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Alertness can be improved by an interaction between orienting attention and alerting attention in schizophrenia

Alertness can be improved by an interaction between orienting attention and alerting attention in... Background: Attention is impaired in schizophrenia. Early attention components include orienting and alerting, as well as executive control networks. Previous studies have shown mainly executive control deficits, while few of them found orienting and alerting abnormalities. Here we explore the different attentive networks, their modulation and interactions in patients with schizophrenia. Methods: Twenty-one schizophrenic patients (DSMIV), compared to 21 controls, performed a modified version of the Attention Network Task, in which an orienting paradigm (with valid, invalid and no cues) was combined with a flanker task (congruent/incongruent) and an alerting signal (tone/no tone), to assess orienting, executive control and alerting networks independently. Results: Patients showed an abnormal alerting effect and slower overall reaction time compared to controls. Moreover, there was an interaction between orienting and alerting: patients are helped more than controls by the alerting signal in a valid orientation to solve the incongruent condition. Conclusion: These results suggest that patients with schizophrenia have altered alerting abilities. However, the orienting and alerting cues interact to improve their attention performance in the resolution of conflict, creating possibilities for cognitive remediation strategies. 1. Introduction generates “descending feed back signals that bias sensory Attention encompasses different functions, which work inputs in favour of information that is behaviourally rele- together in everyday life and are dissociable from percep- vant” [2]. It is also involved in the resolution of conflict tion and action: orientation of attention, triggering an between competing information and regulates activity in alert state, and resolving response conflicts. The orienting other brain networks involved in thought and emotion network selectively allocates attention to a potentially [3]. relevant area of the visual field, enhancing perceptual The distinction between orienting, alerting, and execu- processing. The alerting network prepares for action by tive control is also evident on the neuronal level [4]: The means of a change in internal state. This preparation can orienting neural network allocates attention to relevant be triggered when a visual or auditory warning signal is areas of the environment and involves the posterior par- presented prior to a target. Executive control involves ietal lobe, the superior colliculus, and the thalamus [5]. planning, decision making, error detection, giving novel Local infusion of scopolamine into the posterior parietal responses, or overcoming habitual actions [1]. The cortex in rhesus monkeys during a covert orienting task executive control of attention is a top-down process that showed a dose dependent increase in reaction time (RT) and decrease in performance accuracy. This indicates a major role of the posterior parietal cortex in orienting, * Correspondence: i.amado@ch-sainte-anne.fr with a pivotal cholinergic influence in the modulation of INSERM, Physiopathologie des Maladies Psychiatriques, U894-7; Centre de orientation [6]. The alerting network comprises right Psychiatrie et Neurosciences Paris, France Full list of author information is available at the end of the article © 2011 Amado et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Amado et al. Behavioral and Brain Functions 2011, 7:24 Page 2 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/24 thalamic, frontal and parietal regions [4] and neuroima- reporting an executive deficit in patients, these differ- ging studies using PET and fMRI during reaction time ences might have been maximized by discrepancies in tasks with and without warning, also showed an involve- group matching. Some studies were carried out with ment of the reticular formation [7]. Sturm and Wilmes populations matched for age [28], or comparing popula- (2001)[7] provided neuropsychological evidence that tions with pre-existing differences in executive function alerting is subserved by right hemispheric regions with as detected by the Wisconsin Card sorting test [29], parieto-fronto-thalamic interactions. Alerting is influ- other studies were performed with differences for enced by the cortical distribution of the brain’s norepine- patients versus controls in number of years of study [31]. phrinsystemthatarisesfromthe locuscoeruleus [8]. Only one study had a strict comparison between patients PET studies during the performance of the Stroop color and controls for IQ level and years of education [27]. word task in healthy controls showed that the executive The variability of the ANT results in schizophrenia network is subserved by the anterior areas of the frontal could result from confounding factors due to the type of cortex, i.e. the anterior cingulate cortex [9] and the lateral population itself (IQ, age, treatment), but also to the prefrontal cortex [10], which are target areas of the ven- intrinsic properties of the ANT task. Indeed, MacLeod tral tegmental dopamine system [11]. During a visual dis- et al. (2010) [32] highlighted different psychometric crimination task with fMRI requiring exploratory eye properties of the ANT that could complicate the results movements, Tsunoda et al [12] showed that the number found: the relative dependence of the three different of fixations correlated with decreased gray matter in right networks measurements, the low reliability of the alert- frontal and parietal structures. Using a diffusion tensor ing and orienting score compared to the executive con- imaging technique, Buchsbaum et al. (1998) [13] found trol scores, and the high intra-individual variability lower diffusion anisotropy in the white matter of the pre- observed in control studies. Lastly, some components of frontal cortex in patients with schizophrenia compared attention could be trait-like (e.g executive control), or to controls. Impairments of attentional processes in schi- state-like (alerting or orienting) explaining the variance zophrenia are heterogeneous; difficulties in disengaging structure of the ANT scores. visuo-spatial attention have been observed in chronic Callejas et al. [33,34] used a modified version of the never-medicated schizophrenics [14], acute naïve patients ANT paradigm to dissociate orienting, alerting, and [15] and relatives of patients [16], as well as in patients executive control and to study their interactions. The treated with typical [17,18] or atypical antipsychotics version of ANT used by Callejas et al. [33,34] is remark- [19]. Abnormal reactivity to warning signals has been able in two important aspects: 1) The presence/absence described as a deficit in the maintenance of an alert state of the non-valid trials: in this version, orienting is mea- in naïve [20] or treated patients [21]. In addition, schizo- sured using a non-predictive cue, with 50% valid vs. 50% phrenics show a marked sensitivity to interference in the invalid cues. The ANT includes only 100% valid cues. 2) Stroop [22] and flanker task [23], or in oculomotor para- Alerting is assessed with an auditoryalerting cue whereas digms such as antisaccade tasks [24], which are consid- a visuo-spatialcue is used in the ANT. The non-predic- ered to represent executive functioning. Moreover, using tive cue allows the activation of an exogenous orienting cerebral imaging techniques, hypoactivity in the anterior system (with the automatic capture of attention by a cingulate cortex has been visualised during a conflict non-informative visual stimulus). In the original ANT, monitoring task [25]. the 100% valid cue condition induced an impure, mixed The Attentional Networks Test (ANT), is a paradigm exogenous and endogenous orientation of attention (exo- designed to examine attentional network efficiencies in genous attention raised by the cue presentation, and orienting attention, alerting, and executive control [26,4]. endogenous attention raised by the always predictive The task is based on the combination of (i) a cued reac- meaning of the cue). Also, in Callejas et al.’s [33] version, tion time (RT) task and (ii) a flanker paradigm which the warning sound stimulus fundamentally differs from evaluates the ability to solve conflicts. ANT studies in the orienting visual stimuli, whereas in the ANT, the patients with schizophrenia have previously yielded alerting and orienting networks are activated by the same inconclusive results: 1) An overall slower RT [27-29]. 2) four types of visual cues. These two differences make the A deficit in executive control was found in a vast majority modified Callejas et al version of ANT [33]suitable for a) of studies [27,28,30,31], while only one study found no measuring the function of each attentional network inde- executive deficit [29]. 3) A deficit in orienting, found in pendently, and b) studying interactions between these some [27] but not all studies [29]. 4) Reduced alertness, networks. In healthy subjects, Callejas et al. [34] found which was correlated to illness duration and medication that the alerting network influences the executive control levels. Tensor diffusion brain imaging indicated that the network by inhibiting its functioning, which is consistent reduction in alertness was correlated to a smaller right with Posner’s proposal (5). Moreover, the alerting net- cingulum bundle volume [29]. However, in many studies work influences the orienting network by speeding up Amado et al. Behavioral and Brain Functions 2011, 7:24 Page 3 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/24 the orienting process. Fuentes et al. [35] showed, using there was some lack of independence among the net- this ANT version in healthy controls, that orienting to works in both tests [36]“. Moreover, cued paradigms the target location in advance enhanced target processing including mixed block design such as the ANT task not speed and reduced conflict. The conjunction of a mixed only induced processes of activation (in generating an positive action on orienting and conflict, suggests that alerting effect for example) but also proactive response alerting improves rather than accelerates the orienting inhibition processes [38]. effect. Ishigami and Klein (2010) [36] stated that the Call- The purpose of our study is to explore (1) whether ejas’ version of ANT “permits the researcher to examine orienting, alerting, or executive control are altered in the interaction among the attentional networks with con- patients with schizophrenia, (2) how the three networks fidence”. Concerning the robustness of the attention net- interact in patients, Both groups of participants were work scores when examining the repeatability of the strictly matched for age, sex and IQ level to minimize ANT and ANT-I tests (Callejas ‘ version), these authors the differences that might exist in general aptitudes. In argued that “despite the learning effect, the two tests pro- line with the majority of studies, we expected executive vided robust index of each attention network”, but “over- control of attention to be impaired in patients, but due all the reliability of the network scores was found to be to our strict matching this difference could not be greater with the ANT-I than the ANT”. found, whereas impairment in alerting or orienting Investigation of the different attentional networks in could be evidenced. Therefore, we administered for the schizophrenia and the modulation of their effects on each first time the Callejas’ version of ANT (2004)[32] to other are of crucial importance. On the one hand, the stable outpatients with schizophrenia and healthy interactions of attentional networks occur constantly in controls. everyday life, suggesting that deficits would have a wide impact. On the other hand, disentangling specific deficits 2. Methods in schizophrenia could provide the basis for new cognitive 2.1. Participants remediation techniques to enhance the attentional abilities Characteristics of the participants are summarized in of patients with schizophrenia. Gooding et al.(2006) [28], table 1. Twenty-one outpatients with chronic schizophre- using the ANT, attempted to analyze the interactions nia (SZ), and 21 healthy controls (C) (15 males in both between different attention networks. They showed that SZ and C) participated in the study. Study procedures both patients with schizophrenia and controls were most were described before participants decided to take part in efficient in resolving conflict when they were alerted and the study and signed their written informed consent. SZ when their orientation was towards the attended spatial and C received 30 Euros for their participation. Study position. Neither Gooding et al. [28] nor Wang et al. [27]’ procedures were approved by the local Ethical Commit- found correlations between the attentional networks. In tee (CCPPRB- Pitié-Salpétriére Hospital, Paris). Partici- Gooding et al. (2006)[28] this was due to the confounding pants were not instructed to restrain their cigarette factor that alerting and orienting cues were both presented consumption before the assessment. However, they were in the visual modality. Fan et al. (2009)[37] recently pro- not allowed to smoke during the session test. vided a revised version of the ANT with the aim of charac- For all subjects, exclusion criteria were: a patent neu- terizing attentional network interactions in healthy rological disease, a history of head trauma, substance volunteers. The authors manipulated the length of the abuse or dependence. All participants were assessed cue-target interval and cue validity (with a no cue, spatial with the Diagnostic interview for Genetic Studies, cue and temporal cue condition) and found that orienting DIGS-III [39], the NSS (neurological soft signs) scale to the target location before the alerting stimulus [40], and the WAIS-R [41]. enhanced target processing and reduced conflict. Never- theless, Gooding et al. (2006)[28] suggested using the Table 1 Demographic and clinical characteristics: values ANT version of Callejas et al. (2004,2005)[33,34], which are expressed as means and standard deviations allows the independent measurement of the three atten- SZ C P tional networks and their interactions. This modified task Gender 15M/6F 15M/6F could, thus, reduce the heterogeneity of the results found Age (years) 31(8) 30(9) 0.76 in schizophrenia using the original ANT paradigm and Years of study 13(2) 13(2) 0.99 highlight the influence of the orienting network on execu- WAIS-R Global 101(14) 105(15) 0.4 tive control in patients with schizophrenia. WAIS-R Perform 95(11) 103(20) 0.2 ANT and its modified version are supposed to explore WAIS-R Verbal 103(18) 106(17) 0.7 attention interactions between alerting, orienting and Handedness 17D/4M 18D/3M 0.5 executive control in a relatively independent way. This D: Dextral; S: Sinistral; M: mixed lateralization notion might be modulated, since it was found “that Amado et al. Behavioral and Brain Functions 2011, 7:24 Page 4 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/24 SZ (DSM-IV criteria)[42] were recruited from the Ambulatory Center of the Parisian 15th arrondissement and the University Department of Psychiatry at Sainte- Anne Hospital, Paris, France. Mean duration of the disease FP =[400- 1600]ms 1 Congruent was 9 (± 6) years. Clinical evaluations were conducted with the PANSS (Positive and Negative Syndrome Scale, 50ms + Incongruent [43]. PANSS scores at the time of neuropsychological test- B) Stimuli 400ms ing were: Total score: mean = 59, SD = 13, Positive sub- score: mean = 12, SD = 4, Negative subscore: mean = 17, 50ms SD = 6. All patients had received stable monotherapy with Trial Duration = 50ms atypical antipsychotics (risperidone < 4 mg, clozapine, olanzapine, amisulpride < 600 mg) for at least three RT < 1700ms months (mean duration: 29 (24) months) prior to investi- 3500 – TR – FP ms gation (equivalent chlorpromazine dosage: 388 mg (207 1 A) Procedure for Experiment mg). No other medication was allowed. Figure 1 Sequence of events appearing on each trial in the C were recruited from our Clinical Research Center, modified version of ANT experiment. Part A shows the actual excluding members of the department, subjects that had sequence of events during the ANT task in our study. Part B shows ever had a DSM-IV axis one disorder, and subjects with examples of the target display in the congruent and incongruent condition. Stimuli: The stimulus used for the orienting signal was an a family history of a psychiatric disorder up to the 2nd asterisk presented at the same location as the target (2.9° of visual degree. None of C had ever received any psychotropic angle above or below the fixation point). For the alerting signal, a medication. 2000 Hz and 50 ms sound was used. Lastly, the target display was made up by a target arrow that could point either to the left or to 2.2. Attentional task (figure 1) the right and four flankers that could be just plain black lines or arrows pointing either left or right. The length of the arrows was 2.2.1. Apparatus 0.55° and they were 0.06° away from each other. Description of the Programming and presentation of stimuli was performed task: In half of the trials, 50 ms before the target an auditory with an Intel-Pentium-4 computer with a 17” color alerting signal was presented (fig1). After a 400 inter-stimulus- screen monitor running E-Prime software. interval (ISI), an orienting cue was presented on 2/3 of the trials 2.2.2. Procedure above or below the fixation point for 50 ms. After another 50 ms ISI the target and flankers were presented either at the same or the Participants were seated 53 cm in front of the computer opposite location than the previous orienting signal for 1700 ms, or screen and instructed to respond to the target stimulus until the participant gave a response. Then the fixation point that (direction of the central arrow), by pressing one of two had been presented during the whole trial was kept for a variable possible keyboard keys using their right or left index fin- duration dependent on the duration of the initial fixation point and ger, depending on the side of the answer. Feedback on the reaction time of the subject so that every trial was same duration (4050 ms). No screen was presented between trials. regarding accuracy was given during practice trials but Consequently, participants did not know when a trial had finished not during experimental trials. and the next one was to begin providing uncertainty about the 2.2.3. Task Design (figure 1) appearance of the signals and increasing their informative value. The experiment had a multivariate mixed design including two levels for the Alerting Signal (presence/absence of a sound) × three levels for the Orienting Cue (No Cue/ Signal) × 2 (Orienting Cue) × 2 (Congruent/Incongru- Valid/Invalid) × two levels for the Executive Control (con- ent) × 2 (Group) mixed ANOVA. Effect size was evalu- gruent/incongruent, see Figure 1) × 2 Groups (SZ/C). ated with eta proportion of the total variance that Altogether, there were 12 different conditions (see Figure attributed to an effect. Different indexes were estab- 1). The practice block (24 trials) proceeded the six experi- lished: an alerting effect (RT difference between the mental blocks of 48 trials each. The whole task included alerting cue and no alerting cue conditions), an orient- 24 trials per condition with a pseudo-random presentation ing effect (RT difference between the valid and invalid within each block. Overall, the duration of the experiment conditions) and a conflict effect (RT difference between took nearly 20 minutes; patients had a pause between each the congruent and incongruent conditions) (33); In each block and decided to start the next block by pressing the group, one way ANOVAs were used for comparison space bar. regarding gender and smoking on these indexes. Pearson correlation coefficients were used to explore associations 2.3. Statistical analyses between clinical, IQ, and index variables. In order to Trials with RTs longer than 2000 ms were eliminated illustrate more precisely the link between symptoms, IQ and the ratio for incorrect responses in each trial was and performance we examined very contrasted groups reported. Median RTs were analyzed with a 2 (Alerting for clinical symptoms and IQ, subdividing the SZ group Amado et al. Behavioral and Brain Functions 2011, 7:24 Page 5 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/24 into two categories (high vs. low score for PANSS and 3.4. Accuracy analysis rd IQ,cut-off:3 quartile of the distribution), and we cal- The ANOVA performed on the percentage of incorrect culated the means of the effect in each category. responses revealed a main effect for the Orienting Cue, [F(1, 40) = 18.41; p < .001], and the Congruent/incon- 3. Results gruent factor, [F(1, 40) = 14.56 p < .001]. The Orienting Cue × Congruent/incongruent interaction was signifi- 3.1. Clinical and demographic data cant, [F(1, 40) = 19.13; p < .0001]. The orienting effect There were more men than women in SZ and C. How- was higher in incongruent than in congruent conditions. ever, there was no significant difference between SZ and In other words, when participants are not spatially C for sex ratio, age, years of study, or IQ (see table 1). oriented, accuracy is worse for the incongruent trials. 3.2. RT analysis (table 2) No group effects were found (Figure 2). RTs exceeding 2000 ms were very few (0.17%) with no dif- ference between patients and controls. The main effects 3.5. Correlations between performance and for the three attentional systems were significant. Trials demographical and clinical data with an auditory alerting signal were faster than those In SZ, in the absence of an alerting signal (no tone con- without one [F(1, 40) = 27.36; p < .001;eta = 0.41]. Partici- dition), the conflict effect was negatively correlated with pants were faster when oriented with valid cues compared WAIS-R performance (r = -.46; p = 0.041). Furthermore, to invalid cues [F(1,40) = 175.31; p < .001; eta =0.81]. SZ with low WAIS-R-performance scores (RT = 750 ms; Finally, participants were faster in congruent trials com- SE = 39 ms) had longer RTs than those with high pared to incongruent ones [F(1,40) = 204.12 p < .001; WAIS-R performance scores (RT = 714 ms; SE = 32 eta = 0.84]. Considering performance between the two ms) in the incongruent condition, whereas there was no groups, the main effect was significant, [F(1,40) = 5.98; p = difference in the congruent condition. .019; eta = 0.13]. SZ were 66.5 ms slower than C. Similarly, in C the conflict effect was negatively corre- Importantly, we observed a significant alerting × lated with years of study (r = -.46; p = 0.041). group interaction, [F (1, 40) = 5.41; p = .025; eta = 0.12] with SZ (mean = 36 ms) showing a greater sensi- 4. Discussion tivity to the auditory alerting cue than C (mean = 14 In accordance with our assumption that the ANT ver- sion of Callejas et al., [33,34] allows differentiation of ms). Finally, the four-way interaction of orienting × the three attentional networks and their interactions, we alerting × control × group was statistically significant, [F obtained the following main experimental results: (1,40) = 6.21; p = .017; eta = 0.13] and other interac- 1) SZ exhibited slower overall RTs than C, tions with group were non-significant (p > 0.25). Partial ANOVAs were conducted to disentangle the 2) SZ displayed a greater alerting effect compared to C. four-way interaction. Separate analyses were conducted 3) In SZ only, an interaction was found between alert- on the four congruent/incongruent × orienting condi- ing and orienting. tions. In the incongruent valid cue condition the 2 In line with studies using the ANT [27-29,31], SZ (Alerting Signal) × 2 (Group) mixed ANOVA showed a were slower than C. In our study, the reported effects significant alerting × group interaction [F (1, 40) = were independent of this general slowing, and remained 13.13; p = .001], indicating that SZ benefited more than significant even when we used proportional RT as a controls from the alerting effect in the incongruent con- dependent variable in a supplementary analysis (median dition when their attention was validly oriented (alerting RT per condition divided by overall median RT, data index in SZ: 66 ms in SZ in C:14 ms) (Figure 2). In not shown). others conditions (incongruent- invalid; congruent-valid; Chronic stabilized outpatients showed a greater alert- congruent-invalid) this interaction was non-significant ing effect using this version of ANT than C. Previous (p > 0.18). studies with ANT have not reported this result and Table 2 Median RT(ms) and percentage of errors (for each experimental condition, for Patients (SZ),) and healthy Controls (C) No Alerting Cue With Alerting Cue invalid No Cue Valid Invalid No Cue Valid SZ Congruent 646 0,90% 656 0,40% 615 0,20% 617 0,40% 589 0,40% 584 0,70% Incongruent 754 4,10% 756 3,30% 716 1,30% 738 4,60% 703 2,80% 650 0,90% C Congruent 568 0,40% 584 0,80% 540 0,20% 561 0,60% 533 0,20% 514 0,20% Incongruent 690 3,10% 662 1,10% 624 1,10% 679 4,00% 640 2,70% 612 1,60% Amado et al. Behavioral and Brain Functions 2011, 7:24 Page 6 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/24 findings may demonstrate a failure of alertness in schizo- phrenia. Recently, in an experimental study concerning the induction of a psychotic-like state in healthy subjects, Daumann et al., 2009 [46], using auditory and visual cue- ing stimuli, found a reduction in alertness after a bolus injection of Dymethyltriptamine, a hallucinogenic drug. Thiel and Fink, (2007)[47] provided evidence in healthy subjects for modality specific correlates of visual and auditory alertness in posterior parietal and frontal brain areas. However, a supramodal region, the right superior Figure 2 comparison of reaction times between patients and temporal gyrus, was commonly involved in visual and controls in incongruent valid conditions in the absence or auditory alertness. This brain region is involved in the presence of an auditory alerting signal. Deviations are indicated behavioural relevance of warning cues [48], and “its acti- by use of median absolute deviation. vation is capable of breaking ongoing activity and opti- mizing responses to following target(s)” [47]. Abnormal superior temporal gyrus volumes have been found in indeed have found unchanged [27,28,31] or reduced schizophrenia [49]. alerting efficiency [29]. This could be due to differences Nevertheless, our attempt to superimpose analyses of in the modality of the alerting stimulus. In Callejas et the effect of valid or invalid trials, or congruent or al.’s version of the ANT [33], the alerting stimulus is incongruent trials provided comparable orienting or auditory, the orienting stimulus is visual. In contrast, alerting and orienting cues are ipsimodal (visual) in conflict effects in SZ and controls. This result contra- prior ANT versions. SZ were slower than C in all no- dicts those studies that suggest an executive control tone conditions, suggesting that their reactivity was rela- deficit [27,28,30,31]. Chronicity, hospitalization, non- tively decreased. The sound cue seemed to enhance stabilization, IQ, and educational level could be con- alertness in patients but their overall RTs remained founding factors. In our study, patients and controls longer than those seen in C. In healthy subjects, Frassi- were strictly matched in years of education and IQ. netti et al. (2002)[44] reported that an auditory stimulus Neuropsychological studies comparing schizophrenic can enhance the detection of masked visual flashes. patients and controls most often reported less educa- Recently, Noesselt et al., (2008)[45] tested an auditory tional achievement in patients, reflecting the impact of enhancement of perceptual sensitivity to visual blinks in the disease [27]. The strict comparison of attentional a two-alternative choice paradigm. They found that a performance by equalizing the confounding IQ and edu- cation features is an original aspect of our study. It pro- crossmodal visuo-auditory cue significantly enhances vides a more stringent comparison of the three detection ability, as if this enhancement increases the attentional networks, highlighting the power of the dif- salience of the visual event. Our results show that ference found in the alerting network. It can also patients are sensitive to this increase in target salience, explain the absence of an executive control deficit found helping them to reduce their RTs. Ishigami and Klein in our patients, by a possible underestimation of the (2010)[36] suggested that the auditory modality of the neuropsychological differences between patients and Callejas’ ANT version [33,34] might generate alertness controls. In our study educational level was negatively more automatically than the visual modality of the ANT correlated with the conflict effect in controls. Moreover, could do. The more automatic alert state induced in we found convergent arguments supporting the relation- this task could help patients more efficiently, opening ship between IQ and executive control: 1) In SZ the fruitful ways to enhance performance in schizophrenia that could be used in cognitive remediation techniques. conflict effect in the no-tone condition was negatively Our results clearly demonstrate a greater sensitivity in correlated with WAIS-R performance. 2) RTs in the patients to auditory alerting stimuli compared to con- incongruent condition differed depending on IQ trols. However, although reaction times when alerted performance. provided a substantial positive effect in patients, it was Lastly, we found an interaction between alerting and not enough for them to reach the performance of healthy orienting in SZ, especially for the incongruent condition. subjects. In other words, even if patients improved their In incongruent trials, in the valid orientation condition, alertness ability with the tone, they still showed lower when there is no auditory alerting signal, SZ benefited reaction times in every condition with an auditory cue. less than controls from the valid orientation; this ten- Nestor et al., (2007)[29] found that a reduction in visual dency being reversed with the presence of the auditory alerting cues correlated with a reduced volume of the alerting cue. In controls, in contrast, the absence or pre- cingulum bundle. These results together with our sence of a valid cue has an equivalent effect whatever Amado et al. Behavioral and Brain Functions 2011, 7:24 Page 7 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/24 the presenceofanauditoryalerting signal. One should useful to see if early alterations of the attentional net- ask whether the effect of a valid spatial cue was reduced works could represent possible stage markers of the in patients owing to the presence of invalid trials. In the disease. present paradigm, valid trials indeed represent 50% of Several limitations of this work can be found. First, the non-neutral trials, as compared to 100% in the ANT the restricted sample size could limit the power of our studies. The auditory alerting cue would then compen- analysis. However, the strict inclusion criteria used to sate for this decreased validity effect. This last point select the participants in our study tend to increase the brings confirmation to the facts that 1) the addition of homogeneity of the two groups. Further studies are war- invalid trials is a main change relative to previous stu- ranted using this version of the ANT with a more dies 2) This study was aimed at clarifying interactions extended group of subjects. Second, the participants in between the orienting and alerting network. If we con- the two groups have high general aptitudes and levels of sider the accuracy analyses, it seems that in both groups education. Even if this selection is mainly due to being invalid and incongruent conditions led to the worst per- recruited through the university, if we consider that not formance. Thus, in patients, the adjunction of a correct all patients suffering from schizophrenia exhibit these orientation and a warning tone enhanced their ability aptitudes, this could constitute a bias in the selection of especially in difficult conditions e.g with incongruent sti- the sample. muli. This finding is in line with the interaction between Concerning the main paradigm ANT, Macleod et al. orienting and alerting in healthy subjects observed by (2010)[32] found a low split-half reliability for the alert- Fuentes et al., (2008)[35] using the Callejas version of ing network in healthy subjects. Nevertheless, we used the ANT [33,34], and Fan et al. (2009)[37] with the here a modified version of ANT more reliable than the modified ANT. Patients seem to extract more benefit version elaborated by Fan et al. (2002)[26,36],. Another than controls from this adjunction of cues. This obser- possible limitation of this work lies in the exploration of vation could bring valuable tools to enhance attention the “interaction” of attentional networks. The concept in in schizophrenia, with a putative application in cognitive itself involves the construction of a mixed block of trials, remediation strategies. including warning, orienting and executive stimuli, with Regarding cognitive remediation in schizophrenia, trials presumed to reflect the different combinations. Van meta-analyses have shown no direct benefit of training der Lubbe et al. [52] showed that the use of a mixed techniques of attention [50,51]. Although not improving block design provides an uncertainty about whether a attentional measures, these techniques could positively warning signal, a cue or a target will appear first. This influence executive dimensions and optimize working situation requires strong executive control to withhold memory, response speed, or visual scanning. Accord- automatic responses to warning signals, cues or incon- ingly, improving the capacity to solve executive conflicts gruent targets. It creates a proactive inhibitory control by reinforcing an alert state in patients or helping them that is released only when a target has been identified. to focus their attention could possibly improve effi- Jaffard et al. (2007)[38] observed that the alerting effect ciency. The results found in this study with the Callejas as assessed with warning signals could be fully con- et al. ‘ version of the ANT [33] provide a way to investi- founded with the behavioural outcomes of proactive inhi- gate attentional networks in schizophrenia. The combi- bition control. Hence there could be confusion between nation of orienting and alerting strategies in attentional an effect of an alerting cue reflecting a true phasic modu- tasks assessing conflict resolution could be adopted rou- lation of arousal, and an alerting effect relying more on tinely in integrative programs of cognitive remediation an executive control mechanism. Boulinguez et al. (2009) therapy. [53] observed that the presentation of a warning signal The results found in this study address the question of involves an important executive control network inhibit- the specificity of these alterations, to determine whether ing the mechanisms underlying movement initiation. A the attentional processing style observed here is likely to network of structures is implicated in the proactive inhi- represent an illness feature, i.e. a consequence of the bition mechanism with a strong involvement of the med- expression of the illness, or a measure of some of the ial prefrontal cortex [54]. This point is of crucial interest aetiological factors of schizophrenia, e.g a cognitive mar- in schizophrenia, where disorders of movement initiation ker of the disease. If the latter, this abnormality could be and impairment of top-down inhibitory control have studied as a putative endophenotype of schizophrenia. been found in orienting [55] as well as in oculomotor Of course, the present design did not allow us to tasks, with frontal structures being strongly implicated address this question but it would be very useful to [56]. All the studies demonstrating this proactive inhibi- study the performance of relatives of patients with schi- tion mechanism have been conducted with visual warn- zophrenia. Also, an exploration of patients with prodro- ing signals. We can speculate whether an auditory mal symptoms or schizotype personalities might be alerting signal also enhances a proactive inhibition Amado et al. Behavioral and Brain Functions 2011, 7:24 Page 8 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/24 3. Fan J, McCandliss BD, Fossella J, Flombaum JI, Posner MI: The activation of mechanism. However, to precisely separate the effect of attentional networks. Neuroimage 2005, 26:471-479. an interaction between alerting, orienting and executive 4. Posner MI, Petersen SE: The attention system of the human brain. Annu attentional networks from an extended executive control Rev Neurosci 1990, 13:25-42. 5. Posner MI, Raichle ME: Images of mind. Scientific American Library, New effect by proactive inhibition, new study designs could York; 1994. include mixed block and pure warned/not warned block 6. Davidson MC, Marocco RT: Local infusion of scopolamine into parietal design tasks. cortex slows covert orienting in rhesus monkeys. J Neurophysiol 2000, 83:1536-1549. To conclude, the use of Callejas et al’s version of ANT 7. Sturm W, Willmes K: On the functional neuroanatomy of intrinsic and (2004)[32] gave us striking results showing the benefit of phasic alertness. NeuroImage 2001, 14:76-84. having clear measures for attentional networks and their 8. Coull JT, Sahakian BJ, Hodges JR: The alpha (2) antagonist idazoxan remediates certain attentional and executive dysfunction in patients interaction. We demonstrated that reinforcing an alert- with dementia of frontal type. 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Brain Res Review 2000, 31(2-3):251-269. 12. Tsunoda M, Kawasaki Y, Matsui M, Tonoya Y, Hagino H, Suzuki M, Seto H, This approach could provide fruitful ways of optimizing Kurachi M: Relationship between exploratory eye movements and brain performance in schizophrenic patients in a multitude of morphology in schizophrenia spectrum patients: voxel based cognitive domains. morphometry of three-dimensional magnetic resonance imaging. Eur Arch Psychiatry Clin Neurosci 2005, 255:104-110. 13. Buchsbaum MS, Tang CY, Peled S, Gudbjartsson H, Lu D, Hazlett EA, Downhill J, Haznedar M, Fallon JH, Atlas SW: MRI white matter diffusion List of Abbreviations anisotropy and PET metabolic rate in schizophrenia. Neuroreport 1998, ANT: Attentional Networks Test; C: healthy controls; PANSS: Positive and 9(3):425-30. Negative Syndrome Scale; RT: Reaction Time; SZ: outpatients with 14. 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Daumann J, Wagner D, Heekeren K, Neukirch A, Thiel C, Gouzoulis- Mayfrank E: Neuronal correlates of visual and auditory alertness in the DMT and ketamine model of psychosis. J Psychopharmacol 2009, e-pub. Submit your next manuscript to BioMed Central 47. Thiel C, Fink G: Visual and auditory alertness: modality specific and and take full advantage of: supramodal neural mechanisms and their modulation by nicotine. J Neurophysiol 2007, 97:2758-2768. • Convenient online submission 48. Corbetta M, Kincade JM, Ollinger JM, McAvoy MP, Shulman GL: Voluntary orienting is dissociated from target detection in human posterior • Thorough peer review parietal cortex. Nat Neurosci 2000, 3(3):292-7. • No space constraints or color figure charges 49. Sun J, Maller JJ, Guo L, Fitzgerald PB: Superior temporal gyrus volume • Immediate publication on acceptance change in schizophrenia: A review on Region of Interest volumetric studies. Brain Res Rev 2009, 61(1):14-32. • Inclusion in PubMed, CAS, Scopus and Google Scholar 50. Pilling S, Bebbington P, Kuipers E, Garety P, Geddes J, Martindale B, • Research which is freely available for redistribution Orbach G, Morgan C: Psychological treatments in schizophrenia: II. Meta- Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Behavioral and Brain Functions Springer Journals

Alertness can be improved by an interaction between orienting attention and alerting attention in schizophrenia

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Copyright © 2011 by Amado et al; licensee BioMed Central Ltd.
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Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
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Abstract

Background: Attention is impaired in schizophrenia. Early attention components include orienting and alerting, as well as executive control networks. Previous studies have shown mainly executive control deficits, while few of them found orienting and alerting abnormalities. Here we explore the different attentive networks, their modulation and interactions in patients with schizophrenia. Methods: Twenty-one schizophrenic patients (DSMIV), compared to 21 controls, performed a modified version of the Attention Network Task, in which an orienting paradigm (with valid, invalid and no cues) was combined with a flanker task (congruent/incongruent) and an alerting signal (tone/no tone), to assess orienting, executive control and alerting networks independently. Results: Patients showed an abnormal alerting effect and slower overall reaction time compared to controls. Moreover, there was an interaction between orienting and alerting: patients are helped more than controls by the alerting signal in a valid orientation to solve the incongruent condition. Conclusion: These results suggest that patients with schizophrenia have altered alerting abilities. However, the orienting and alerting cues interact to improve their attention performance in the resolution of conflict, creating possibilities for cognitive remediation strategies. 1. Introduction generates “descending feed back signals that bias sensory Attention encompasses different functions, which work inputs in favour of information that is behaviourally rele- together in everyday life and are dissociable from percep- vant” [2]. It is also involved in the resolution of conflict tion and action: orientation of attention, triggering an between competing information and regulates activity in alert state, and resolving response conflicts. The orienting other brain networks involved in thought and emotion network selectively allocates attention to a potentially [3]. relevant area of the visual field, enhancing perceptual The distinction between orienting, alerting, and execu- processing. The alerting network prepares for action by tive control is also evident on the neuronal level [4]: The means of a change in internal state. This preparation can orienting neural network allocates attention to relevant be triggered when a visual or auditory warning signal is areas of the environment and involves the posterior par- presented prior to a target. Executive control involves ietal lobe, the superior colliculus, and the thalamus [5]. planning, decision making, error detection, giving novel Local infusion of scopolamine into the posterior parietal responses, or overcoming habitual actions [1]. The cortex in rhesus monkeys during a covert orienting task executive control of attention is a top-down process that showed a dose dependent increase in reaction time (RT) and decrease in performance accuracy. This indicates a major role of the posterior parietal cortex in orienting, * Correspondence: i.amado@ch-sainte-anne.fr with a pivotal cholinergic influence in the modulation of INSERM, Physiopathologie des Maladies Psychiatriques, U894-7; Centre de orientation [6]. The alerting network comprises right Psychiatrie et Neurosciences Paris, France Full list of author information is available at the end of the article © 2011 Amado et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Amado et al. Behavioral and Brain Functions 2011, 7:24 Page 2 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/24 thalamic, frontal and parietal regions [4] and neuroima- reporting an executive deficit in patients, these differ- ging studies using PET and fMRI during reaction time ences might have been maximized by discrepancies in tasks with and without warning, also showed an involve- group matching. Some studies were carried out with ment of the reticular formation [7]. Sturm and Wilmes populations matched for age [28], or comparing popula- (2001)[7] provided neuropsychological evidence that tions with pre-existing differences in executive function alerting is subserved by right hemispheric regions with as detected by the Wisconsin Card sorting test [29], parieto-fronto-thalamic interactions. Alerting is influ- other studies were performed with differences for enced by the cortical distribution of the brain’s norepine- patients versus controls in number of years of study [31]. phrinsystemthatarisesfromthe locuscoeruleus [8]. Only one study had a strict comparison between patients PET studies during the performance of the Stroop color and controls for IQ level and years of education [27]. word task in healthy controls showed that the executive The variability of the ANT results in schizophrenia network is subserved by the anterior areas of the frontal could result from confounding factors due to the type of cortex, i.e. the anterior cingulate cortex [9] and the lateral population itself (IQ, age, treatment), but also to the prefrontal cortex [10], which are target areas of the ven- intrinsic properties of the ANT task. Indeed, MacLeod tral tegmental dopamine system [11]. During a visual dis- et al. (2010) [32] highlighted different psychometric crimination task with fMRI requiring exploratory eye properties of the ANT that could complicate the results movements, Tsunoda et al [12] showed that the number found: the relative dependence of the three different of fixations correlated with decreased gray matter in right networks measurements, the low reliability of the alert- frontal and parietal structures. Using a diffusion tensor ing and orienting score compared to the executive con- imaging technique, Buchsbaum et al. (1998) [13] found trol scores, and the high intra-individual variability lower diffusion anisotropy in the white matter of the pre- observed in control studies. Lastly, some components of frontal cortex in patients with schizophrenia compared attention could be trait-like (e.g executive control), or to controls. Impairments of attentional processes in schi- state-like (alerting or orienting) explaining the variance zophrenia are heterogeneous; difficulties in disengaging structure of the ANT scores. visuo-spatial attention have been observed in chronic Callejas et al. [33,34] used a modified version of the never-medicated schizophrenics [14], acute naïve patients ANT paradigm to dissociate orienting, alerting, and [15] and relatives of patients [16], as well as in patients executive control and to study their interactions. The treated with typical [17,18] or atypical antipsychotics version of ANT used by Callejas et al. [33,34] is remark- [19]. Abnormal reactivity to warning signals has been able in two important aspects: 1) The presence/absence described as a deficit in the maintenance of an alert state of the non-valid trials: in this version, orienting is mea- in naïve [20] or treated patients [21]. In addition, schizo- sured using a non-predictive cue, with 50% valid vs. 50% phrenics show a marked sensitivity to interference in the invalid cues. The ANT includes only 100% valid cues. 2) Stroop [22] and flanker task [23], or in oculomotor para- Alerting is assessed with an auditoryalerting cue whereas digms such as antisaccade tasks [24], which are consid- a visuo-spatialcue is used in the ANT. The non-predic- ered to represent executive functioning. Moreover, using tive cue allows the activation of an exogenous orienting cerebral imaging techniques, hypoactivity in the anterior system (with the automatic capture of attention by a cingulate cortex has been visualised during a conflict non-informative visual stimulus). In the original ANT, monitoring task [25]. the 100% valid cue condition induced an impure, mixed The Attentional Networks Test (ANT), is a paradigm exogenous and endogenous orientation of attention (exo- designed to examine attentional network efficiencies in genous attention raised by the cue presentation, and orienting attention, alerting, and executive control [26,4]. endogenous attention raised by the always predictive The task is based on the combination of (i) a cued reac- meaning of the cue). Also, in Callejas et al.’s [33] version, tion time (RT) task and (ii) a flanker paradigm which the warning sound stimulus fundamentally differs from evaluates the ability to solve conflicts. ANT studies in the orienting visual stimuli, whereas in the ANT, the patients with schizophrenia have previously yielded alerting and orienting networks are activated by the same inconclusive results: 1) An overall slower RT [27-29]. 2) four types of visual cues. These two differences make the A deficit in executive control was found in a vast majority modified Callejas et al version of ANT [33]suitable for a) of studies [27,28,30,31], while only one study found no measuring the function of each attentional network inde- executive deficit [29]. 3) A deficit in orienting, found in pendently, and b) studying interactions between these some [27] but not all studies [29]. 4) Reduced alertness, networks. In healthy subjects, Callejas et al. [34] found which was correlated to illness duration and medication that the alerting network influences the executive control levels. Tensor diffusion brain imaging indicated that the network by inhibiting its functioning, which is consistent reduction in alertness was correlated to a smaller right with Posner’s proposal (5). Moreover, the alerting net- cingulum bundle volume [29]. However, in many studies work influences the orienting network by speeding up Amado et al. Behavioral and Brain Functions 2011, 7:24 Page 3 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/24 the orienting process. Fuentes et al. [35] showed, using there was some lack of independence among the net- this ANT version in healthy controls, that orienting to works in both tests [36]“. Moreover, cued paradigms the target location in advance enhanced target processing including mixed block design such as the ANT task not speed and reduced conflict. The conjunction of a mixed only induced processes of activation (in generating an positive action on orienting and conflict, suggests that alerting effect for example) but also proactive response alerting improves rather than accelerates the orienting inhibition processes [38]. effect. Ishigami and Klein (2010) [36] stated that the Call- The purpose of our study is to explore (1) whether ejas’ version of ANT “permits the researcher to examine orienting, alerting, or executive control are altered in the interaction among the attentional networks with con- patients with schizophrenia, (2) how the three networks fidence”. Concerning the robustness of the attention net- interact in patients, Both groups of participants were work scores when examining the repeatability of the strictly matched for age, sex and IQ level to minimize ANT and ANT-I tests (Callejas ‘ version), these authors the differences that might exist in general aptitudes. In argued that “despite the learning effect, the two tests pro- line with the majority of studies, we expected executive vided robust index of each attention network”, but “over- control of attention to be impaired in patients, but due all the reliability of the network scores was found to be to our strict matching this difference could not be greater with the ANT-I than the ANT”. found, whereas impairment in alerting or orienting Investigation of the different attentional networks in could be evidenced. Therefore, we administered for the schizophrenia and the modulation of their effects on each first time the Callejas’ version of ANT (2004)[32] to other are of crucial importance. On the one hand, the stable outpatients with schizophrenia and healthy interactions of attentional networks occur constantly in controls. everyday life, suggesting that deficits would have a wide impact. On the other hand, disentangling specific deficits 2. Methods in schizophrenia could provide the basis for new cognitive 2.1. Participants remediation techniques to enhance the attentional abilities Characteristics of the participants are summarized in of patients with schizophrenia. Gooding et al.(2006) [28], table 1. Twenty-one outpatients with chronic schizophre- using the ANT, attempted to analyze the interactions nia (SZ), and 21 healthy controls (C) (15 males in both between different attention networks. They showed that SZ and C) participated in the study. Study procedures both patients with schizophrenia and controls were most were described before participants decided to take part in efficient in resolving conflict when they were alerted and the study and signed their written informed consent. SZ when their orientation was towards the attended spatial and C received 30 Euros for their participation. Study position. Neither Gooding et al. [28] nor Wang et al. [27]’ procedures were approved by the local Ethical Commit- found correlations between the attentional networks. In tee (CCPPRB- Pitié-Salpétriére Hospital, Paris). Partici- Gooding et al. (2006)[28] this was due to the confounding pants were not instructed to restrain their cigarette factor that alerting and orienting cues were both presented consumption before the assessment. However, they were in the visual modality. Fan et al. (2009)[37] recently pro- not allowed to smoke during the session test. vided a revised version of the ANT with the aim of charac- For all subjects, exclusion criteria were: a patent neu- terizing attentional network interactions in healthy rological disease, a history of head trauma, substance volunteers. The authors manipulated the length of the abuse or dependence. All participants were assessed cue-target interval and cue validity (with a no cue, spatial with the Diagnostic interview for Genetic Studies, cue and temporal cue condition) and found that orienting DIGS-III [39], the NSS (neurological soft signs) scale to the target location before the alerting stimulus [40], and the WAIS-R [41]. enhanced target processing and reduced conflict. Never- theless, Gooding et al. (2006)[28] suggested using the Table 1 Demographic and clinical characteristics: values ANT version of Callejas et al. (2004,2005)[33,34], which are expressed as means and standard deviations allows the independent measurement of the three atten- SZ C P tional networks and their interactions. This modified task Gender 15M/6F 15M/6F could, thus, reduce the heterogeneity of the results found Age (years) 31(8) 30(9) 0.76 in schizophrenia using the original ANT paradigm and Years of study 13(2) 13(2) 0.99 highlight the influence of the orienting network on execu- WAIS-R Global 101(14) 105(15) 0.4 tive control in patients with schizophrenia. WAIS-R Perform 95(11) 103(20) 0.2 ANT and its modified version are supposed to explore WAIS-R Verbal 103(18) 106(17) 0.7 attention interactions between alerting, orienting and Handedness 17D/4M 18D/3M 0.5 executive control in a relatively independent way. This D: Dextral; S: Sinistral; M: mixed lateralization notion might be modulated, since it was found “that Amado et al. Behavioral and Brain Functions 2011, 7:24 Page 4 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/24 SZ (DSM-IV criteria)[42] were recruited from the Ambulatory Center of the Parisian 15th arrondissement and the University Department of Psychiatry at Sainte- Anne Hospital, Paris, France. Mean duration of the disease FP =[400- 1600]ms 1 Congruent was 9 (± 6) years. Clinical evaluations were conducted with the PANSS (Positive and Negative Syndrome Scale, 50ms + Incongruent [43]. PANSS scores at the time of neuropsychological test- B) Stimuli 400ms ing were: Total score: mean = 59, SD = 13, Positive sub- score: mean = 12, SD = 4, Negative subscore: mean = 17, 50ms SD = 6. All patients had received stable monotherapy with Trial Duration = 50ms atypical antipsychotics (risperidone < 4 mg, clozapine, olanzapine, amisulpride < 600 mg) for at least three RT < 1700ms months (mean duration: 29 (24) months) prior to investi- 3500 – TR – FP ms gation (equivalent chlorpromazine dosage: 388 mg (207 1 A) Procedure for Experiment mg). No other medication was allowed. Figure 1 Sequence of events appearing on each trial in the C were recruited from our Clinical Research Center, modified version of ANT experiment. Part A shows the actual excluding members of the department, subjects that had sequence of events during the ANT task in our study. Part B shows ever had a DSM-IV axis one disorder, and subjects with examples of the target display in the congruent and incongruent condition. Stimuli: The stimulus used for the orienting signal was an a family history of a psychiatric disorder up to the 2nd asterisk presented at the same location as the target (2.9° of visual degree. None of C had ever received any psychotropic angle above or below the fixation point). For the alerting signal, a medication. 2000 Hz and 50 ms sound was used. Lastly, the target display was made up by a target arrow that could point either to the left or to 2.2. Attentional task (figure 1) the right and four flankers that could be just plain black lines or arrows pointing either left or right. The length of the arrows was 2.2.1. Apparatus 0.55° and they were 0.06° away from each other. Description of the Programming and presentation of stimuli was performed task: In half of the trials, 50 ms before the target an auditory with an Intel-Pentium-4 computer with a 17” color alerting signal was presented (fig1). After a 400 inter-stimulus- screen monitor running E-Prime software. interval (ISI), an orienting cue was presented on 2/3 of the trials 2.2.2. Procedure above or below the fixation point for 50 ms. After another 50 ms ISI the target and flankers were presented either at the same or the Participants were seated 53 cm in front of the computer opposite location than the previous orienting signal for 1700 ms, or screen and instructed to respond to the target stimulus until the participant gave a response. Then the fixation point that (direction of the central arrow), by pressing one of two had been presented during the whole trial was kept for a variable possible keyboard keys using their right or left index fin- duration dependent on the duration of the initial fixation point and ger, depending on the side of the answer. Feedback on the reaction time of the subject so that every trial was same duration (4050 ms). No screen was presented between trials. regarding accuracy was given during practice trials but Consequently, participants did not know when a trial had finished not during experimental trials. and the next one was to begin providing uncertainty about the 2.2.3. Task Design (figure 1) appearance of the signals and increasing their informative value. The experiment had a multivariate mixed design including two levels for the Alerting Signal (presence/absence of a sound) × three levels for the Orienting Cue (No Cue/ Signal) × 2 (Orienting Cue) × 2 (Congruent/Incongru- Valid/Invalid) × two levels for the Executive Control (con- ent) × 2 (Group) mixed ANOVA. Effect size was evalu- gruent/incongruent, see Figure 1) × 2 Groups (SZ/C). ated with eta proportion of the total variance that Altogether, there were 12 different conditions (see Figure attributed to an effect. Different indexes were estab- 1). The practice block (24 trials) proceeded the six experi- lished: an alerting effect (RT difference between the mental blocks of 48 trials each. The whole task included alerting cue and no alerting cue conditions), an orient- 24 trials per condition with a pseudo-random presentation ing effect (RT difference between the valid and invalid within each block. Overall, the duration of the experiment conditions) and a conflict effect (RT difference between took nearly 20 minutes; patients had a pause between each the congruent and incongruent conditions) (33); In each block and decided to start the next block by pressing the group, one way ANOVAs were used for comparison space bar. regarding gender and smoking on these indexes. Pearson correlation coefficients were used to explore associations 2.3. Statistical analyses between clinical, IQ, and index variables. In order to Trials with RTs longer than 2000 ms were eliminated illustrate more precisely the link between symptoms, IQ and the ratio for incorrect responses in each trial was and performance we examined very contrasted groups reported. Median RTs were analyzed with a 2 (Alerting for clinical symptoms and IQ, subdividing the SZ group Amado et al. Behavioral and Brain Functions 2011, 7:24 Page 5 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/24 into two categories (high vs. low score for PANSS and 3.4. Accuracy analysis rd IQ,cut-off:3 quartile of the distribution), and we cal- The ANOVA performed on the percentage of incorrect culated the means of the effect in each category. responses revealed a main effect for the Orienting Cue, [F(1, 40) = 18.41; p < .001], and the Congruent/incon- 3. Results gruent factor, [F(1, 40) = 14.56 p < .001]. The Orienting Cue × Congruent/incongruent interaction was signifi- 3.1. Clinical and demographic data cant, [F(1, 40) = 19.13; p < .0001]. The orienting effect There were more men than women in SZ and C. How- was higher in incongruent than in congruent conditions. ever, there was no significant difference between SZ and In other words, when participants are not spatially C for sex ratio, age, years of study, or IQ (see table 1). oriented, accuracy is worse for the incongruent trials. 3.2. RT analysis (table 2) No group effects were found (Figure 2). RTs exceeding 2000 ms were very few (0.17%) with no dif- ference between patients and controls. The main effects 3.5. Correlations between performance and for the three attentional systems were significant. Trials demographical and clinical data with an auditory alerting signal were faster than those In SZ, in the absence of an alerting signal (no tone con- without one [F(1, 40) = 27.36; p < .001;eta = 0.41]. Partici- dition), the conflict effect was negatively correlated with pants were faster when oriented with valid cues compared WAIS-R performance (r = -.46; p = 0.041). Furthermore, to invalid cues [F(1,40) = 175.31; p < .001; eta =0.81]. SZ with low WAIS-R-performance scores (RT = 750 ms; Finally, participants were faster in congruent trials com- SE = 39 ms) had longer RTs than those with high pared to incongruent ones [F(1,40) = 204.12 p < .001; WAIS-R performance scores (RT = 714 ms; SE = 32 eta = 0.84]. Considering performance between the two ms) in the incongruent condition, whereas there was no groups, the main effect was significant, [F(1,40) = 5.98; p = difference in the congruent condition. .019; eta = 0.13]. SZ were 66.5 ms slower than C. Similarly, in C the conflict effect was negatively corre- Importantly, we observed a significant alerting × lated with years of study (r = -.46; p = 0.041). group interaction, [F (1, 40) = 5.41; p = .025; eta = 0.12] with SZ (mean = 36 ms) showing a greater sensi- 4. Discussion tivity to the auditory alerting cue than C (mean = 14 In accordance with our assumption that the ANT ver- sion of Callejas et al., [33,34] allows differentiation of ms). Finally, the four-way interaction of orienting × the three attentional networks and their interactions, we alerting × control × group was statistically significant, [F obtained the following main experimental results: (1,40) = 6.21; p = .017; eta = 0.13] and other interac- 1) SZ exhibited slower overall RTs than C, tions with group were non-significant (p > 0.25). Partial ANOVAs were conducted to disentangle the 2) SZ displayed a greater alerting effect compared to C. four-way interaction. Separate analyses were conducted 3) In SZ only, an interaction was found between alert- on the four congruent/incongruent × orienting condi- ing and orienting. tions. In the incongruent valid cue condition the 2 In line with studies using the ANT [27-29,31], SZ (Alerting Signal) × 2 (Group) mixed ANOVA showed a were slower than C. In our study, the reported effects significant alerting × group interaction [F (1, 40) = were independent of this general slowing, and remained 13.13; p = .001], indicating that SZ benefited more than significant even when we used proportional RT as a controls from the alerting effect in the incongruent con- dependent variable in a supplementary analysis (median dition when their attention was validly oriented (alerting RT per condition divided by overall median RT, data index in SZ: 66 ms in SZ in C:14 ms) (Figure 2). In not shown). others conditions (incongruent- invalid; congruent-valid; Chronic stabilized outpatients showed a greater alert- congruent-invalid) this interaction was non-significant ing effect using this version of ANT than C. Previous (p > 0.18). studies with ANT have not reported this result and Table 2 Median RT(ms) and percentage of errors (for each experimental condition, for Patients (SZ),) and healthy Controls (C) No Alerting Cue With Alerting Cue invalid No Cue Valid Invalid No Cue Valid SZ Congruent 646 0,90% 656 0,40% 615 0,20% 617 0,40% 589 0,40% 584 0,70% Incongruent 754 4,10% 756 3,30% 716 1,30% 738 4,60% 703 2,80% 650 0,90% C Congruent 568 0,40% 584 0,80% 540 0,20% 561 0,60% 533 0,20% 514 0,20% Incongruent 690 3,10% 662 1,10% 624 1,10% 679 4,00% 640 2,70% 612 1,60% Amado et al. Behavioral and Brain Functions 2011, 7:24 Page 6 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/24 findings may demonstrate a failure of alertness in schizo- phrenia. Recently, in an experimental study concerning the induction of a psychotic-like state in healthy subjects, Daumann et al., 2009 [46], using auditory and visual cue- ing stimuli, found a reduction in alertness after a bolus injection of Dymethyltriptamine, a hallucinogenic drug. Thiel and Fink, (2007)[47] provided evidence in healthy subjects for modality specific correlates of visual and auditory alertness in posterior parietal and frontal brain areas. However, a supramodal region, the right superior Figure 2 comparison of reaction times between patients and temporal gyrus, was commonly involved in visual and controls in incongruent valid conditions in the absence or auditory alertness. This brain region is involved in the presence of an auditory alerting signal. Deviations are indicated behavioural relevance of warning cues [48], and “its acti- by use of median absolute deviation. vation is capable of breaking ongoing activity and opti- mizing responses to following target(s)” [47]. Abnormal superior temporal gyrus volumes have been found in indeed have found unchanged [27,28,31] or reduced schizophrenia [49]. alerting efficiency [29]. This could be due to differences Nevertheless, our attempt to superimpose analyses of in the modality of the alerting stimulus. In Callejas et the effect of valid or invalid trials, or congruent or al.’s version of the ANT [33], the alerting stimulus is incongruent trials provided comparable orienting or auditory, the orienting stimulus is visual. In contrast, alerting and orienting cues are ipsimodal (visual) in conflict effects in SZ and controls. This result contra- prior ANT versions. SZ were slower than C in all no- dicts those studies that suggest an executive control tone conditions, suggesting that their reactivity was rela- deficit [27,28,30,31]. Chronicity, hospitalization, non- tively decreased. The sound cue seemed to enhance stabilization, IQ, and educational level could be con- alertness in patients but their overall RTs remained founding factors. In our study, patients and controls longer than those seen in C. In healthy subjects, Frassi- were strictly matched in years of education and IQ. netti et al. (2002)[44] reported that an auditory stimulus Neuropsychological studies comparing schizophrenic can enhance the detection of masked visual flashes. patients and controls most often reported less educa- Recently, Noesselt et al., (2008)[45] tested an auditory tional achievement in patients, reflecting the impact of enhancement of perceptual sensitivity to visual blinks in the disease [27]. The strict comparison of attentional a two-alternative choice paradigm. They found that a performance by equalizing the confounding IQ and edu- cation features is an original aspect of our study. It pro- crossmodal visuo-auditory cue significantly enhances vides a more stringent comparison of the three detection ability, as if this enhancement increases the attentional networks, highlighting the power of the dif- salience of the visual event. Our results show that ference found in the alerting network. It can also patients are sensitive to this increase in target salience, explain the absence of an executive control deficit found helping them to reduce their RTs. Ishigami and Klein in our patients, by a possible underestimation of the (2010)[36] suggested that the auditory modality of the neuropsychological differences between patients and Callejas’ ANT version [33,34] might generate alertness controls. In our study educational level was negatively more automatically than the visual modality of the ANT correlated with the conflict effect in controls. Moreover, could do. The more automatic alert state induced in we found convergent arguments supporting the relation- this task could help patients more efficiently, opening ship between IQ and executive control: 1) In SZ the fruitful ways to enhance performance in schizophrenia that could be used in cognitive remediation techniques. conflict effect in the no-tone condition was negatively Our results clearly demonstrate a greater sensitivity in correlated with WAIS-R performance. 2) RTs in the patients to auditory alerting stimuli compared to con- incongruent condition differed depending on IQ trols. However, although reaction times when alerted performance. provided a substantial positive effect in patients, it was Lastly, we found an interaction between alerting and not enough for them to reach the performance of healthy orienting in SZ, especially for the incongruent condition. subjects. In other words, even if patients improved their In incongruent trials, in the valid orientation condition, alertness ability with the tone, they still showed lower when there is no auditory alerting signal, SZ benefited reaction times in every condition with an auditory cue. less than controls from the valid orientation; this ten- Nestor et al., (2007)[29] found that a reduction in visual dency being reversed with the presence of the auditory alerting cues correlated with a reduced volume of the alerting cue. In controls, in contrast, the absence or pre- cingulum bundle. These results together with our sence of a valid cue has an equivalent effect whatever Amado et al. Behavioral and Brain Functions 2011, 7:24 Page 7 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/24 the presenceofanauditoryalerting signal. One should useful to see if early alterations of the attentional net- ask whether the effect of a valid spatial cue was reduced works could represent possible stage markers of the in patients owing to the presence of invalid trials. In the disease. present paradigm, valid trials indeed represent 50% of Several limitations of this work can be found. First, the non-neutral trials, as compared to 100% in the ANT the restricted sample size could limit the power of our studies. The auditory alerting cue would then compen- analysis. However, the strict inclusion criteria used to sate for this decreased validity effect. This last point select the participants in our study tend to increase the brings confirmation to the facts that 1) the addition of homogeneity of the two groups. Further studies are war- invalid trials is a main change relative to previous stu- ranted using this version of the ANT with a more dies 2) This study was aimed at clarifying interactions extended group of subjects. Second, the participants in between the orienting and alerting network. If we con- the two groups have high general aptitudes and levels of sider the accuracy analyses, it seems that in both groups education. Even if this selection is mainly due to being invalid and incongruent conditions led to the worst per- recruited through the university, if we consider that not formance. Thus, in patients, the adjunction of a correct all patients suffering from schizophrenia exhibit these orientation and a warning tone enhanced their ability aptitudes, this could constitute a bias in the selection of especially in difficult conditions e.g with incongruent sti- the sample. muli. This finding is in line with the interaction between Concerning the main paradigm ANT, Macleod et al. orienting and alerting in healthy subjects observed by (2010)[32] found a low split-half reliability for the alert- Fuentes et al., (2008)[35] using the Callejas version of ing network in healthy subjects. Nevertheless, we used the ANT [33,34], and Fan et al. (2009)[37] with the here a modified version of ANT more reliable than the modified ANT. Patients seem to extract more benefit version elaborated by Fan et al. (2002)[26,36],. Another than controls from this adjunction of cues. This obser- possible limitation of this work lies in the exploration of vation could bring valuable tools to enhance attention the “interaction” of attentional networks. The concept in in schizophrenia, with a putative application in cognitive itself involves the construction of a mixed block of trials, remediation strategies. including warning, orienting and executive stimuli, with Regarding cognitive remediation in schizophrenia, trials presumed to reflect the different combinations. Van meta-analyses have shown no direct benefit of training der Lubbe et al. [52] showed that the use of a mixed techniques of attention [50,51]. Although not improving block design provides an uncertainty about whether a attentional measures, these techniques could positively warning signal, a cue or a target will appear first. This influence executive dimensions and optimize working situation requires strong executive control to withhold memory, response speed, or visual scanning. Accord- automatic responses to warning signals, cues or incon- ingly, improving the capacity to solve executive conflicts gruent targets. It creates a proactive inhibitory control by reinforcing an alert state in patients or helping them that is released only when a target has been identified. to focus their attention could possibly improve effi- Jaffard et al. (2007)[38] observed that the alerting effect ciency. The results found in this study with the Callejas as assessed with warning signals could be fully con- et al. ‘ version of the ANT [33] provide a way to investi- founded with the behavioural outcomes of proactive inhi- gate attentional networks in schizophrenia. The combi- bition control. Hence there could be confusion between nation of orienting and alerting strategies in attentional an effect of an alerting cue reflecting a true phasic modu- tasks assessing conflict resolution could be adopted rou- lation of arousal, and an alerting effect relying more on tinely in integrative programs of cognitive remediation an executive control mechanism. Boulinguez et al. (2009) therapy. [53] observed that the presentation of a warning signal The results found in this study address the question of involves an important executive control network inhibit- the specificity of these alterations, to determine whether ing the mechanisms underlying movement initiation. A the attentional processing style observed here is likely to network of structures is implicated in the proactive inhi- represent an illness feature, i.e. a consequence of the bition mechanism with a strong involvement of the med- expression of the illness, or a measure of some of the ial prefrontal cortex [54]. This point is of crucial interest aetiological factors of schizophrenia, e.g a cognitive mar- in schizophrenia, where disorders of movement initiation ker of the disease. If the latter, this abnormality could be and impairment of top-down inhibitory control have studied as a putative endophenotype of schizophrenia. been found in orienting [55] as well as in oculomotor Of course, the present design did not allow us to tasks, with frontal structures being strongly implicated address this question but it would be very useful to [56]. All the studies demonstrating this proactive inhibi- study the performance of relatives of patients with schi- tion mechanism have been conducted with visual warn- zophrenia. Also, an exploration of patients with prodro- ing signals. We can speculate whether an auditory mal symptoms or schizotype personalities might be alerting signal also enhances a proactive inhibition Amado et al. Behavioral and Brain Functions 2011, 7:24 Page 8 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/24 3. Fan J, McCandliss BD, Fossella J, Flombaum JI, Posner MI: The activation of mechanism. However, to precisely separate the effect of attentional networks. Neuroimage 2005, 26:471-479. an interaction between alerting, orienting and executive 4. Posner MI, Petersen SE: The attention system of the human brain. Annu attentional networks from an extended executive control Rev Neurosci 1990, 13:25-42. 5. Posner MI, Raichle ME: Images of mind. 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Brain Res Review 2000, 31(2-3):251-269. 12. Tsunoda M, Kawasaki Y, Matsui M, Tonoya Y, Hagino H, Suzuki M, Seto H, This approach could provide fruitful ways of optimizing Kurachi M: Relationship between exploratory eye movements and brain performance in schizophrenic patients in a multitude of morphology in schizophrenia spectrum patients: voxel based cognitive domains. morphometry of three-dimensional magnetic resonance imaging. Eur Arch Psychiatry Clin Neurosci 2005, 255:104-110. 13. Buchsbaum MS, Tang CY, Peled S, Gudbjartsson H, Lu D, Hazlett EA, Downhill J, Haznedar M, Fallon JH, Atlas SW: MRI white matter diffusion List of Abbreviations anisotropy and PET metabolic rate in schizophrenia. Neuroreport 1998, ANT: Attentional Networks Test; C: healthy controls; PANSS: Positive and 9(3):425-30. Negative Syndrome Scale; RT: Reaction Time; SZ: outpatients with 14. Potkin SG, Swanson JM, Urbanchek M, Carreon D, Bravo G: Lateralized schizophrenia; WAIS-R: Wechsler Adult Intelligent scale Revised version deficits in covert shifts of visual attention in chronic and never- medicated schizophrenics compared with normal controls. Schizophr Res Acknowledgements 1989, 2:95. We would like to thank Guy Tiberghien for his help in the elaboration of 15. Amado I, Bourdel MC, Daban C, Poirier MF, Loo H, Bouhours P, Krebs MO: this manuscript. We would like to thank Afsaneh Gray for her help with the Preattentional processes and disorganization in untreated patients in final writing of the manuscript. The study was promoted by Sainte Anne schizophrenia: influence of a 6-week risperidone treatment. Prog Hospital, and financial help was given by the Fédération Hospitalière de Neuropsychopharmacol Biol psychiatry 2009, 33(7):1107-12. France 16. Chirio M, Krebs MO, Waismann R, Vanelle JM, Olié JP, Amado I: Attention and Visual Orienting in siblings, schizophrenic patients, and controls: Author details impairment in attentional disengagement. J Clin Exp Neuropsychol 2009, INSERM, Physiopathologie des Maladies Psychiatriques, U894-7; Centre de 1-6, e-pub. Psychiatrie et Neurosciences Paris, France. University Paris Descartes, Faculty 17. Posner MI, Early TS, Reiman E, Pardo PJ, Dhawan M: Asymmetries in of Medicine Paris Descartes, Service Hospitalo-Universitaire, Hôpital Sainte- hemispheric control of attention in schizophrenia. Arch Gen Psychiatry Anne, Paris, France. University of Granada, Faculty of Psychology, 1988, 45(9):814-21. Department of Experimental Psychology, Granada, Spain. Service de 18. Strauss ME, Novakovic T, Tien AY, Bylsma F, Pearlson GD: Disengagement Psychiatrie, Hôpital Saint Jacques, Nantes, France. University of Humboldt, of attention in schizophrenia. Psychiatry Res 1991, 37(2):139-46. 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Published: Jul 5, 2011

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