Sami Schiff

Improving the Inhibitory Control Task to Detect Minimal Hepatic Encephalopathy

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 (23.2+/-12.8 vs 12.9+/-5.8, respectively, P<.01) and lower ICT target accuracy (0.88+/-0.17 vs 0.96+/-0.03, respectively, P<.01) compared with controls. However, lures were comparable (25.2+/-12.5 vs 21.4+/-13.9, 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=0.71+/-0.07). However, target accuracy alone was as effective as a stand-alone variable (area under the curve=0.81+/-0.06). 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.

The role of dual-task and task-switch in prospective memory: Behavioural data and neural correlates

Event-based prospective memory (PM) requires remembering the delayed execution of an intended action in response to a pre-specified PM cue while being actively engaged in an ongoing task in which the cue is embedded. To date, experimental paradigms vary as to whether or not they require participants immediately to stop working on the ongoing task whenever they encounter a PM event (cue) and directly switch to the prospective action (task-switch approach). Alternatively, several other paradigms used in the literature encourage participants to continue working on the ongoing task item after the cue, and only then, perform the prospective action (dual-task approach). The present study explores the possible behavioural and electrophysiological effects that both approaches may have on PM performance. Seventeen young adults performed both versions of a standard PM task in a counterbalanced order during which behavioural data and electroencephalogram (EEG) were recorded. Behavioural data showed a decrement in PM performance in the task-switch compared to the dual-task condition. In addition, EEG data revealed differences between the dual-task and task-switch approach in event-related potential (ERP) components associated with response inhibition and with post-retrieval monitoring (i.e. late positive complex). No differences between the two tasks were found with regard to the PM event detection processes (i.e. N300) and the retrieval of the intended action from long-term memory. In sum, findings demonstrate that it does make a difference which task approach is applied and suggest that dual-task and task-switch paradigms may result in different processing and neurophysiological dynamics particularly concerning attentional resources and cognitive control.

The effect of aging on auditory components of event-related brain potentials.

OBJECTIVE To describe auditory perceptual, pre-attentive, attention-related and cognitive processes along lifespan in normal people by a simple auditory oddball paradigm easily usable in clinical practice. METHODS ERPs were recorded in 72 normal subjects. Four blocks of tones were delivered (20% rare 2,000 Hz and 80% frequent 1,000 Hz). In the former two blocks, subjects performed a concomitant distracting visual search task (distracted condition); in the latter two blocks, they had to attend the occurrence of the rare tones (active condition). Latency and amplitude of ERPs were analyzed according to age, gender, educational level and repetition. RESULTS N100 amplitude was greater in active than in distracted condition. MMN amplitude decreased with age. N2b and P300 latencies increased with age, while their amplitudes decreased. Females produced greater P300 than males. In the elderly, P300 latency was found to be longer in the second block than in the first one. CONCLUSIONS N100 and MMN were found to be less affected by age than N2b and P300. When repeated, P300 showed increased latency in elderly subjects. SIGNIFICANCE The protocol detected the higher influence of aging on late cognitive processes than on the perceptual and pre-attentive ones. Age-adjusted normative data were produced.

Attention Dysfunction in Cirrhotic Patients: An Inquiry on the Role of Executive Control, Attention Orienting and Focusing

Attention alterations are reported in cirrhotics. Aiming at clarifying attention functioning in cirrhotics, an inquiry on the functioning of the anterior (AAS) and the posterior (PAS) attention system was performed. Thirty-six cirrhotics without overt hepatic encephalopathy (24 with EEG or TMT-A alterations) and 16 matched control subjects were enrolled. The AAS was studied by the Stroop task measuring selective attention control, the PAS was studied by the Posner task and the Focus task measuring automatic covert orienting and visual focusing of attention respectively.Cirrhotics presented a task-dependent psychomotor slowing (Stroop > Posner > Focus) with an increased percentage of errors in the incongruent condition of the Stroop task [F(1, 57) = 4.9, p < 0.03]. Class C patients had both a selective slowing [F(1, 33) = 4.3, p < 0.05] and an increased percentage of errors in the incongruent condition [F(1, 34) = 5.1, p < 0.05] compared to Class A–B patients and controls. The patients with an altered EEG performed the Stroop test significantly slowly than those without EEG alterations [F(1, 41) = 8.9, p < 0.01] and with a clear trend for a higher number of errors in the incongruent condition [F(1, 39) = 3.8, p < 0.06]. In contrast, attention orienting and focusing were maintained. In conclusion, the AAS is more sensitive than the PAS to the early stages of hepatic encephalopathy.

Different biochemical correlates for different neuropsychiatric abnormalities in patients with cirrhosis.

The diagnosis of hepatic encephalopathy (HE) relies on clinical, neurophysiological, psychometric and laboratory variables. The relationships between such tests remain debated. The aim of this study was to determine the laboratory correlates/prognostic value of neurophysiological/psychometric abnormalities in patients with cirrhosis. Seventy‐two patients and 14 healthy volunteers underwent EEG and paper‐and‐pencil psychometry (PHES). Blood was obtained for C reactive protein (CRP), interleukin 6 (IL6), tumor necrosis factor (TNF)α, ammonia and indole/oxindole. Patients were followed prospectively for a median of 22 months in relation to the occurrence of death, transplantation and HE‐related hospitalizations. Thirty‐three patients had normal PHES and EEG, 6 had abnormal PHES, 18 abnormal EEG and 13 abnormal PHES and EEG. Patients with abnormal PHES had higher CRP (17 ± 22 vs 7 ± 6, P < 0.01), IL6 (32 ± 54 vs 12 ± 13, P < 0.05) and TNFα (17 ± 8 vs 11 ± 7, P < 0.001) levels than those with normal PHES. Patients with abnormal EEG had higher indole (430 ± 270 vs 258 ± 255, P < 0.01) and ammonia (66 ± 35 vs 45 ± 27, P < 0.05) levels than those with normal EEG. Psychometric test scores showed significant correlations with CRP, TNFα and IL6; EEG indices with ammonia and IL6. CRP and TNFα concentrations were independent predictors of abnormal PHES, ammonia and indole of abnormal EEG on multivariate analysis. Seven patients were lost to follow‐up; of the remaining 65, 20 died and 14 underwent transplantation; 15 developed HE requiring hospitalization. PHES and EEG performance were independent predictors of HE and death (P < 0.05). Conclusion: PHES and EEG abnormalities in patients with cirrhosis have partially different biochemical correlates and independently predict outcome. (HEPATOLOGY 2011;53:558‐566)

Electroencephalography in Patients With Cirrhosis

BACKGROUND & AIMS Electroencephalography has not been completely quantified in patients with cirrhosis. We investigated the electroencephalogram (EEG) dynamics in patients with cirrhosis. METHODS We performed closed-eye EEGs on 175 patients with cirrhosis (age, 55 ± 11 years; 24% Child-Pugh class A, 48% class B, and 285 class C), conducted clinical and psychometric assessments for hepatic encephalopathy (HE), and followed the patients for 1 year. EEG characteristics were assessed in the frequency domain, in the frontal (F3-F4) and parietal (P3-P4) derivations. Intrahemispheric (frontoparietal, right, and left) and interhemispheric (F3-F4 and P3-P4) coherence were computed. The EEGs of 50 healthy volunteers (age, 56 ± 17 years) served as controls. RESULTS Compared with controls, the EEGs of patients with cirrhosis had a reduced frequency in the posterior derivations (P3/P4 mean dominant frequency, 9.1 ± 1.8 and 8.9 ± 1.7 Hz vs 10.4 ± 1.3 and 10.2 ± 1.3 Hz, respectively; P < .01) and an increase in interhemispheric parietal relative coherence within the theta band (22.3% ± 5.5% vs 18.9% ± 3.5%; P < .01). These features were more prominent in patients with Child class C and in patients with a history of overt HE; they correlated with hyperammonemia and hyponatremia. The decrease in EEG frequency, along with the increase in interhemispheric theta coherence in the posterior derivations, was inversely associated with survival and the occurrence of overt HE during the follow-up period. CONCLUSIONS In patients with cirrhosis, alterations in the EEG were significantly associated with the severity of liver disease and HE; the EEG might be used in determining prognosis.

Neurophysiological correlates of post-hypnotic alexia: A controlled study with Stroop test

Abstract To clarify whether hypnotically-induced alexia was able to reduce the Stroop effect due to color/word interference, 12 volunteers (6 with high and 6 with low hypnotizability according to Stanford Hypnotic Susceptibility Scale Form C) underwent a Stroop test consisting of measuring, both in basal conditions and during post-hypnotic alexia, the reaction times (RT) at appearance of a colored word indicating a color. In basal conditions, RT were greater in case of incongruence. In highly hypnotizable participants, the interference was less pronounced during post-hypnotic alexia (−34%, p = 0.03). During alexia, late positive complexamplitude was also greater for congruent than incongruent conditions (p < 0.03), and cardiovascular response to stress was less pronounced as well. In participants showing low hypnotizability, no reduction of Stroop effect was detected during post-hypnotic alexia. Post-hypnotic alexia is therefore a real and measurable phenomenon, capable of reducing the color-word interference and the haemodynamic effects of the Stroop test.

Induced hyperammonemia may compromise the ability to generate restful sleep in patients with cirrhosis

In patients with cirrhosis, hyperammonemia and hepatic encephalopathy are common after gastrointestinal bleeding and can be simulated by an amino acid challenge (AAC), or the administration of a mixture of amino acids mimicking the composition of hemoglobin. The aim of this study was to investigate the clinical, psychometric, and wake‐/sleep‐electroencephalogram (EEG) correlates of induced hyperammonemia. Ten patients with cirrhosis and 10 matched healthy volunteers underwent: (1) 8‐day sleep quality/timing monitoring; (2) neuropsychiatric assessment at baseline/after AAC; (3) hourly ammonia/subjective sleepiness assessment for 8 hours after AAC; (4) sleep EEG recordings (nap opportunity: 17:00‐19:00) at baseline/after AAC. Neuropsychiatric performance was scored according to age‐/education‐adjusted Italian norms. Sleep stages were scored visually for 20‐second epochs; power density spectra were calculated for consecutive 20‐second epochs and average spectra determined for consolidated episodes of non‐rapid eye movement (non‐REM) sleep of minimal common length. The AAC resulted in: (i) an increase in ammonia concentrations/subjective sleepiness in both patients and healthy volunteers; (ii) a worsening of neuropsychiatric performance (wake EEG slowing) in two (20%) patients and none of the healthy volunteers; (iii) an increase in the length of non‐REM sleep in healthy volunteers [49.3 (26.6) versus 30.4 (15.6) min; P = 0.08]; (iv) a decrease in the sleep EEG beta power (fast activity) in the healthy volunteers; (v) a decrease in the sleep EEG delta power in patients. Conclusion: AAC led to a significant increase in daytime subjective sleepiness and changes in the EEG architecture of a subsequent sleep episode in patients with cirrhosis, pointing to a reduced ability to produce restorative sleep. (HEPATOLOGY 2012)

Covert hepatic encephalopathy: Agreement and predictive validity of different indices

AIM To investigate the agreement and prognostic value of different measures of covert hepatic encephalopathy (CHE). METHODS One-hundred-and-thirty-two cirrhotic outpatients underwent electroencephalography (EEG), paper-and-pencil psychometry (PHES) and critical flicker frequency, scored on the original/modified (CFFo/CFFm) thresholds. Eighty-four patients underwent Doppler-ultrasound to diagnose/exclude portal-systemic shunt. Seventy-nine were followed-up for 11 ± 7 mo in relation to the occurrence of hepatic encephalopathy (HE)-related hospitalisations. RESULTS On the day of study, 36% had grade I HE, 42% abnormal EEG, 33% abnormal PHES and 31/21% abnormal CFFo/CFFm. Significant associations were observed between combinations of test abnormalities; however, agreement was poor (Cohens κ < 0.4). The prevalence of EEG, PHES and CFFo/CFFm abnormalities was significantly higher in patients with grade I overt HE. The prevalence of EEG and CFFm abnormalities was higher in patients with shunt. The prevalence of EEG abnormalities was significantly higher in patients with a history of HE. During follow-up, 10 patients died, 10 were transplanted and 29 had HE-related hospitalisations. Grade I HE (P = 0.004), abnormal EEG (P = 0.008) and abnormal PHES (P = 0.04) at baseline all predicted the subsequent occurrence of HE; CFF did not. CONCLUSION CHE diagnosis probably requires a combination of clinical, neurophysiological and neuropsychological indices.

Top-down and bottom-up processes in the extrastriate cortex of cirrhotic patients: An ERP study

OBJECTIVE This study aims to evaluate the efficiency of top-down and bottom-up processes in the extrastriate cortex of cirrhotic patients without overt hepatic encephalopathy (HE). METHODS Reaction times (RTs), accuracy and event-related potentials (ERPs) were recorded during the execution of a visual Simon task in 17 cirrhotic patients and 10 healthy controls. Amplitude and latency of the P1 and N1 (indexes of bottom-up processes) and of the N2pc (index of top-down processes) were measured. RESULTS Patients were slower than controls, and patients with minimal HE (MHE) were slower than patients without MHE. The distribution analysis of RTs showed that the Simon effect decays with slower RTs in all the groups and that the shape of the distribution was different in MHE patients. No differences were found between cirrhotic patients and controls for P1 and N1 amplitude and latency. In contrast, N2pc latency was delayed in cirrhotic patients compared to controls independently of MHE. CONCLUSIONS In the extrastriate cortex of cirrhotic patients without HE, top-down processes are altered whereas bottom-up processes are preserved. SIGNIFICANCE The analysis of exogenous and endogenous visual components of ERPs provides a model to study the functional dissociation between top-down and bottom-up processes inside the extrastriate cortex.