Hepatic encephalopathy (HE) is a frequent and severe. Improving the Inhibitory Control Task to Detect Minimal Hepatic Encephalopathy

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1 GASTROENTEROLOGY 2010;139: Improving the Inhibitory Control Task to Detect Minimal Hepatic Encephalopathy PIERO AMODIO,* LORENZO RIDOLA, SAMI SCHIFF,*, SARA MONTAGNESE,* CHIARA PASQUALE, SILVIA NARDELLI, ILARIA PENTASSUGLIO, MARIA TREZZA, CHIARA MARZANO, CRISTIANA FLAIBAN, PAOLO ANGELI,* GIORGIA CONA, PATRIZIA BISIACCHI, ANGELO GATTA,* and OLIVIERO RIGGIO *Department of Clinical and Experimental Medicine, University of Padua, Padua; Unit of Gastroenterology, University of Rome, Rome; IRCCS Ospedale St. Camillo, Venice; and Department of General Psychology, University of Padua, Padua, Italy BACKGROUND & AIMS: Quantification of the number of noninhibited responses (lures) in the inhibitory control task (ICT) has been proposed for the diagnosis of minimal hepatic encephalopathy (MHE). We assessed the efficacy of ICT compared with recommended diagnostic standards. METHODS: We studied patients with cirrhosis and healthy individuals (controls) who underwent the ICT at 2 centers (center A: n 51 patients and 41 controls, center B: n 24 patients and 14 controls). Subjects were evaluated for MHE by psychometric hepatic encephalopathy score (PHES). Patients from center B also were assessed for MHE by critical flicker frequency and spectral electroencephalogram analyses. RESULTS: Patients with cirrhosis had higher ICT lures ( vs , respectively, P.01) and lower ICT target accuracy ( vs , respectively, P.01) compared with controls. However, lures were comparable ( vs , respectively, P.32) among patients with/without altered PHES (center A). There was a reverse, U-shaped relationship between ICT lure and target accuracy; a variable adjusting lures was devised based on target accuracy (weighted lures at center B). This variable differed between patients with and without MHE. The variable weighted lures was then validated from data collected at center A by receiver operator characteristic curve analysis; it discriminated between patients with and without PHES alterations (area under the curve ). However, target accuracy alone was as effective as a stand-alone variable (area under the curve ). CONCLUSIONS: The ICT is not useful for the diagnosis of MHE, unless adjusted by target accuracy. Testing inhibition (lures) does not seem to be superior to testing attention (target accuracy) for the detection of MHE. Keywords: Electroencephalogram; EEG; Attention; Inhibition. Hepatic encephalopathy (HE) is a frequent and severe complication of cirrhosis characterized by a wide spectrum of neuropsychiatric changes and alterations in neuromuscular function. The milder form of HE, which is detectable by psychometric or neurophysiologic testing in patients who appear clinically normal, is labeled as minimal hepatic encephalopathy (MHE). 1 3 MHE might affect from 20% to 60% of patients with cirrhosis, depending on the tests used for its diagnosis and the severity of hepatic failure. 4,5 MHE impinges on the health-related quality of life, 6 8 and it is likely to affect driving ability 9 13 of these individuals. It has a negative prognostic value in relation to the occurrence of both bouts of overt hepatic encephalopathy and death. 16,18 The cognitive profile of MHE is characterized by a peculiar kind of mild cognitive impairment 19 regarding selective attention and executive functions, visuomotor ability, psychomotor speed, response inhibition, and response selection, 3,17,20 25 MHE also causes brain dysfunction detectable by the slowing of the electroencephalogram (EEG), 26,27 prolonged cognitive evoked potentials, 27,28 reduced ability to detect light flickering, 18,29 and reduced eye pursuit control. 30 Therefore, where possible, the diagnosis of MHE is preferably based on a combination of psychometric and neurophysiologic/psychophysiologic tools. Nonetheless, cognitive investigation is the simplest and most widely used way of diagnosing MHE, and the psychometric hepatic encephalopathy score, a paper-andpencil test battery, is one of the preferred tools to this aim. 31 However, its administration requires dedicated, competent personnel, and normative data are available for a limited number of European countries only. 18,32 34 The inhibitory control task (ICT), a computerized psychometric test, has been recently proposed as a simple diagnostic tool for MHE. 20,35 ICT evaluates both sustained attention and the ability to inhibit responses to potentially relevant stimuli during a stressful working memory updating condition. Working memory impair- Abbreviations used in this paper: CFF, critical flicker frequency; EEG, electroencephalogram; ICT, inhibitory control task; HE, hepatic encephalopathy; LTT, line tracing test; MHE, minimal hepatic encephalopathy; PHES, psychometric hepatic encephalopathy score; ROC, receiving operative curves; TMT, trail making test; WL, weighted lures by the AGA Institute /$36.00 doi: /j.gastro

2 August 2010 ICT AND MINIMAL HEPATIC ENCEPHALOPATHY 511 Table 1. Demographic Variables and ICT Measures in Controls and Patients With Cirrhosis in Study Centers A and B Center A (Rome) Center B (Padua) Controls (n 41) Patients with cirrhosis (n 51) Controls (n 14) Patients with cirrhosis (n 24) Age (y) a Sex (males, %) Education (y) a a Etiology of cirrhosis (virus/alcohol/other) (%) 66/20/14 55/40/5 Child-Pugh class (A/B/C) (%) 33/47/20 21/57/22 ICT target accuracy a a Reaction times to ICT targets (ms) ICT lures (number failed inhibitions out of 40) a Reaction times to ICT lures (ms) ICT, inhibitory control task. a P.05 patients with cirrhosis vs controls. ment had been previously shown to be a feature of MHE. 17,36 During the ICT, a continuous stream of letters are presented one after the other. Subjects are invited to pay attention only to the letters X and Y, and their task ( go task ) is to press a button every time X and Y are alternated (called targets), independently of the irrelevant letters presented between them. In contrast, subjects must refrain from responding (ie, inhibit the response; viz, no-go task ) when the 2 identical target letters are consecutively presented (called lures). 37 A cut off of 5 lures (ie, noninhibited responses) has been claimed to discriminate patients with/without MHE with 88% sensitivity and 77% specificity compared with formal neuropsychologic testing. 20 Thus, ICT seems to be a promising tool for the diagnosis of MHE. However, its applicability to different populations of patients with cirrhosis and its relation to other measures of MHE needs to be confirmed. The aim of the present study was to assess the specificity and sensitivity of ICT for the diagnosis of MHE. Materials and Methods Seventy-five patients with cirrhosis and 55 healthy controls were studied in 2 reference centers for the study of hepatic encephalopathy: the Gastroenterology Unit of the University Hospital Umberto I of Rome, Italy (center A), and the 5th Clinical Medicine Unit of the University Hospital of Padua, Padua, Italy (center B). Subjects from center A were used to assess the specificity/sensibility of ICT for the diagnosis of MHE and to evaluate the test-retest reliability, as well as the influence of age and education (pooled with normal subjects from center B). The same individuals were used to validate a model for optimizing ICT interpretation devised in center B. Subjects from center B were used for in-depth analysis of both ICT errors and reaction times as well as their relationship with other objective measures of brain dysfunction useful for the diagnosis of MHE: EEG spectral analysis 38 and critical flicker frequency (CFF). 29 They were also used to produce a novel model for interpretation of the ICT outcome results. Patients with cirrhosis from both centers were enrolled consecutively, whereas healthy controls came from convenience samples of volunteers. The main clinical and demographic features of the study populations are presented in Table 1. The diagnosis of cirrhosis was based on case history; clinical examination; biochemical, endoscopic, and ultrasound findings; or, when needed, on liver biopsy. The diagnostic criteria were as follows: the presence of hepatic stigmata on routine clinical examination, together with biochemical indices of decompensated liver disease (low serum albumin, high bilirubin, prolonged prothrombin time, low platelet count), endoscopic or ultrasound signs of portal hypertension, or a history of previous decompensation (ascites, jaundice, bleeding from esophageal varices). The exclusion criteria were as follows: chronic obstructive lung disease/respiratory failure of other origin, renal failure (creatinine plasma level 200 mol/l), coronary heart disease or heart failure of any origin (New York Heart Association 1), significant neurologic/psychiatric disease, overt HE or bouts of over HE within 15 days prior to the study, bleeding or infections within 15 days prior to the study, as well as psychoactive medication (benzodiazepines, antidepressant, neuroleptic drugs), active alcohol misuse, or unwillingness/inability to undergo the study procedures. Out of the enrolled patients, 15 in group A and 11 in group B had had previous bouts of overt hepatic encephalopathy, according to the West Haven criteria ( 15 days before the study). The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the local ethics and the research committees.

3 512 AMODIO ET AL GASTROENTEROLOGY Vol. 139, No. 2 Psychometric Assessment All patients underwent the psychometric hepatic encephalopathy score (PHES) that is obtained by a battery of psychometric tests aimed at the diagnosis of HE: the trail making test part A (TMT-A), the trail making test part B (TMT-B), the digit symbol test, the serial dotting test, and the line tracing test (LTT). 3,34 Each test was scored against age and education adjusted norms. 32 The PHES is the sum of the integer scores of each test computed from the adjusted Z values as follows: score 3 for Z 3, score 2 for 3 Z 2, score 1 for 2 Z 1, score 0 for 1 Z 1, score 1 for Z 1. In our standardization, PHES is altered if its value The ICT was administered immediately after the PHES. Two software tools for ICT assessment were used, both kindly provided by Dr. Jasmohan Bajaj, who proposed ICT for the diagnosis of MHE. 20 Both tools consist of the same go, no-go task that is based on the presentation of several letters at 500-ms intervals (Supplementary Figure 1). Interspersed within the other letters are the letters X and Y. During the initial part of the test, the subject is instructed to respond (pressing the space bar of the computer keyboard) to every X and Y ( primed response to target letters). During the second part of the test, the subject is instructed to respond only when X and Y are alternating (ie, targets of the go task ) and to refrain from responding when X and Y are not alternating (ie, lures of the no-go task ). In other words, the subject is instructed to respond only if an X is preceded by a Y or a Y is preceded by an X. Responses must be inhibited if an X is preceded by an X or a Y preceded by a Y ( lures ); for this section, both failures to respond to targets and failures to inhibit responses to lures (lures) are qualified as errors (omission and commission errors). After a practice run, 5 test runs of approximately 2 minutes each were administered for a total of 40 lures, 212 targets, and 1728 random letters in between. At the end of the test, both the number of lures and target accuracy (ratio of the correct responses over the total number of presented targets) were automatically calculated. The software tool adopted in center B also allowed the reaction times to be recorded for each task condition and for each trial because it worked into ad hoc experimental software (E-Prime; Psychological Software Tools, Pittsburgh, PA) so that all the measures provided by preceding publications 20 could be reproduced. The psychometric evaluation and the ICT were performed in a quiet room without distracting noises. Test-Retest Reliability A subgroup of 33 controls and 36 patients from center A agreed to undergo ICT for a second time within 7 days after the first evaluation, to assess test-retest reliability. None of the patients experienced changes in neuropsychiatric status, developed other complications of cirrhosis, or underwent significant modifications of their treatment regime in between repeat tests. CFF Measurement In center B, patients underwent CFF measurement in a quiet, semidarkened room without distracting noises. A portable, battery-powered analyzer was used (Hepatonorm Analyzer; R&R Medi Business Freiburg GmbH, Freiburg, Germany). The analyzer evokes an intrafoveal light stimulus with defined pulses of light at a wavelength of 650 nm, luminance of 270 cd/m 2, and luminous intensity of 5.3 mcd, ie 1/1000 of a candela. The frequency of the red light, which is initially generated as a high-frequency pulse (60 Hz) and which gives the patient the impression of a steady light, was reduced gradually until the patient had the impression that the steady light has changed into a flicker. The patient registers this change by pressing a hand-held switch. After a practice run, the test was repeated 5 times and an average value obtained; this was qualified as abnormal if 39 Hz. 29 EEG Assessment In center B, patients underwent recording of spontaneous, awake, eye-closed EEG activity by digital EEG equipment (Brainquick 3200; Micromed, Mogliano Veneto, Italy) in the morning, generally after breakfast. A standard 21-channel cup (Micromed) was used, and the electrodes placed according to the international system. 39 The ground was placed on Fpz (midline frontal derivation), the reference on Oz (midline occipital derivation). Impedance was kept under 5 k. Each channel had its own analogue-to-digital converter, and signals were digitally filtered in the range of Hz. The sampling frequency was 256 Hz, the conversion resolution was 0.19 mv/digit. Attention was paid to avoid somnolence and artefacts. After a visual inspection to exclude artefacts, the EEG tracing was assessed by spectral analysis based on fast Fourier transform. 40 This was carried out on the derivation P3-P4 in the frequency range of Hz, as previously described. 16,38 The variables considered for EEG evaluation were the mean dominant frequency (MDF, an estimate of the background frequency of the EEG) and the relative amount of slow EEG activity within the and frequency bands. 1,38 Statistical Analysis Results are presented as mean SD. Comparisons among the groups were performed by analysis of variance ANOVA (post hoc: Tukey test) or Student t test for unpaired or paired data, as appropriate. Based on the available published data on ICT lures, 20 the number of subjects (controls vs experimental patients) required to give a protection of 0.95 (probability type I error 0.05) and a power of 0.80 (probability type II error 0.20) is 38.

4 August 2010 ICT AND MINIMAL HEPATIC ENCEPHALOPATHY 513 was found to be independent of both education level and age. Figure 1. Lures in control subjects by degree of education (rhomboid, mean; bar, 95% confidence interval). Differences in proportions were tested by 2 test. The correlations between variable were analyzed by means of Pearson s correlation or Spearman s rank correlation, as appropriate. The sensitivity and specificity of ICT lures and ICT target accuracy was calculated by the receiving operative curves (ROC). The Number Cruncher Statistical System software (NCSS, Kaysville, UT, 2007) and the Statistica 7.1 (Stat Soft Italia srl; Vigonza, Italia, 2005) software programs were used. ICT: Comparison Between Patients With and Without Abnormal PHES In center A, 20 patients had normal PHES performance, whereas the remaining 31 had abnormal PHES (ie, the acknowledged criterion for the psychometrical diagnosis of MHE 31 ). Patients with abnormal PHES had lower target accuracy compared with those with normal PHES ( vs , respectively, P.01). In contrast, lures were comparable between the 2 groups ( vs , respectively, P values nonsignificant) (Supplementary Table 1). ICT: Test-Retest Reliability Patients with cirrhosis showed a reduction of lures in the second evaluation compared with the first ( vs , respectively, P.05) but not of target accuracy ( vs , respectively, P values nonsignificant). In contrast, control subjects did not show any relevant change either in lures (11.5 7vs13 5.6, respectively, P values nonsignificant) or target accuracy ( vs , respectively, P values nonsignificant) (Supplementary Table 2). ICT: Insight Into the Task In center B, a U-shaped relationship between target accuracy and lures was shown in patients with cirrhosis (Figure 2). Therefore, in individuals who were unable to Results ICT: Comparison Between Patients With Cirrhosis and Controls ICT target accuracy was lower in patients with cirrhosis compared with controls, whereas ICT lures were higher (Table 1). Reaction times to both target and lures were more prolonged in patients with cirrhosis compared with controls, although the difference did not reach statistical significance (Table 1). ICT: Relationship With Age and Education Target accuracy was comparable in control subjects from center A and B, whereas lure responses were higher in control subjects from center A. However, the difference was abolished once education was included as covariate (F 1, , P.50). Having verified that ICT measures were comparable in control subjects from center A and B, these were pooled together to assess the potential confounding effect of age and education. Lures were influenced by education level (F 2, , P.01; Figure 1), but they appeared to be independent of age (r 0.13, P.35). Target accuracy Figure 2. Plot of target accuracy vs lures in the patients with cirrhosis and controls (center B). In a subgroup of patients with cirrhosis (outside the rectangle), ICT performance is different from that of controls (inside the rectangle). A reversed U-shape relationship (panel on the left) was detected between lures and target accuracy in patients with cirrhosis. If target accuracy was low, the estimation of lures is meaningless. Note: the curve is computed by mean square technique with negative exponentials.

5 514 AMODIO ET AL GASTROENTEROLOGY Vol. 139, No. 2 Table 2. Matrix of Correlation Coefficients Between ICT Outcome Measures and Other Measures of Brain Dysfunction in Patients With Cirrhosis From Center B Target accuracy Target reaction time Lures Lure reaction time Weighted lures Psychometric measures TMT-A 0.48 a TMT-B 0.69 a a a DST 0.55 a a SDT 0.51 a LTT PHES 0.57 a Spectral EEG measures MDF (%) (%) a 0.62 a 0.35 (%) a 0.17 (%) CFF NOTE. Other measures of brain dysfunction are paper and pencil psychometric tests, EEG, and CFF. TMT-A, trail making test part A; TMT-B, trail making test part B; DST, digit symbol test; SDT, serial dotting test; LTT, line tracing test; PHES, psychometric hepatic encephalopathy score; MDF, mean dominant frequency; CFF, critical flicker frequency. a P.05. reach target accuracy, the information provided by lures was found to be substantially meaningless (ie, if the subject cannot develop sufficient sustained attention to respond to targets accurately, his/her inhibition ability can paradoxically appear elevated). This was further supported by the absence of a relationship between lures and the PHES (R 0.16, P.42), the EEG mean dominant frequency (R 0.20, P.37), or the CFF (R 0.18, P.35). The importance of target accuracy for ICT interpretation was also supported by the relationship of target accuracy with PHES and its component tests (Table 2). Only the reaction time of lures was found to be related to another measure of brain function: the relative power of activity of the EEG (Table 2). The above results made it obvious that adequate interpretation of the lures had to take into account target accuracy. Therefore, a new variable adjusting lures by target accuracy (weighted lures: WL) was calculated as follows: WL 24 and target accuracy 0.75 appeared to be reasonable cut-off values (Figure 3 and Supplementary Figure 2). Testing the Model in an Independent Sample The model devised in center B was applied to patients and controls from center A. ROC curves were calculated for ICT target accuracy, lure responses, and WL (Figure 4). WL provided a sensitivity/specificity profile, which was better than that of lures, but not superior to that of target accuracy in discriminating patients with cirrhosis with/without PHES alteration (Figure 4). The WL L/ TA 2 where WL: weighted lure L: number of lures (failed inhibition of response; ie, commission errors) TA: target accuracy WL was found to be related to some of the PHES tests, taken as stand-alone variables (Table 2). WL proved to be more useful than lure responses in discriminating controls from the patients with cirrhosis with/without MHE resulting from extensive investigation (altered PHES, spectral EEG or CFF) (Figure 3). Target accuracy was the only other ICT measure that proved both good correlation with cognitive performance and discriminating value (Table 2). On visual analysis, Figure 3. Lures and weighted lures (WL) in controls and patients with cirrhosis without and with MHE (abnormal PHES, EEG, or CFF; center B). Note: Small box, median; large box, 25th 75th percentile; bar, minimum-maximal interval without outliers.

6 August 2010 ICT AND MINIMAL HEPATIC ENCEPHALOPATHY 515 Figure 4. ROC curves for responses to lures (left), weighted lures WL (middle), and target accuracy (right). Sensitivity and specificity are calculated in relation to the presence of PHES alteration. Note: AUC, area under the curve. best discriminating values estimated on the basis of the ROC curves are reported in Table 3. Similarly to lure responses, WL were found to be independent of age and influenced by education levels (F 2,51 7.2, P.01): the individuals with 8 years of education had about 6 points more than the ones with at least 13 years of education (18 6vs12 6, respectively, P.05). Nonetheless, even adjusting for education, the sensitivity/specificity profile of the test did not change. Compared with the patients who had not experienced bouts of overt HE in the past, the patients who had had bouts of overt HE showed a trend, albeit not significant, for lower PHES ( vs , respectively, P values nonsignificant), target accuracy ( vs , respectively, P values nonsignificant), and higher WL ( vs , respectively, P values nonsignificant) but not higher even lower lures ( vs , respectively). Compared with the patients with nonalcoholic cirrhosis, the patients with alcoholic cirrhosis did not differ for target accuracy ( vs , P values nonsignificant) or lures ( vs , P values nonsignificant), as well as WL ( vs , P values nonsignificant). Age, education level, and severity of liver disease did not differ between patients with or without alcoholic cirrhosis. Table 3. Prevalence of Individuals With Abnormal Weighted Lures and Target Accuracy at Different Thresholds Obtained From ROC Curve Analysis Controls (%) Patients with cirrhosis (%) PHES normal a PHES abnormal Weighted lures Weighted lures L Target accuracy Target accuracy NOTE. The thresholds were selected by visual inspection. a PHES is the acknowledged psychometrical tool for the diagnosis of MHE; therefore, PHES normal no MHE, and PHES abnormal MHE. Discussion In the present study, the number of ICT lures, ie, a measure of the inhibition ability, was shown to depend on target accuracy, which reflects attention ability. Accordingly, the number of lures as a stand-alone variable was found not to be adequate for discriminating controls from patients with cirrhosis who have PHES alteration. In contrast, ICT target accuracy as a stand-alone and lures weighted by target accuracy, a newly devised measurement method, were shown to have a better discriminating value, even if the agreement with PHES was found to be limited. The detection of MHE is a relevant health issue because of the impact that it has on quality of life and driving ability. 9,13 Among the psychometric tools to diagnose MHE by mere cognitive investigation, PHES is considered to be the preferable one, at least in the countries where this battery is standardized. 31 However, the use of classical psychometric batteries, such as PHES, in a clinical setting may be problematic in countries where psychometric tests can only be administered by qualified personnel. For this reason, the use of a computerized test directed towards the study of the cognitive domains that are impaired from the onset of HE is interesting. Computerized tests are generally based on the repetition of a great number of trials; therefore, if the instructions are well understood, the results produced are reasonably more precise than those of paper and pencil tests. The ICT, 20,35 together with the scan test 17,36 and possibly the cognitive drug research battery, 41 are the only computerized tests that have been expressly applied to patients with cirrhosis, based on known cognitive features of MHE. In our study, the ICT test was performed in 2 reference centers for the study of HE using 2 comparable software tools. The tool adopted in center B works within a specific framework for accurate neuropsychologic investigation (E-Prime) that ensures complete control of all the experimental conditions. Moreover, in center B, the ICT,

7 516 AMODIO ET AL GASTROENTEROLOGY Vol. 139, No. 2 as well other cognitive investigation methods, was performed by expert neuropsychologists (S.S. and G.C.), whereas, in center A, the tests were performed by clinicians. Despite these differences, the ICT measures were comparable in the 2 centers. This finding provides evidence of good accuracy of the ICT measurements in our study. The finding that ICT measurements showed a relationship mainly with TMT-B but no relationship with LTT is easily explained by the fact that both ICT and TMT-B reflect prefrontal and right parietal functions, 42,43 whereas LTT reflects motor functions. This can also explain the lack of a relationship with CFF, which is a psychophysical measurement. The relationship of lures and their reaction times with EEG dynamics is in line with the idea that lures have an objective relationship with brain dysfunction, even if the relationship between ICT and neurophysiologic dynamics requires further ad hoc investigation. However, the results did not fit completely with the report originally published by Bajaj et al, 20 whose controls had quicker reaction times to both targets detection and lures than ours ( vs ms and vs ms, respectively), as well as lower lure responses (3 2vs12 6, respectively). In contrast, target accuracy was comparable ( vs , respectively). Neither age nor education can explain the difference between the Italian and the United States controls because they were comparable. A possible explanation for this unexpected finding is that US controls might have been more familiar with computer use and games. This hypothesis is also supported by the fact that a trend for a lower attitude in performing the ICT test in Italian citizens compared with the US citizens is also supported by the same worse ICT performance in the Italian patients with cirrhosis compared with the US patients. This finding indicates the need for standardization of the ICT in different populations. In agreement with Bajaj et al, 20 ICT performance was comparable in patients with alcoholic cirrhosis compared with those with nonalcoholic cirrhosis. The detection of a U-shaped relationship between target accuracy (attention) and lures (inhibition) suggests that testing inhibition in the context of insufficient attention produces unreliable results. This phenomenon can explain why lures did not differ between patients with/ without PHES abnormalities and consequently justify their poor ROC curve profile. The newly devised variable WL (lures weighted by target accuracy) proved to be useful. WL allows us to evaluate inhibition ability based on each individual s attention ability. The value of WR measurement was supported by a ROC curve profile that was clearly better than that of lures. However, even WL did not prove to be better than target accuracy, as a simple measure of attention. This is in agreement with previous studies 17,22,25 proving that selective attention and working memory tasks within a context of time pressure are very good psychometric tools to detect MHE. A further clue supporting the use of WL was the finding that patients who had had previous bouts of overt HE performed lower lures but higher WL than the patients without a history of previous overt HE but showed a trend for lower psychometric performance on PHES and target accuracy. Additional findings obtained from our study were the sensitivity of lures and WLR to education level, supporting, yet again, the need for standardization to obtain a correct interpretation of test results. In addition, a trend was also observed for a learning effect, at least in the patients with cirrhosis. The absence of learning effect in control subjects can be explained by the ceiling effect because normal subjects with normal performance might simply not be in a position to improve their performance any further. A limitation of our study was the small but significant higher education and lower age of controls compared with patients with cirrhosis. However, because these variations could have only improved ICT performance in controls, its diagnostic power might have been, if anything, slightly overestimated, which would not affect the study conclusion. In conclusion, the present study proves that (1) the ICT provides cognitive measures that are related, albeit only roughly, to recommended diagnostic standards for cognitive investigation of MHE; (2) the ICT, like most psychometric tools, is influenced by demographic variables and exhibits some learning effect; (3) the value of the ICT outcome lures (inhibition ability) becomes more valuable if it is adjusted by target accuracy (attention ability); (4) testing for attention is as important as testing for inhibition to diagnose cognitive dysfunction in patients with cirrhosis. Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at and at doi: /j.gastro References 1. Ferenci P, Lockwood A, Mullen K, et al. 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9 518 AMODIO ET AL GASTROENTEROLOGY Vol. 139, No Ford JM, Gray M, Whitfield SL, et al. Acquiring and inhibiting prepotent responses in schizophrenia. Event-related brain potentials and functional magnetic resonance imaging. Arch Gen Psychiatry 2004;61: Lezac MD, Howieson DB, Loring DW, et al. Nuropsychological assessment. 4th ed. New York: Oxford University Press, Received December 31, Accepted April 29, Reprint requests Address requests for reprints to: Piero Amodio, MD, Department of Clinical and Experimental Medicine, Via Giustiniani No. 2, Padova, Italy. piero.amodio@unipd.it; fax (39) Acknowledgments The study was carried on under the auspices of CIRMANMEC University of Padua, Padua, Italy. Piero Amodio and Oliviero Riggio participated to an equal extent in planning, analyzing, evaluating, and writing the paper. Conflicts of interest The authors disclose no conflicts. Funding Supported by grants of the University of Padua (to P.A.) and of the University of Rome (to O.R.) and by a Young Investigator Award given (to L.R.) by the Italian Society of Gastroenterology (SIGE).

10 August 2010 ICT AND MINIMAL HEPATIC ENCEPHALOPATHY 518.e1 Supplementary Figure 1. Schematic example of the ICT: sequence of letters are displayed on the computer screen; each letter is displayed 500 ms in the center of the screen. The letters X and Y are interspersed within irrelevant letters. The subject is instructed to respond only if an X is preceded byayorayispreceded by an X (target); responses must be inhibited if an X is preceded by an X or a Y preceded by a Y (missed inhibition are called lures ). Supplementary Table 1. Comparison Between Patients With and Without Altered PHES Normal PHES (n 20) Altered PHES (n 31) Age (y) a Sex (M/F) 13/7 20/11 Education (y) a Child Pugh class (A/B/C) (%) 45/35/20 26/55/19 ICT target accuracy a ICT lures (number failed inhibitions out of 40) ICT, inhibitory control task. a P.01.

11 518.e2 AMODIO ET AL GASTROENTEROLOGY Vol. 139, No. 2 Supplementary Table 2. Test-Retest Reliability Controls (n 33) Patients with cirrhosis (n 36) First evaluation Second evaluation First evaluation Second evaluation ICT target accuracy ICT lures (number failed inhibitions out of 40) a ICT, inhibitory control task. a P.05. 1,1 1,0 0,9 Target accuracy 0,8 0,7 0,6 0,5 0,4 0,3 controls without MHE with MHE Supplementary Figure 2. Target accuracy in controls and patients with cirrhosis without and with MHE (abnormal psychometric hepatic encephalopathy score, electroencephalogram, or critical flicker frequency; center B). Small box, median; large box, 25th 75th percentile; bar, minimum-maximal interval without outliers. MHE, minimal hepatic encephalopathy.