Intact visual latent inhibition in schizophrenia patients in a within-subject paradigm
Introduction
Latent inhibition (LI) is the normal decrement in the rate of association of a CS and a UCS that occurs when the to-be-conditioned stimulus is initially preexposed to the subject without the UCS Lubow and Moore, 1959, Lubow, 1973. Conceptually, it is thought that LI occurs when a subject learns to ignore a “preexposed” (PE) stimulus that does not predict an important event (“preexposure phase”). When the stimulus subsequently starts to predict an important event (“test phase”), the learned “ignore” response must be overcome before a new CS-UCS association can be acquired. While the mechanism responsible for LI may actually reflect something other than “learning to ignore” the preexposed stimulus, LI is demonstrated operationally by a reduction in the acquisition of a CS-UCS association in which the CS is the preexposed stimulus, compared to the acquisition in which the CS is a non-preexposed (NPE) stimulus.
Baruch et al., 1988a, Baruch et al., 1988b reported that some schizophrenia (SZ) patients exhibit deficits in LI, when tested with an auditory LI task. Because reduced LI can be associated with faster-than-expected learning with PE stimuli, it may not be easily explained by generalized performance deficits. This original observation of LI deficits in acutely hospitalized schizophrenia patients has been replicated by the same group (Gray et al., 1992a), who also reported that LI is disrupted in normal controls by 5 mg of amphetamine, but not by a higher dose (10 mg) (Gray et al., 1992b).
Over the past decade, a number of attempts to replicate and extend these findings with LI have met with mixed success. Using the identical paradigm as Baruch et al., 1988a, Baruch et al., 1988b, as well as a novel visual LI paradigm, we failed to detect LI deficits in a large sample of schizophrenia patients (Swerdlow et al., 1996a). In these studies, schizophrenia patients exhibited slowed acquisition under both PE and NPE conditions, but not specific deficits in LI. Others have reported either abnormal (Rascle et al., 2001) or normal (Leumann et al., 2002) levels of LI in schizophrenia patients, or that LI deficits in SZ are evident only in one or another clinical subgroup or sex Lubow et al., 1987, Lubow et al., 2000, or alternatively, reflect the effects of antipsychotic medications (Williams et al., 1998) or learning deficits in NPE conditions (Martins Serra et al., 2001). In some cases, LI deficits have been seen only in unmedicated, drug-naive schizophrenia patients with illness duration <12 months (n=6; Gray et al., 1995), while in other cases LI deficits are seen only in medicated (but not unmedicated) patients (Williams et al., 1998). Interestingly, while consistent patterns of LI deficits in schizophrenia have been somewhat elusive, the “derivative” LI models have continued to expand, including findings of antipsychotic-potentiated LI in rats (cf. Kilts, 2001, Weiner, 2003) and LI deficits in normal populations labelled “high schizotypy” based on questionnaire response patterns Gray et al., 2002, Lubow et al., 2001, Lubow and De la Casa, 2002 and in normals treated with dopamine (DA) agonists Thornton et al., 1996, Kumari et al., 1999, Salgado et al., 2000, Swerdlow et al., 2003. Substantial progress has also been made towards identifying the neural regulation of LI in rats that includes portions of limbic-cortical and basal ganglia circuitry (cf. Weiner, 2003).
One challenge for understanding the implications of LI deficits in schizophrenia reflects the fact that many studies reporting LI deficits in schizophrenia patients do so only in the context of generalized deficits in learning or attention. In studies using instrumental trials-to-criterion paradigms, evidence for such performance deficits is typically seen as impaired performance in NPE conditions (e.g. Gray et al., 1992a, Swerdlow et al., 1996a). In instances where only a particular clinical subgroup of patients is identified to have LI deficits [e.g. in one case (Gray et al., 1995), unmedicated patients of <12-month illness duration or in another case (Lubow et al., 2000) female patients], it is often the case that compared to patients with “normal” LI, the “LI-deficient” subgroup exhibits impaired NPE performance. Because the amount of LI is typically calculated based on a difference in learning in NPE vs. PE conditions, generalized learning or attentional deficits under NPE conditions can yield “false positive” of LI deficits. Others have reported on normal LI but generalized basic associative learning in schizophrenia patients and their family members (Martins Serra et al., 2001), and the more general issue of associative deficits contributing to LI performance in schizophrenia has been critically reviewed (Escobar et al., 2002).
Another complexity in the LI literature reflects the wide range of experimental paradigms that are used to assess the presumed unitary underlying process of LI (cf. Lubow, 2004). Each of these approaches carries with it different sets of variables, stimulus characteristics and session designs, making it difficult to translate findings from one to another, to identify a basis for contradictory findings or even to determine whether the same construct (“LI”) is being measured by the different approaches. A number of investigations report LI using measures of electrophysiological or autonomic reactivity. These paradigms differ categorically from the instrumental trials-to-criterion paradigms commonly reported in studies of LI in schizophrenia (and discussed above), but they also detect evidence of generalized learning or performance deficits in schizophrenia patients. For example, Guterman et al. (1996) used the contingent negative variation (CNV) to assess LI in a between-subject paradigm. These investigators reported CNV deficits in non-preexposed schizophrenia patients (d=1.87) that was substantially greater than the overall “LI” effect in controls (d=0.90) (Table 2, p. 321), and which may suggest more generalized attentional impairment. Kathmann et al. (2000) utilized the N100 event-related potential (ERP) to assess LI in a between-subject design. The primary deficit in this report reflected responses (N100 amplitudes) of non-preexposed schizophrenia patients, while N100 amplitudes of preexposed schizophrenia patients were comparable to those of controls (Fig. 5, p. 111). Interestingly, in this same study, patients and controls demonstrated comparably robust LI in a go/no-go task. Vaitl et al. (2002) developed a within-subject measure of Pavlovian conditioning of electrodermal responses, and reported blunted orienting responses to (and presumably processing of) NPE stimuli, as well as absent LI in unmedicated but not medicated schizophrenia patients.
Validation of LI deficits in schizophrenia patients, and the reconciliation of differences in findings across studies, is clearly made difficult by the diverse characteristics of the patients to whom these deficits are attributed. In addition to the apparent importance of either or both the chronicity and medication state of the patient populations (defined differently in different reports), there may be complex effects of gender, and perhaps menstrual cycle phase, on schizophrenia-linked inhibitory deficits. For example, some forms of LI appear to exhibit sex-specific patterns Lubow et al., 2000, Lubow et al., 2001, Lubow and De la Casa, 2002. Other measures that detect inhibitory deficits in schizophrenia, such as prepulse inhibition of startle, appear to be sensitive to hormonal regulation, and to fluctuate across the normal menstrual cycle Swerdlow et al., 1997, Koch, 1998, Jovanovic et al., 2004. To our knowledge, menstrual cyclicity of LI has never been examined in the published literature.
Most studies to date have utilized between-subject paradigms, in which performance in patients preexposed to the CS is compared to performance of patients who were not preexposed to the CS. This between-subject design demands more than twice the number of subjects than would be needed for a within-subject design, and carries the disadvantage of extra variability associated with between- vs. within-subject studies. Conceivably, this variability may have contributed to some failures to detect LI deficits in patient populations (Swerdlow et al., 1996a). We recently reported our experience with a within-subject visual LI paradigm in normal adult male subjects (Swerdlow et al., 2003). This paradigm is a modified version of the instrumental trials-to-criterion between-subject visual LI paradigm that we previously tested in patients with schizophrenia (Swerdlow et al., 1996a), obsessive compulsive disorder (OCD) (Swerdlow et al., 1999) and Tourette Syndrome (TS) (Swerdlow et al., 1996b). In our recent studies, within-subject visual LI was eliminated by the indirect DA agonist d-amphetamine (20 mg p.o.) and by the direct DA agonist bromocriptine (1.25 mg p.o.) (Swerdlow et al., 2003). Thus, LI measured by this paradigm appears to be sensitive to increased DA activity, a substrate that is at least conceptually linked to the reported disruption of LI in schizophrenia patients (Gray, 1998).
This new LI measure may prove useful for understanding LI deficits in schizophrenia, based both on its within-subject design and its known sensitivity to disruption by increased DA function. However, previous studies did not establish the sensitivity of this measure to LI in clinically normal females, nor did they assess its sensitivity to menstrual cycle phase. In the present studies, we tested the sensitivity of visual LI to sex differences and menstrual cyclicity in normals, and then used this measure to assess LI in acute hospitalized schizophrenia patients and clinically stable schizophrenia outpatients.
Based on previous findings in the literature, we had two specific predictions for the outcome of the present study. First, based on previous reports Lubow et al., 2000, Lubow et al., 2001, Lubow and De la Casa, 2002, we predicted that there would be sex-specific patterns of LI in this paradigm. A corollary of this prediction, based on findings in conceptually related inhibitory measures Swerdlow et al., 1997, Jovanovic et al., 2004, is that, among normal females, LI may differ in luteal vs. follicular phase. A second prediction, based on conclusions reached from numerous other reports in the literature (discussed above), is that LI would be impaired in schizophrenia patients compared to normal control subjects. This second prediction is ultimately the one of most central importance to our understanding of cognitive deficits in schizophrenia.
Section snippets
Methods and materials
The methods used in these studies were approved by the UCSD Human Subjects Institutional Review Board (IRB #'s 011202 and 010904). The initial participants included 38 people with DSM-IV-diagnosed schizophrenia and 60 normal control subjects. Demographic and clinical information for these subjects is seen in Table 1, Table 2, Table 3.
Phone screening procedures for normal control subjects were identical to those described in previous reports from our group Swerdlow et al., 2000, Swerdlow et al.,
“Non-learners” and final group composition
Relevant characteristics of the initial and final normal control subjects and SZ subjects are seen in Table 1, Table 2. Of the original 98 subjects, 5/60 normal control subjects (8.3%) and 18/38 SZ patients (47.4%) failed to learn the NPE association (χ2=19.74, p<0.001). Poor attention (assessed by the preexposure phase diamond counting task) was evident in 6/23 (26.1%) of the non-learners (all 6 were SZ patients) and in 5/75 (6.7%) of the learners (2 of whom were SZ patients) (association of
Discussion
In the present study, visual LI was not impacted by sex or menstrual cycle phase among normal controls, nor did it differ among controls characterized by high vs. low scores on several personality measures. In partial support of our first prediction (“sex-specific patterns of LI”), women (but not men) with high harm avoidance scores did not exhibit LI, reminiscent of reports by Lubow et al., 2000, Lubow et al., 2001 that LI is relatively diminished among normal female (but not male) university
Acknowledgements
Supported by NIMH awards MH59803, MH01436 and MH42228. The authors are especially grateful for the assistance of Drs. William Perry, David Braff, Mark Geyer and Gregory Light, and Ms. Joyce Sprock in the completion of this study.
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2008, PsychoneuroendocrinologyCitation Excerpt :Latent inhibition (LI) is a cross-species selective attention phenomenon manifested as retarded conditioning to a stimulus that was repeatedly pre-exposed without consequence and is commonly considered to index the ability to ignore stimuli that were irrelevant in the past (Lubow et al., 1981; Lubow, 1989; Weiner, 1990, 2003); as such LI abnormalities in rodents are used to model the widely documented attentional impairment in schizophrenia (Weiner, 1990, 2003). LI is disrupted in rats and mice by amphetamine (e.g. Killcross and Robbins, 1993; Meyer et al., 2004; Moran et al., 1996; Weiner et al., 1984, 1988) and this is paralleled by disrupted LI in amphetamine-treated normal humans (Gray et al., 1992b; Salgado et al., 2000; Swerdlow et al., 2003; Thornton et al., 1996) and in the acute stages of schizophrenia (Baruch et al., 1988; Gray et al., 1992a, 1995; Rascle et al., 2001; but see Swerdlow et al., 2005). APDs restore LI in amphetamine-treated rats, and in patients (Baruch et al., 1988; Gosselin et al., 1996; Kumari et al., 1999; Shadach et al., 1999; Warburton et al., 1994; Weiner et al., 1996b).
The relevance of irrelevance to schizophrenia
2005, Neuroscience and Biobehavioral ReviewsContribution of non primate animal models in understanding the etiology of schizophrenia
2011, Journal of Psychiatry and NeuroscienceCitation Excerpt :These differences noted between patients with acute and chronic schizophrenia do not appear to be the result of stabilization due to medication, but rather the result of an evolution of the intrinsic factors of schizophrenia.112 Impairments in LI have been found in first-degree relatives of schizophrenia probands, regardless of whether these relatives displayed schizotypal features.113,114 One study, however, has not found an association between LI and schizophrenia.115