Schizophrenia Research 119 (2010) 183–190

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Schizophrenia Research

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P50 gating in deficit and nondeficit schizophrenia

José Luis Santos a, Eva María Sánchez-Morla a,b,⁎, Ana Aparicio a, María Ángeles García-Jiménez c,Clara Villanueva a, Vicente Martínez-Vizcaíno d, Celso Arango e

a Department of Psychiatry, Hospital Virgen de la Luz, Cuenca, Spainb Department of Psychiatry, Hospital Universitario de Guadalajara, Guadalajara, Spainc Neurophysiology Unit, Hospital Virgen de La Luz, Cuenca, Spaind Department of Epidemiology, Health and Psychosocial Research Center, Universidad de Castilla La Mancha, Cuenca, Spaine Unidad de Adolescentes, Department of Psychiatry, Hospital General Universitario Gregorio Marañón, Centro de Investigación Biomédica en Red de Salud Mental,CIBERSAM, Madrid, Spain

a r t i c l e i n f o

⁎ Corresponding author. C/Hermandad Donantes dGuadalajara, Spain. Tel.: +34 949209200.

E-mail address: emsanchez@sescam.jccm.es (E.M.

0920-9964/$ – see front matter © 2010 Elsevier B.V.doi:10.1016/j.schres.2010.01.010

a b s t r a c t

Article history:Received 1 November 2009Received in revised form 22 January 2010Accepted 23 January 2010Available online 12 February 2010

Dysfunctional auditory sensory processing has generally been found in schizophrenia and it hasbeen suggested that these deficits might be related to clinical and psychosocial variables. Thepresent study included P50 recordings using a simple-paired click auditory evoked potentialparadigm in sixty patients with deficit schizophrenia (DS), sixty patients with nondeficitschizophrenia (NDS), and sixty comparison subjects. The Schedule for the Deficit Syndromewas used to categorize patients as DS or NDS. The two patient groups did not differ in clinicalvariables, except for higher negative dimension and lower community outcome scores in DSthan in NDS patients. There were no differences in P50 ratios between deficit and nondeficitsubgroups; compared with normal subjects both groups of schizophrenia patients showedimpaired P50 ratios (p<0.0001). This ratio appears to be independent of positive and negativesymptoms. However, impairment in P50 gating correlated with poorer community outcome.The data document the existence of early auditory sensory processing abnormalities in DS andNDS, and might suggest that common neuronal network abnormalities underlie both forms ofschizophrenia. Deficient P50 gating may be associated with impaired functional outcome inschizophrenia.

© 2010 Elsevier B.V. All rights reserved.

Keywords:Auditory evoked potentialsInformation processingDeficit syndromeNegative symptomsFunctional outcome

1. Introduction

Middle latency auditory event-related potentials (MLAERPs)are a series of brain waves that are recorded at the scalpfollowing auditory stimulation. MLAERPs decrease in amplitudewhen a second click is delivered about 500 ms after thefirst click(Boutros et al., 2004a). This inhibitory mechanism of the centralnervous system has been named sensory gating. The earlypositive component of MLAERPs, occurring between 35 and90 ms after the stimulus (P50), may reflect a preattentive stage

e Sangre, s/n. 19002.

Sánchez-Morla).

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of information processing, and has been widely evaluated inschizophrenia. Many studies have shown P50 gating deficits inschizophrenia patients (Adler et al., 1982; Boutros et al., 1991,1993; Braff et al., 2007; Clementz et al., 1998; Clementz andBlumenfeld, 2001; Freedman et al., 1983; Judd et al., 1992;Sánchez-Morla et al., 2008). Nevertheless, some studies havefailed to find any significant association between deficits in P50gating and schizophrenia (Arnfred et al., 2003; Guterman andJosiassen, 1994; Kathmann and Engel, 1990), or found thisassociation only in a subgroup of schizophrenia patients (Jinet al., 1998). Deficient P50 gating persists during stable periodsand conventional antipsychotic medications do not remediatethis deficit in schizophrenia patients (Freedman et al., 1987;Nagamoto et al., 1996), although the effects of new-generationantipsychoticmedications with improvements in sensory gating

184 J.L. Santos et al. / Schizophrenia Research 119 (2010) 183–190

deficits are inconclusive (Adler et al., 2004; Arango et al., 2003;Sánchez-Morla et al., 2009). Two meta-analyses (Bramon et al.,2004; de Wilde et al., 2007) support a high variability in effectsize. These differences might be explained by differences inmethodology and the lack of homogeneity of the samples(Patterson et al., 2008).

Some studies have reported that negative symptomscorrelated with higher or more abnormal P50 ratios (Louchart-de La Chapelle et al., 2005; Ringel et al., 2004). Nevertheless, themajority of studies have failed to demonstrate a significantrelationship between P50 sensory gating and negative symp-toms (Adler et al., 1990; Arnfred and Chen, 2004; Light et al.,2000; Potter et al., 2006; Sánchez-Morla et al., 2008; Yee et al.,1998). The lack of homogeneity in the nature of the negativesymptoms could explain the differences in data between studies(Buchanan, 2007). In fact, to our knowledge, the relationshipbetween sensory gating and primary enduring negative symp-toms has not been addressed.

Carpenter et al. (1985) provided a distinction between theprimary and secondary negative symptoms of schizophrenia.Primary negative symptoms are idiopathic with enduringfeatures and persist between periods of relapse. These authors(Carpenter et al., 1988, 1993; Kirkpatrick et al., 2001)proposed a subtypeof schizophrenia characterized byprimaryand enduring negative symptoms named deficit schizophre-nia (DS) which is distinct from other forms of schizophrenia(nondeficit schizophrenia, NDS). The deficit syndrome repre-sents an attempt to find homogeneous clinical samples ofpatients diagnosed with schizophrenia. Comparisons ofsubtypes have long been an aspect of schizophrenia research.Hence, differences in psychopathologic (Galderisi et al., 2002),neurologic (Arango et al., 2000; Buchanan et al., 1990),neuropsychological (Brazo et al., 2002; Buchanan et al.,1994; Cohen et al., 2007), structural (Arango et al., 2008;Galderisi et al., 2008), metabolic (Kirkpatrick et al., 2009) andregional cerebral blood distribution abnormalities (Gonulet al., 2003; Vaiva et al., 2002) have been reported betweendeficit and nondeficit samples (for a review see Kirkpatricket al., 2001). Also, it has been suggested that deficit andnondeficit schizophrenia differ with regard to defects in basicneurophysiological mechanisms. Neurophysiological studieshave found that only schizophrenia patients with nondeficitforms or without pronounced negative symptoms showabnormalities in P3 components (Meisenzahl et al., 2004;Turetsky et al., 1998). More recently, Mucci et al. (2007) havereported the same results and suggest that schizophreniapatients with deficit forms have abnormalities of the earlystages of attentional information processing, while patientswith nondeficit schizophrenia have abnormalities of the latestages of information processing.

In the current study, the objective was to examine P50auditory sensory gating, using a conditioning-test paradigm,in deficit schizophrenia patients and nondeficit schizophre-nia patients in comparison with a control sample. Wehypothesized that schizophrenia patients with the deficitsyndromewould havemore abnormalities of the early stagesof attentional information processing than schizophreniapatients without the deficit syndrome. Moreover, weexamined whether auditory sensory gating correlates withclinical symptoms or functional outcome in both groups ofpatients.

2. Methods

2.1. Patients

One hundred and twenty clinically stable outpatients witha diagnosis of schizophrenia according to the StructuredClinical Interview for DSM-IV (SCID-I) were recruited for thestudy. The clinical assessment was performed by twoexperienced clinical psychiatrists. Patients were recruitedamong thosewhowere regularly attending the SevereMentalDisorder Program at Cuenca Hospital (Spain). They met theinclusion criterion of age between 18 and 55 years. Theexclusion criteria were the following: 1) severe medical orneurological disease; 2) mental retardation; 3) drug abuse ordependence in the last 24 months; 4) previous electrocon-vulsive therapy, and 5) a history of brain trauma with loss ofconsciousness. All patients were clinically stable prior toenrolment in the study. They were considered clinicallystabilized if during at least three months prior to assessment,there were no hospital admissions, the positive subscale scoreof the Positive and Negative Syndrome Scale (PANSS-P) didnot change by more than 3 points, and there had been nochanges in pharmacologic treatment. Patients meeting thesecriteria were then classified as having either DS or NDS afterbeing interviewed by two trained psychiatrists using theSpanish version (Bernardo et al., 2007) of the Schedule for theDeficit Syndrome (SDS) (Kirkpatrick et al., 1989). Threehundred and two stabilized outpatients diagnosed withschizophrenia (DSM-IV) were evaluated with the SDS;eighty-two patients were classified as DS. Sixty randomlychosen patients with DS according to the SDS were includedinto the study. For each recruited patient with DS, an age- andsex-matched patient with NDS was recruited from thegeneral group of patients with nondeficit schizophrenia.

2.2. Healthy controls

The control group was made up by sixty healthyvolunteers, 18 to 55 years of age. All control subjects metthe same exclusion criteria as patients and were given theSCID structured interview to rule out present or pastpsychiatric illness. Furthermore, subjects with first-degreerelatives diagnosed with bipolar disorder, psychosis, oranother psychiatric disorder were excluded in the screeninginterview. All subjects were from the same area and ethnicorigin as the patient group.

2.3. Clinical evaluation

The patients' clinical status was determined using theSpanish version (Peralta and Cuesta, 1994) of the Positive andNegative Syndrome Scale (Kay et al., 1987) administered bytwo experienced psychiatrists on the research team (JSG andESM). In addition, community outcomewas assessedwith theSpanish version (Rodríguez-Fornells et al., 1995) of theQuality of Life Scale (QLS) (Heinrichs et al., 1984). The QLSconsists of 21 items scored from 0 to 6, with the highestscores reflecting normal functioning. The scale assesses fourareas: interpersonal relations (household, friends, acquain-tances, social activity, social network, social initiative,withdrawal, and sociosexual behavior), instrumental role

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(occupational role, work functioning, work level, and worksatisfaction), intrapsychic foundations (sense of purpose,motivation, curiosity, anhedonia, aimless inactivity, empathy,and emotional interaction), and common objects and activ-ities. The total score is the sum of the scores from each area.Overall functioning status was assessed using the GlobalAssessment of Functioning Scale (GAF, DSM-IV).

2.4. P50 gating

2.4.1. ProcedureThree sets of 30 pairs of auditory clicks (stimulus 1 [S1]

and stimulus 2 [S2]) were delivered with an interstimulusinterval of 500 ms and an interpair interval of 10 s. A 0.1 mssquare wave pulse was amplified in the 20–12,000 Hzbandwidth and delivered through earphones with a peakintensity of 65 dB above the hearing threshold.

2.4.2. Evoked potential recordingsAll recordingswere performedwith the subjects supine, to

minimize large muscle artifacts, and relaxed but awake, witheyes fixed on a specific spot on the wall. The recording roomwas quiet, but not soundproof. None of the participants wasallowed to smoke during the 2h prior to the study.Recordings were obtained with gold-plated silver-disc elec-trodes applied to the vertex and referenced to one ear. Theelectrooculogram (EOG) from the superior orbital ridgereferenced to the lateral canthus was also recorded to detectocular movement artifacts. Online EEG and EOG channelswere screened to avoid spurious or non-physiologicalcomponents, and trials containing artifacts (activity exceeded50 μV in the EOG or EEG channel) were not included in thewaveform averaging. Two-channel Synergy evoked potentialequipment was used with the bandpass filter at 1–200 Hz andamplitude at 20 μV; impedance was less than 4 kΩ.

A single average was compiled from the three sets of 30artifact-free trials. The P50 component was identified asdescribed in previous reports (Nagamoto et al., 1989;Sánchez-Morla et al., 2008). The P50 was defined as themost positive deflection between 40 and 90 ms after stimulusdelivery. We also adopted a criterion, to safeguard againstchoosing an artifact as the P50 component (Boutros, 2008),that required the P50 component to be larger in amplitudethan the noise level preceding the stimulus and at least 0.5 μVamplitude when measured from its peak to the precedingnegativity. The response to the selected S2 test stimulus wasthe most positive wave in the latency range equal to thelatency of the S1 response±10 ms. The evoked potentialpeaks, amplitudes, and latencies were first screened with anautomated computer algorithm and then manually verifiedoff-line by researchers blind to subject and condition. The P50gating ratio or auditory sensory inhibition was measured bydividing the amplitude of the S2 response by that of the S1response. The P50 difference (amplitude of S2-P50 subtractedfrom amplitude of S1-P50) was calculated according to theliterature (Smith et al., 1994).

2.5. Statistical analysis

The statistical analyses were performed using SPSSversion 16.0 for Windows (Chicago, IL). ANOVA was used

for comparisons between the three groups (both groups ofschizophrenia patients and the control group) after verifyingthe normal distribution of the variables. The Bonferroni testwas used as a post hoc test. ANCOVA was used to adjust forage, gender, education, and smoking status. Spearman's rankcorrelation coefficient was used to analyze the relationshipbetween psychopathological variables and P50 measures. Weused partial correlations adjusting for sociodemographicvariables to analyze the relation between P50 measurementsand functional outcome variables.

All subjects provided written informed consent afterreceiving a complete description of the study, prior toparticipation in the study. The local ethics committee approvedthe study.

3. Results

The two groups of schizophrenia patients did not differ inage, gender, education, age of onset, chronicity, or smokingstatus. Patients with deficit schizophrenia had significantlyhigher scores on the PANSS negative symptom subscale andthe PANSS general psychopathology subscale, and signifi-cantly lower scores in psychosocial functioning (QLS andGAF) than patients with nondeficit schizophrenia (Table 1).There were no significant differences in pharmacologicaltreatment between the two groups of schizophrenia patients(Table 2). Moreover, no significant differences were foundbetween patient groups in the number of medicationsreceived at the time of testing (deficit schizophrenia: 1.6[SD 0.8]; nondeficit schizophrenia: 1.5 [SD 0.7]; p=0.558).

3.1. P50 wave

P50 could not be recorded in two control subjects and fivepatients with schizophrenia (two patients with deficit schizo-phrenia and three patients with nondeficit schizophrenia).

We tested the effect of sociodemographic variables suchas gender, smoking and medication (patients receivingtypical antipsychotics vs. patients receiving atypical anti-psychotics) on sensory gating measurements in the schizo-phrenia patient group. We found no significant effect ofgender (Pillai's trace: 0.003, F=0.158, p=0.854) or medica-tion (Pillai's trace: 0.013, F=0.716, p=0.491). However,there was an effect of smoking status on P50 gating (Pillai'strace: 0.078, F=4.593, p=0.012). Non-smoking patients hadhigher P50 ratios than smoking patients (P50 ratio in non-smokers, mean: 0.77; SD: 0.37; P50 ratio in smokers, mean:0.62; SD: 0.34, F=4.360: p=0.039). We found no significanteffect of age on P50 gating (Pillai's trace: 0.026, F=1.430,p=0.244).

One-way ANOVA revealed significant group differences inP50 ratio (p<0.001). Post hoc analysis showed that bothgroups of patients had a higher P50 ratio than the controlgroup; no significant differences in P50 ratio were foundbetween the two patient groups. Furthermore, significantdifferences were found between groups for the P50 ampli-tude difference (p<0.007). In this neurophysiological mea-surement, only patients with nondeficit schizophrenia hadsignificant differences in comparison with the control group.Moreover, the mean amplitude of S2 was significantly lower

Table 1Sociodemographic and clinical characteristics for healthy controls and schizophrenia patients.

DS (n=58)Mean (SD)

NDS (n=57)Mean (SD)

HC (n=58)Mean (SD)

F p

Age (years) 41.9 (8.5) 39.0 (7.3) 40.8 (11.2) 1.6 0.195Education (years) 11.3 (3.2) 12.0 (3.1) 14.4 (3.9) 15.1 0.0001 HC>DS, NDSAge at onset 22.7(5.7) 22.3 (4.6) – 0.11 0.790 –

Chronicity (years) 18.8 (8.3) 16.4 (6.3) – 3.14 0.079 –

PANSS-P 12.4 (4.4) 11.4 (11.9) – 1.6 0.195PANSS-N 24.6 (6.7) 13.4 (5.1) – 104.6 0.0001 DS>NDSPANSS-PG 30.1 (6.1) 24.5 (5.7) – 27.1 0.0001 DS>NDSGAF 45.2 (9.9) 62.5 (18.1) 90.3 (3.6) 261.9 0.0001 HC>NDS>DSQLS-T 47.8 (18.5) 72.9 (25.3) 117.1 (10.6) 185.4 0.0001 HC>NDS>DSQLS-Inter 17.55 (7.9) 24.85 (10.3) 44.3 (6.7) 150.9 0.0001 HC>NDS>DSQLS-Occup 5.9 (4.4) 11.4 (7.0) 20.1 (2.0) 117.3 0.0001 HC>NDS>DSQLS-Intra 17.2 (6.5) 27.4 (8.4) 41.0 (3.6) 190.7 0.0001 HC>NDS>DS

DS Number (%) NDS Number (%) HC Number (%) χ2 p

Sex (female) 16 (26.7%) 19 (31.7%) 28 (46.7%) 5.714 0.057Smokers 40 (66.6%) 39 (65.0%) 16 (26.6%) 0.363 0.547

DS: deficit schizophrenia. NDS: nondeficit schizophrenia; HC: healthy controls. PANSS-P: Positive and Negative Syndrome Scale—subscale of positive symptoms;PANSS-N: Positive and Negative Syndrome Scale—subscale of negative symptoms, PANSS-PG: Positive and Negative Syndrome Scale—general psychopathology.GAF: Global Assessment Functioning.QLS-T: Quality of Life Scale total score. QLS-inter: interpersonal relations subscale score; QLS-Occup: occupational role subscale score. QLS-Intra: intrapsychicsubscale score.

186 J.L. Santos et al. / Schizophrenia Research 119 (2010) 183–190

in both groups of schizophrenia patients compared to thecontrol group (p<0.001) (Table 3).

One-way ANOVA showed significant group differences inlatency S1 (p<0.001). On the basis of post hoc tests, themeanlatencies of the P50 responses to S1 were significantly higherin the nondeficit schizophrenia than in the control group(p<0.001) and the group of patients with deficit schizophre-nia (p<0.031). Moreover, when sociodemographic data(gender, education, smoking status) were used as co-variatesin the ANOVA the results remained unchanged. However,when antipsychotic medication (antipsychotic treatmentmeasured as haloperidol equivalents, biperiden treatmentmeasured as presence or absence of this medication) wasused as a co-variate in the ANOVA there were no significantdifferences in latency S1 (p=0.512).

No correlation was found between the PANSS positive andnegative subscales and the neurophysiological measurements(Table 4).

GAF positively correlated with QLS total score (r=0.89;p<0.001), and QLS subscales (interpersonal relations: r=0.84,

Table 2Psychotropics received by both groups of schizophrenia patients.

DS number(%)

NDS number(%)

Clozapine 21 (35.0%) 21 (35.0%) Chi2: 0.701; p<0.704Conventionalantipsychotics

18 (30.0%) 14 (23.3%)

New-generationantipsychotics

20 (33.3%) 23 (38.3%)

Combination ofantipsychotics a

1 (1.7%) 2 (3.3%)

Biperiden 8 (13.3%) 7 (11.7%) Chi2: 0.076; p<0.783Antidepressants 5 (8.3%) 8 (13.3%) Chi2: 0.776; p<0.378Benzodiazepines 19 (31.7%) 12 (20.3%) Chi2: 1.981; p<0.159

DS: deficit schizophrenia. NDS: nondeficit schizophrenia. Chi2: chi-square testa Combination of conventional and new-generation antipsychotics.

.

p<0.001; instrumental role: r=0.83, p<0.001; intrapsychicfoundations: r=0.89, p<0.001; common objects and activi-ties: r=0.71, p<0.001). Moreover, there was a significantnegative correlation between GAF, QLS total score, and QLSsubscales (interpersonal relations and intrapsychic founda-tions) and P50 ratio and S2 amplitude (p<0.001). Table 5shows that P50 difference correlated with QLS total score,interpersonal relations subscale and intrapsychic foundationsscores.

4. Discussion

This study had three major findings. Firstly, auditorysensory gating, evaluated by P50 ratio, was impaired in bothsubtypes of schizophrenia (deficit schizophrenia and non-deficit schizophrenia). Secondly, deficit forms of schizophre-nia did not show more severe sensory gating impairmentthan nondeficit schizophrenia. Thirdly, patients with a higherP50 ratio showed a poorer community outcome.

The identification of specific subtypes of patients withschizophrenia would facilitate research in complex disorderssuch as schizophrenia. It has been suggested that deficitpsychopathology defines a subgroup of patients with adisease different from schizophrenia without deficit features,as the deficit and nondeficit subgroups differ in their signsand symptoms, course, biological correlates, treatmentresponse, etiologic factors, and pathophysiology (Kirkpatricket al., 2001). Previous studies have found that a subgroup ofschizophrenia patients with negative symptoms, classifiedwith the negative subscale of the PANSS, had a higher P50ratio in comparison with the subgroup with non-negativesymptoms (Louchart-de la Chapelle et al., 2005; Ringel et al.,2004). In contrast, in the current study, we found a deficit inP50 suppression with similar characteristics in both schizo-phrenia subgroups, those with the deficit syndrome andthose without the deficit syndrome, compared with thecontrol group. These data are in accordance with previous

Table 3P50 parameters for patients with deficit and nondeficit schizophrenia and healthy controls.

DS (n=58)Mean (SD)

NDS (n=57)Mean (SD)

HC (n=58)Mean (SD)

F p

Amplitude S1 (µV) 4.50 (2.72) 4.26 (2.18) 4.01 (2.13) 0.619 0.540Latency S1 (ms) 53.32 (4.19) 55.39 (5.00) 52.33 (3.55) 7.659 0.001 HC, DF<NDSAmplitude S2 (µV) 2.64 (1.78) 2.86 (1.84) 1.55 (1.22) 10.703 0.0001 SD, NDS>HCP50 ratio 0.63 (0.31) 0.73 (0.39) 0.36 (0.20) 21.104 0.0001 SD, NDS>HCP50 difference 1.86 (2.02) 1.40 (1.78) 2.47 (1.53) 5.173 0.007 NDS>HC

DS: deficit schizophrenia. NDS: nondeficit schizophrenia; HC: healthy controls. S1: stimulus 1. S2: stimulus 2.

187J.L. Santos et al. / Schizophrenia Research 119 (2010) 183–190

studies (Adler et al., 1990) in which there were no significantdifferences in the percentage of inhibition in P50 ratio andN100 between schizophrenia with negative symptoms andnon-negative symptoms. This apparent contradiction be-tween previous studies could be explained by differentcriteria used in those studies for assignment of patients tothe negative group. In our study, the subgroup of patientswith the deficit syndrome was composed of patients withprimary negative symptoms with the criteria for deficitschizophrenia. In contrast, in another study, the criteria forassignment were the scores on the negative subscale of thePANSS, whichmeasure both primary and negative symptoms.

On the other hand, studies of evoked potential recordingswith an oddball paradigm have suggested that the deficitsubtypes of schizophrenia have an abnormality that affectsthe early stages of information processing (Turetsky et al.,1998) while the nondeficit subtype has abnormalities in laterstages of information processing related to attentionalprocesses (Mucci et al., 2007). However, in our study, bothgroups of patients had a higher P50 ratio than the control

Table 4Correlations (Spearman) between P50 measurements and clinical scores inschizophrenia patients.

PANSS-P PANSS-N PANSS-PG

Amplitude S1 0.047 −0.018 −0.035Latency S1 −0.007 −0.129 −0.164Amplitude S2 −0.072 −0.154 −0.178P50 ratio −0.088 −0.177 −0.179P50 difference 0.115 0.148 0.148

PANSS-P: Positive andNegative Syndrome Scale—subscale of positive symptoms;PANSS-N:PositiveandNegativeSyndromeScale—subscaleofnegative symptoms,PANSS-PG: Positive and Negative Syndrome Scale—subscale of generalpsychopathology.

Table 5Partial correlations between P50 measurements and functional outcome scores in s

GAF QLS-T

Amplitude S1 −0.059 −0.118Latency S1 0.115 −0.096Amplitude S2 0.104 0.070P50 ratio −0.198 (.039)* −0.194 (.047)*P50 difference 0.162 0.225 (.017)*

Sociodemographic variables used for adjusting: age, gender, education and chronicGAF: Global Assessment Functioning. QLS-T: Quality of Life Scale—total score. QLS-InQuality of Life Scale—occupational role subscale score. QLS-Intra: Quality of Life Sca*p>0.05.

group. Our findings suggest that both subtypes of schizo-phrenia have pathophysiological abnormalities during pre-attentive information processing. However, it should be takeninto account that further refinement of physiological pheno-types is needed that could identify specific underlyingphysiological deficits which could explain the differences inpsychotic disorders (Thaker, 2008). In this direction, Boutroset al. (2009) recently found correlation between N100 gatingdeficit and the negative-cognitive deficits dimensions in agroup of schizophrenia patients.

We did not find a correlation between neurophysiologicalmeasurements and clinical symptoms in schizophrenia patients.Our data are generally consistent with several previous cross-sectional studies that evaluated the relationship between clinicalsymptoms and abnormalities in P50 gating in patients withschizophrenia (Yee et al., 1998; Light et al., 2000; Erwin et al.,1998;Ward et al., 1996), although not with all studies (Ringel etal., 2004). In contrast, P50 gating deficit was associated withlower community outcome in our schizophrenia sample (GAFScale ratings and specific domains of the QLS, such asinterpersonal relationships and intrapsychic foundations). It isconsistent with the hypothesis that the causal link betweengenes and functional outcome in schizophrenia reflects theimpact of forebrain circuits that regulate basic gating mechan-isms, more than those that control the expression of specificsymptom states (Braff and Light, 2004). Studies that examinesensorimotor gating through prepulse inhibition (PPI) of thestartle response showed findings in line with our results. Thus,PPI deficit is associated with long-standing functional impair-ment in schizophrenia (Swerdlow et al., 2006). It has beensuggested that gating deficits may cause schizophrenia patientsto become overloaded with excessive exteroceptive and inter-oceptive stimuli, leading to the collapse of normal cognitiveintegrity (Freedman et al., 1987; Braff and Geyer, 1990).

chizophrenia group.

QLS-Inter QLS-Occup QLS-Intra

−0.127 −0.081 −0.094−0.066 −0.085 −0.103

0.085 0.060 0.081−0.239 (.011)* −0.126 −0.183 (.052)*

0.251 (.007)* 0.156 0.209 (.027)*

ity.ter: Quality of Life Scale—interpersonal relations subscale score. QLS-Occup:le—intrapsychic foundations subscale score.

188 J.L. Santos et al. / Schizophrenia Research 119 (2010) 183–190

Likewise, numerous studies (Green, 1996; Green et al., 2000)have clearly demonstrated an association between neurocogni-tive impairment and several domains of functional outcome inschizophrenia patients.

Other components of the MLAERPs are associated withfunctional outcome. Mismatch negativity deficits in schizo-phrenia patients have been related to patients' impairments indaily functioning, level of independence in their community,living situation, and functional outcome (Kawakubo et al.,2007; Light and Braff, 2005a,b). Therefore, different findingssuggest that deficits of early information processing are relatedtopsychosocial functioning.More studies areneeded to identifyrelevant variables that mediate the relationship of P50 andother preattentive processing deficits to everyday functioning.An understanding of the interactions between basic neuro-physiological cognitive operations and clearly defined andmeasured daily functioning is an important future direction inschizophrenia research. It could be argued that studies of thebiology of schizophrenia and its relationship to functionaloutcomemay be best advanced through quantitativemeasuresof forebrain inhibitory mechanism of auditory sensory proces-sing (Swerdlow et al., 2008).

There are contradictory data on P50 latencies in schizo-phrenia patients. In a meta-analysis (Bramon et al., 2004),there were no significant differences between schizophreniapatients and controls in P50 latency. Adler et al. (1982) foundshortened latencies in schizophrenia patients free of antipsy-chotic medication, although these latencies were not signif-icantly diminished in patients who were receivingantipsychotics, which suggests, that these antipsychoticagents returned the latency to normal (Freedman et al.,1983). However, in line with our data, several studies haveidentified significantly longer latencies in schizophreniapatients receiving antipsychotic agents (Adler et al., 1990;Boutros et al., 2004b; Louchart-de la Chapelle et al., 2005).Moreover, significantly increased mean latencies of the P50responses to S1 and S2 have been found predominantly inschizophrenia patients with prominent negative symptoms(Louchart-de la Chapelle et al., 2005; Adler et al., 1990;Boutros et al., 2004b). In our study, significantly prolongedmean latencies were present in nondeficit schizophreniapatients. However, the statistical significance is lost whenmedication status was controlled for. Thus, the slight increasein latency found in patients with schizophrenia may be aneffect of antipsychotic medication.

Indeed, the evaluation ofmedicated schizophrenia patients isan important limitation of this study, because antipsychoticagents can modify amplitude and latency of auditory evokedpotentials (Straumanis et al., 1982). It has been suggested thatclozapine improves sensory gating (Adler et al., 2004; Nagamotoet al., 1996, 1999). A third of our sample was receiving clozapineand this could be related to the lack of differences betweenpatients. However, the percentage of patients treated withclozapine was similar in both groups. In addition, we could notfind an effect of medication status on P50 gating. Likewise, tworecent studies found that clozapine treatment was not related tomore normal sensory gating (Hong et al., 2009; Sánchez-Morlaet al., 2009). Therefore, it is unlikely that, in our study,antipsychotic treatment explains the lack of differences in P50gating between patients with deficit schizophrenia and non-deficit schizophrenia.

Therefore, some methodological aspects might be consid-ered. The effect of sound intensity on the sensory gating shouldbe taken into account since a stimulus that is too loud maycause startle and thus decrease gating (de Wilde et al., 2007).During the experiment the stimuli used were with a soundintensity of 65 dB above threshold, close to the recommenda-tions in Griffith et al. (1995) and similar to another group(Nagamoto et al., 1996). In addition, recently, no significantmain effect of intensity was found in P50 gating (Pattersonet al., 2008). Thus, there is low probability that auditory clickintensity could explain the lack of differences in P50 gatingbetween the twogroupsof schizophrenia patients.On theotherhand, it should be noted that P50 reliability is low (White andYee, 2006) andmay be influenced by psychological states, suchas diminished attention or vigilance, fatigue and drowsiness(Fuerst et al., 2007). Patients in this studywere chronic patientsso results are not generalizable to all patients.

This report documents our initial observation thatabnormalities in auditory sensory processes that affect earlystages of information processing are present in deficit andnondeficit forms of schizophrenia. These abnormalities wereassociated with poor community outcome in schizophreniapatients.

Role of funding sourceThis study was supported by the following: Institute of Health of the

Castilla La Mancha Grant (03016-01).

ContributorsJLS and EMSM designed the study and wrote the protocol. JLS, EMSM, CV

and CAmanaged the literature searches and analyses. JLS and AA selected thesample and evaluated patients. JLS and VM undertook the statistical analysis.JLS and CA wrote the first draft of the manuscript. All authors contributed toand have approved the final manuscript.

Conflict of interestThe authors declare that they have no conflicts of interest.

AcknowledgmentThis work was supported by a research grant (03016-01) provided by

the Institute of Health of the Castilla La Mancha Regional Executive in Spain.

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