neurocognitive and clinical functioning. Schizophr Res 7:33– 41. Cornblatt BA, Keilp JG (1994): Impaired attention, genetics, and the pathophysiology of schizophrenia. Schizophr Bull 20:31– 46. Doniger GM, Foxe JJ, Murray MM, Higgins BA, Javitt DC (2002): Impaired visual object recognition and dorsal/ventral stream interaction in schizophrenia. Arch Gen Psychiatry 59:1011–1020. Egan MF, Duncan CC, Suddath RL, Kirch DG, Mirsky AF, Wyatt RJ (1994): Event-related potential abnormalities correlate with structural brain alterations and clinical features in patients with chronic schizophrenia. Schizophr Res 11:259 –271. Ekselius L, Lindstrom E, von Knorring L, Bodlund O, Kullgren G (1994): SCID II interviews and the SCID Screen questionnaire as diagnostic tools for personality disorders in DSM-III-R. Acta Psychiatr Scand 90:120 –123. First MB, Gibbon M, Spitzer RL, Williams JBW, Benjamin L (1997): Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II). New York: Biometrics Research Deparment, New York State Psychiatric Institute. First MB, Spitzer RL, Gibbon M, Williams JBW (1996): Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I, Research Version). New York: Biometric Research Department, New York State Psychiatric Institute. Ford JM, White PM, Csernansky JG, Faustman WO, Roth WT, Pfefferbaum A (1994): ERPs in schizophrenia: Effects of antipsychotic medication. Biol Psychiatry 36:153–170. Frangou S, Sharma T, Alarcon G, Sigmudsson T, Takei N, Binnie C, et al (1997): The Maudsley Family Study, II: Endogenous event-related potentials in familial schizophrenia. Schizophr Res 23:45–53. Friedman D, Cornblatt B, Vaughan H Jr, Erlenmeyer-Kimling L (1986): Eventrelated potentials in children at risk for schizophrenia during two versions of the continuous performance test. Psychiatry Res 18:161–177. Gottesman II, Gould TD (2003): The endophenotype concept in psychiatry: Etymology and strategic intentions. Am J Psychiatry 160:636 – 645. Grove WM, Lebow BS, Clementz BA, Cerri A, Medus C, Iacono WG (1991): Familial prevalence and coaggregation of schizotypy indicators: A multitrait family study. J Abnorm Psychol 100:115–121. Han S, He X, Yund EW, Woods DL (2001): Attentional selection in the processing of hierarchical patterns: An ERP study. Biol Psychol 56:113–130. Handy TC, Mangun GR (2000): Attention and spatial selection: Electrophysiological evidence for modulation by perceptual load. Percept Psychophys 62:175–186. Handy TC, Soltani M, Mangun GR (2001): Perceptual load and visuocortical processing: Event-related potentials reveal sensory-level selection. Psychol Sci 12:213–218. Hillyard SA, Munte TF (1984): Selective attention to color and location: An analysis with event-related brain potentials. Percept Psychophys 36:185– 198. Jones LA, Cardno AG, Sanders RD, Owen MJ, Williams J (2001): Sustained and selective attention as measures of genetic liability to schizophrenia. Schizophr Res 48:263–272. Kendler KS, Lieberman JA, Walsh D (1989): The Structured Interview for Schizotypy (SIS): A preliminary report. Schizophr Bull 15:559 –571. Kidogami Y, Yoneda H, Asaba H, Sakai T (1991): P300 in first degree relatives of schizophrenics. Schizophr Res 6:9 –13. Kirino E, Belger A, Goldman-Rakic P, McCarthy G (2000): Prefrontal activation evoked by infrequent target and novel stimuli in a visual target detection task: An event-related functional magnetic resonance imaging study. J Neurosci 20:6612– 6618. Knott V, Mahoney C, Labelle A, Ripley C, Cavazzoni P, Jones B (1999): Eventrelated potentials in schizophrenic patients during a degraded stimulus version of the visual continuous performance task. Schizophr Res 35:263– 278. Laurent A, Biloa-Tang M, Bougerol T, Duly D, Anchisi AM, Bosson JL, et al (2000): Executive/attentional performance and measures of schizotypy in patients with schizophrenia and in their nonpsychotic first-degree relatives. Schizophr Res 46:269 –283.

BIOL PSYCHIATRY 2006;60:242–252 251 Leckman JF, Sholomskas D, Thompson WD, Belanger A, Weissman MM (1982): Best estimate of lifetime psychiatric diagnosis: A methodological study. Arch Gen Psychiatry 39:879 – 883. Liu SK, Chen WJ, Chang CJ, Lin HN (2000): Effects of atypical neuroleptics on sustained attention deficits in schizophrenia: A trial of risperidone versus haloperidol. Neuropsychopharmacology 22:311–319. Liu SK, Chiu CH, Chang CJ, Hwang TJ, Hwu HG, Chen WJ (2002): Deficits in sustained attention in schizophrenia and affective disorders: Stable versus state-dependent markers. Am J Psychiatry 159:975–982. Lukoff D, Nuechterlein KH, Ventura J, (1986): Manual for the Expanded Brief Psychiatric Rating Scale. Schizophr Bull 12:594 – 602. Mackworth NH (1957): Some factors affecting vigilance. Adv Sci 53:389 –397. Maier W, Franke P, Hain C, Kopp B, Rist F (1992): Neuropsychological indicators of the vulnerability to schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 16:703–715. McCarthy G, Luby M, Gore J, Goldman-Rakic P (1997): Infrequent events transiently activate human prefrontal and parietal cortex as measured by functional MRI. J Neurophysiol 77:1630 –1634. Milliery M, Bouvard M, Aupetit J, Cottraux J (2000): Sustained attention in patients with obsessive-compulsive disorder: A controlled study. Psychiatry Res 96:199 –209. Nuechterlein KH (1983): Signal detection in vigilance tasks and behavioral attributes among offspring of schizophrenic mothers and among hyperactive children. J Abnorm Psychol 92:4 –28. Nuechterlein KH (1991): Vigilance in schizophrenia and related disorders. In: Steinhauer SR, Gruzelier JH, Zubin J, editors. Handbook of Schizophrenia: Neuropsychology, Psychophysiology, and Information Processing, vol 5. New York: Elsevier, 397– 433. Nuechterlein KH, Dawson ME, Ventura J, Gitlin M, Subotnik KL, Snyder KS, et al (1994): The vulnerability/stress model of schizophrenic relapse: A longitudinal study. Acta Psychiatr Scand Suppl 382:58 – 64. Nuechterlein KH, Parasuraman R, Jiang Q (1983): Visual sustained attention: Image degradation produces rapid sensitivity decrement over time. Science 220:327–329. Nurnberger JI Jr, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J, et al (1994): Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Arch Gen Psychiatry 51:849 – 859; discussion 863– 864. Pardo JV, Fox PT, Raichle ME (1991): Localization of a human system for sustained attention by positron emission tomography. Nature 349:61– 64. Pass HL, Klorman R, Salzman LF, Klein RH, Kaskey GB (1980): The late positive component of the evoked response in acute schizophrenics during a test of sustained attention. Biol Psychiatry 15:9 –20. Posner MI, Petersen SE (1990): The attention system of the human brain. Ann Rev Neurosci 13:25– 42. Potkin SG, Alva G, Fleming K, Anand R, Keator D, Carreon D, et al (2002): A PET study of the pathophysiology of negative symptoms in schizophrenia. Positron emission tomography. Am J Psychiatry 159:227–237. Potts GF, O’Donnell BF, Hirayasu Y, McCarley RW (2002): Disruption of neural systems of visual attention in schizophrenia. Arch Gen Psychiatry 59:418 – 424. Raine A (1991): The SPQ: a scale for the assessment of schizotypal personality based on DSM-III-R criteria. Schizophr Bull 17:555–564. Rund BR, Zeiner P, Sundet K, Oie M, Bryhn G (1998): No vigilance deficit found in either young schizophrenic or ADHD subjects. Scand J Psychol 39:101–107. Saoud M, d’Amato T, Gutknecht C, Triboulet P, Bertaud JP, Marie-Cardine M, et al (2000): Neuropsychological deficit in siblings discordant for schizophrenia. Schizophr Bull 26:893–902. Sax KW, Strakowski SM, Keck PE Jr, McElroy SL, West SA, Stanton SP (1998): Symptom correlates of attentional improvement following hospitalization for a first episode of affective psychosis. Biol Psychiatry 44:784 –786. Semlitsch HV, Anderer P, Schuster P, Presslich O (1986): A solution for reliable and valid reduction of ocular artifacts, applied to the P300 ERP. Psychophysiology 23:695–703. Siegel BV Jr, Buchsbaum MS, Bunney WE Jr, Gottschalk LA, Haier RJ, Lohr JB, et al (1993): Cortical-striatal-thalamic circuits and brain glucose metabolic activity in 70 unmedicated male schizophrenic patients. Am J Psychiatry 150:1325–1336. Strandburg RJ, Marsh JT, Brown WS, Asarnow RF, Guthrie D, Harper R, et al (1999): Continuous-processing related ERPS in adult schizophrenia: Con-

www.sobp.org/journal

252 BIOL PSYCHIATRY 2006;60:242–252 tinuity with childhood onset schizophrenia. Biol Psychiatry 45:1356 –1369. Strandburg RJ, Marsh JT, Brown WS, Asarnow RF, Guthrie D, Higa J (1990): Event-related potential correlates of impaired attention in schizophrenic children. Biol Psychiatry 27:1103–1115. Strandburg RJ, Marsh JT, Brown WS, Asarnow RF, Guthrie D, Higa J, et al (1994): Reduced attention-related negative potentials in schizophrenic adults. Psychophysiology 31:272–281. Suslow T, Arolt V (1997): Paranoid schizophrenia: Non-specificity of neuropsychological vulnerability markers. Psychiatry Res 72:103–114. Turetsky BI, Cannon TD, Gur RE (2000): P300 subcomponent abnormalities in schizophrenia: III. Deficits in unaffected siblings of schizophrenic probands. Biol Psychiatry 47:380 –390.

www.sobp.org/journal

S.R. Sponheim et al Vogel EK, Luck SJ (2000): The visual N1 component as an index of a discrimination process. Psychophysiology 37:190 –203. Wagner M, Kurtz G, Engel RR (1989): Normal P300 in acute schizophrenics during a continuous performance test. Biol Psychiatry 25:792–795. Weisbrod M, Hill H, Niethammer R, Sauer H (1999): Genetic influence on auditory information processing in schizophrenia: P300 in monozygotic twins. Biol Psychiatry 46:721–725. Wilder-Willis KE, Sax KW, Rosenberg HL, Fleck DE, Shear PK, Strakowski SM (2001): Persistent attentional dysfunction in remitted bipolar disorder. Bipolar Disord 3:58 – 62. Winterer G, Egan MF, Raedler T, Sanchez C, Jones DW, Coppola R, et al (2003): P300 and genetic risk for schizophrenia. Arch Gen Psychiatry 60:1158 – 1167.