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Attention, Memory, and Cognitive Function in Hepatic Encephalopathy
Abstract
Deficits in attention and arousal play a major role in the clinical presentation of hepatic encephalopathy. Attention deficits are also the main components of minimal hepatic encephalopathy. The present paper summarizes some findings about attentional and memory dysfunction in hepatic encephalopathy, with reference to basic knowledge about normal attention and memory function and their cerebral representation.
... Neuropsychological findings have demonstrated that executive control deficiency in cirrhotic patients is associated with dysfunction of the anterior attention system, whose function is modulated by the prefrontal cortex, anterior cingulate cortex (ACC), supplemental motor cortex, and basal ganglia (4). Weissenborn et al. (8,9) proposed that executive dysfunction in cirrhosis contributes to an alteration of energy metabolism in the medial and lateral frontal cortex, anterior cingulate gyrus, and parietal structures. In addition, neuroimaging studies using task-based functional magnetic resonance imaging (fMRI) have also revealed less activation in the brain network that involves the ACC, prefrontal cortex, parietal lobe, and temporal fusiform gyrus when cirrhotic patients without OHE performed the Stroop task (7) [a test assessing executive function that requires a number of cognitive abilities to occur in tandem, such as selective attention, dual processing, processing speed, and cognitive flexibility (10)]. ...
... In the current study, we examined brain intrinsic networks associated with executive function in cirrhotic patients and healthy controls. Significant FC reduction within three core cognitive networks (i.e., ECN, DMN, and SN) was identified in the patient group, which further supports the hypothesis that the metabolic dysfunction induced by cirrhosis contributes to disruption of brain networks (8,9,13,29,30). In addition, the neuropsychological test based on the Stroop task was conducted to assess executive function of subjects. Consistent with previous reports (4,7,20), the patients performed significantly worse as reflected by the longer time with more errors to complete the Stroop task. ...
... Consistent with these reports, our findings derived from a hypothesis-driven approach further validate that disruption of functional integration is the major change in the intrinsic brain network, which precedes overt manifestations of HE. This network disconnectivity may be attributed to the following cirrhosis-induced abnormalities: (1) a disturbance in brain tissue energy metabolism given that many regions with decreased glucose uptake, as revealed by positron emission tomography, involve the three network areas described above (8,9,31); (2) an alteration in cerebral blood flow (32,33), considering the tight coupling between brain blood supply and FC strength (34); and (3) damage to white matter fibers such as reduced axonal integrity and demyelination (35) given the fundamental role of fibers in connecting the distinct regions within the intrinsic brain networks (36). Taken together, our results provide further evidence of cirrhosis-related disruption of FC prior to the OHE episode. ...
Objective
Patients with cirrhosis often exhibit cognitive deficits, particularly executive dysfunction, which is considered a predictor of overt hepatic encephalopathy (OHE). We examined brain intrinsic networks associated with executive function to investigate the neural basis of this cognitive deficiency in cirrhosis.
Methods
Resting-state functional MRI data were acquired from 20 cirrhotic patients and 18 healthy controls. Seed-based correlation analysis was used to identify the three well-known networks associated with executive function, including executive control (ECN), default mode (DMN), and salience (SN) networks. Functional connectivity (FC) within each network was compared between groups and correlated with patient executive performance (assessed by the Stroop task).
Results
Patients showed decreased FC between the ECN seed (right dorsolateral prefrontal cortex) and several regions (including right middle/inferior frontal gyrus, left inferior frontal gyrus, bilateral inferior/superior parietal lobules, bilateral middle/inferior temporal gyrus, and right medial frontal gyrus), between the DMN seed [posterior cingulate cortex (PCC)] and several regions (including bilateral medial frontal gyrus, bilateral anterior cingulate cortex, bilateral superior frontal gyrus, bilateral precuneus/PCC, left supramarginal gyrus, and left middle temporal gyrus), and between the SN seed (right anterior insula) and right supramarginal gyrus. FC strength in the ECN and SN was negatively correlated with patient performance during the Stroop task.
Conclusion
Disrupted functional integration in the core brain cognitive networks, which is reflected by reductions in FC, occurs before OHE bouts and may play an important role in the neural mechanism of executive dysfunction associated with cirrhosis.
... Hepatic Encephalopathy (HE) is a complex neuropsychiatric syndrome characterized by a functional alteration of the central nervous system associated to liver disease [1, 2]. Around 33-50% of cirrhotic patients without clinical symptoms of HE show minimal hepatic encephalopathy (MHE) with mild cognitive impairment, attention deficits [3,4] and impaired visuomotor and bimanual coordination [5,6]. MHE decreases the quality of life, and increases the probability of suffering HE [7,8]. ...
... Attention deficit is one of the earliest and key features in the development of MHE [3][4][5]. We also observed a significant decrease in rs-FC in MHE patients compared to controls in DAN, which agree with previous studies [15,17]. ...
... A"triple network" model has been recently proposed including the SN, the DMN and the CEN, in which SN would facilitate the change of activation between DMN and CEN, through appropriate transient signals that activate CEN to mediate cognitive control processes and deactivate DMN [27]. Functional coupling and anti-correlated matching between these three networks is critical for the execution of certain brain tasks such as working memory, attention and executive control [27,37], all of them altered in MHE [3][4][5]. ...
Background and aims
Minimal hepatic encephalopathy (MHE) is associated with cognitive alterations and changes in connectivity. We assessed the relationship of the abnormalities of resting-state functional connectivity (rs-FC) and gray matter (GM) volume with different cognitive alterations and biochemical parameters associated to MHE.
Methods
Thirty-nine cirrhotic patients (26 without and 13 with MHE) and 24 controls were widely cognitive assessed with a battery of psychometric tests. Atrophy was determined using Voxel-Based Morphometry and rs-FC was assessed by independent component analysis. Receiver operating characteristic (ROC) curves was performed to assess the diagnostic utility of rs-FC and GM reduction for the discrimination of patients with and without MHE. Blood ammonia, cGMP, and levels of pro-inflammatory interleukins were measured.
Results
MHE patients showed significant decrease of GM volume and lesser degree of rs-FC in different networks related to attention and executive functions as compared to controls and patients without MHE. There is a progressive reduction in rs-FC in the default mode network with the progression of cognitive impairment. MHE patients showed GM reduction in the right frontal lobe, right insula and right cerebellum compared to patients without MHE. Alterations in GM volume and rs-FC correlated with the scores of different cognitive tests.
Conclusions
Decreased cognitive performance is associated by reduced rs-FC and GM atrophy in MHE patients. These changes could have predictive value for detecting MHE.
... CLD-related neurophysiological and psychometric dysfunctions vary, ranging from psychomotor speed to executive functioning (Ortiz et al., 2005;Zhan and Stremmel, 2012) and get worsened as approach to overt hepatic encephalopathy (HE) (Butterworth, 2000;Sánchez-Carrión et al., 2008). Patients with HE present with overt clinical symptoms, such as disorientation, and consciousness disorders, which contributes to an increased risk of death in cirrhotic patients (Bustamante et al., 1999;Weissenborn et al., 2001aWeissenborn et al., , 2005Bajaj et al., 2007a;Prasad et al., 2007;Stewart et al., 2007). ...
... For example, the West Haven scale is a subjective and semiquantitative clinical scale that classifies mental state changes (Conn et al., 1977;Groeneweg et al., 1998;Hartmann et al., 2000;Ferenci et al., 2002;Amodio et al., 2004). In addition, there is a battery of psychometric tests that aims to detect neurocognitive impairments, such as neuropsychological and perceptual motor dysfunction (Weissenborn et al., 2005), named the psychometric hepatic encephalopathy score (PHES). The PHES consists of five subtests, including the A and B number connection tests (NCT-A, NCT-B), the line tracing test (LTT), the serial dotting test (SDT), and the digit symbol test (DST) (Weissenborn et al., 2001b;Ferenci et al., 2002;Bajaj et al., 2009), a primarily paper-andpencil test. ...
Early detection and evaluation of cognitive alteration in chronic liver disease is important for predicting the subsequent development of hepatic encephalopathy. While visuomotor tasks have been rigorously employed for cognitive evaluation in chronic liver disease, there is a paucity of auditory processing task. Here we focused on auditory perception and examined behavioral and haemodynamic responses to a melodic contour identification task (CIT) to compare cognitive abilities in patients with chronic liver disease (CLD, N = 30) and healthy controls (N = 25). Further, we used support vector machines to examine the optimal combination of channels of functional near-infrared spectroscopy that can classify cognitive alterations in CLD. Behavioral findings showed that CIT performance was significantly worse in the patient group and CIT significantly correlated with neurocognitive evaluation (i.e., number connection test, digit span test). The findings indicated that CIT can measure auditory cognitive capacity and its difference existing between patient group and healthy controls. Additionally, optimal subsets classified the 16-dimensional haemodynamic data with 78.35% classification accuracy, yielding markers of cognitive alterations in the prefrontal regions (CH6, CH7, CH10, CH13, CH14, and CH16). The results confirmed the potential use of behavioral as well as haemodynamic responses to music perception as an alternative or supplementary method for evaluating cognitive alterations in chronic liver disease.
... End-stage liver disease (ESLD) is associated with a wide spectrum of neurocognitive impairment ranging from minimal alterations in attention, working memory, and psychomotor speed to coma and death. [1][2][3] Approximately 80% of patients with ESLD have neurocognitive changes associated with poorer quality of life, including deteriorating sleep and work performance. As many as 20% of adults with ESLD can develop the most severe form of cognitive impairment, overt hepatic encephalopathy (HE), which may portend up to 43% mortality at one year. ...
... The median (IQR) number of messages per patient was 3 (1-10) in the pre-transplant period, 10 (4-24) post-transplant, and 3 (2-5) for controls. For patients with MELD ≥ 30, the median number of messages per patient was 5 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) in the pre-transplant period, 15 (5-39) post-transplant, and 2 (1-4) for controls. A transjugular Intrahepatic portosystemic shunt was placed in 2% of cases and no controls. ...
End-stage liver disease (ESLD) is associated with cognitive impairment ranging from subtle alterations in attention to overt hepatic encephalopathy that resolves after transplant. Natural language processing (NLP) may provide a useful method to assess cognitive status in this population. We identified 81 liver transplant recipients with ESLD (4/2013-2/2018) who sent at least one patient-to-provider electronic message pre-transplant and post-transplant, and matched them 1:1 to "healthy" controls-who had similar disease, but had not been evaluated for liver transplant-by age, gender, race/ethnicity, and liver disease. Messages written by patients pre-transplant and post-transplant and controls was compared across 19 NLP measures using paired Wilcoxon signed-rank tests. While there was no difference overall in word length, patients with Model for End-Stage Liver Disease Score (MELD) ≥ 30 (n = 31) had decreased word length in pre-transplant messages (3.95 [interquartile range (IQR) 3.79, 4.14]) compared to post-transplant (4.13 [3.96, 4.28], p = 0.01) and controls (4.2 [4.0, 4.4], p = 0.01); there was no difference between post-transplant and controls (p = 0.4). Patients with MELD ≥ 30 had fewer 6+ letter words in pre-transplant messages (19.5% [16.4, 25.9] compared to post-transplant (23.4% [20.0, 26.7] p = 0.02) and controls (25.0% [19.2, 29.4]; p = 0.01). Overall, patients had increased sentence length pre-transplant (12.0 [9.8, 13.7]) compared to post-transplant (11.0 [9.2, 13.3]; p = 0.046); the same was seen for MELD ≥ 30 (12.3 [9.8, 13.7] pre-transplant vs. 10.8 [9.6, 13.0] post-transplant; p = 0.050). Application of NLP to patient-generated messages identified language differences-longer sentences with shorter words-that resolved after transplant. NLP may provide opportunities to detect cognitive impairment in ESLD.
... Thalamic swelling or edema likely has widespread consequences because the thalamus plays a central role in attention, arousal, sleep, and circadian rhythms (Filley 2002;Gosseries et al. 2011a, b) and serves as a relay station of sensory impulses to cortical cognitive functions (Weissenborn et al. 2005). The normal functions of the thalamic circuits are compromised by edema and ultimately result in coma Filley 2002;Weissenborn et al. 2005). ...
... Thalamic swelling or edema likely has widespread consequences because the thalamus plays a central role in attention, arousal, sleep, and circadian rhythms (Filley 2002;Gosseries et al. 2011a, b) and serves as a relay station of sensory impulses to cortical cognitive functions (Weissenborn et al. 2005). The normal functions of the thalamic circuits are compromised by edema and ultimately result in coma Filley 2002;Weissenborn et al. 2005). Such functional deficits to a large degree appropriately describe the complex clinical picture of manifest HE. ...
Hepatic encephalopathy (HE) is a frequent and debilitating complication of cirrhosis and its pathogenesis is not definitively clarified. Recent hypotheses focus on the possible existence of low-grade cerebral edema due to accumulation of osmolytes secondary to hyperammonemia. In the present study we investigated increases in cerebral water content by a novel magnetic resonance impedance (MRI) technique in cirrhosis patients with and without clinically manifest HE. We used a 3 T MRI technique for quantitative cerebral water content mapping in nine cirrhosis patients with an episode of overt HE, ten cirrhosis patients who never suffered from HE, and ten healthy aged-matched controls. We tested for differences between groups by statistical non-parametric mapping (SnPM) for a voxel-based spatial evaluation. The patients with HE had significantly higher water content in white matter than the cirrhosis patients (0.6%), who in turn, had significantly higher content than the controls (1.7%). Although the global gray matter water content did not differ between the groups, the patients with HE had markedly higher thalamic water content than patients who never experienced HE (6.0% higher). We found increased white matter water content in cirrhosis patients, predominantly in those with manifest HE. This confirms the presence of increasing degrees of low-grade edema with exacerbation of pathology. The thalamic edema in manifest HE may lead to compromised basal ganglia-thalamo-cortical circuits, in accordance with the major clinical symptoms of HE. The identification of the thalamus as particularly inflicted in manifest HE is potentially relevant to the pathophysiology of HE.
... The cognitive impairment associated with cirrhosis is a criterion of hepatic encephalopathy (HE), according to the West Haven criteria (Ferenci et al. 2002, Ciećko-Michalska et al. 2013, Vilstrup et al. 2014. Patients with HE had deficits in attention, vigilance, working memory, and orientation (Weissenborn et al. 2001(Weissenborn et al. , 2005. The incidence of HE varies according to the stage of disease. ...
Aims
up to 80% of patients with alcohol use disorder display cognitive impairments. Some studies have suggested that alcohol-related cognitive impairments could be worsened by hepatic damage. The primary objective of this study was to compare mean scores on the Brief Evaluation of Alcohol-Related Neurocognitive Impairments measure between alcohol use disorder patients with (CIR+) or without cirrhosis (CIR−).
Methods
we conducted a prospective case–control study in a hepatology department of a university hospital. All patients were assessed using the Evaluation of Alcohol-Related Neuropsychological Impairments test.
Results
a total of 82 patients (50 CIR+, 32 CIR−) were included in this study. CIR− patients were significantly younger than CIR+ patients (respectively, 45.5 ± 6.8 vs 60.1 ± 9.0; P < .0001). After adjusting for age and educational level, the mean Evaluation of Alcohol-Related Neuropsychological Impairments total scores in the CIR+ group were significantly lower than in the group of CIR− patients (14.1 ± 0.7 vs 7.8 ± 0.4, respectively, P < .0001). The mean subscores on delayed verbal memory, alphabetical ordination, alternating verbal fluency, visuospatial abilities, and ataxia subtests were also significantly lower in the CIR+ than in the CIR− group (respectively, 1.9 ± 0.2 vs 2.8 ± 0.2; 1.8 ± 0.2 vs 2.7 ± 0.2; 2.2 ± 0.2 vs 3.6 ± 0.2; 0.7 ± 0.2 vs 1.6 ± 0.2; 0.7 ± 0.2 vs 3.1 ± 0.2; P < .0001 for all comparisons).
Conclusions
in the present study, alcohol use disorder patients with cirrhosis presented more severe cognitive impairments than those without cirrhosis. Longitudinal studies are needed to investigate how cirrhosis can influence cognitive impairments.
... Chronic hyperammonemia is a main contributor to the cognitive and motor impairment in cirrhotic patients with minimal hepatic encephalopathy (MHE) or clinical HE [1][2][3][4][5], which impair quality of life [6][7][8][9]. ...
Hyperammonemia contributes to hepatic encephalopathy. In hyperammonemic rats, cognitive function is impaired by altered glutamatergic neurotransmission induced by neuroinflammation. The underlying mechanisms remain unclear. Enhanced sphingosine-1-phosphate receptor 2 (S1PR2) activation in the cerebellum of hyperammonemic rats contributes to neuroinflammation. in In hyperammonemic rats, we assessed if blocking S1PR2 reduced hippocampal neuroinflammation and reversed cognitive impairment and if the signaling pathways were involved. S1PR2 was blocked with intracerebral JTE-013, and cognitive function was evaluated. The signaling pathways inducing neuroinflammation and altered glutamate receptors were analyzed in hippocampal slices. JTE-013 improved cognitive function in the hyperammonemic rats, and hyperammonemia increased S1P. This increased IL-1β, which enhanced Src activity, increased CCL2, activated microglia and increased the membrane expression of the NMDA receptor subunit GLUN2B. This increased p38-MAPK activity, which altered the membrane expression of AMPA receptor subunits and increased BDNF, which activated the TrkB → PI3K → Akt → CREB pathway, inducing sustained neuroinflammation. This report unveils key pathways involved in the induction and maintenance of neuroinflammation in the hippocampus of hyperammonemic rats and supports S1PR2 as a therapeutic target for cognitive impairment.
... Diagnostic tools for MHE to be used in clinical routine must be easy to use and sensitive, valid, objective, and reliable (Häussinger et al. 2022, Vilstrup et al. 2014, Kircheis et al. 2002, Bajaj et al. 2007, Shawcross et al. 2016). Especially a number of psychometric, digital psychological and psychophysical tests of selective attention, concentration and reaction have been used for detection of low-grade HE that allow a fast, objective and precise diagnostic of this disorder (Bajaj et al. 2013, Weissenborn et al. 2005 ...
Background: An early detection of low-grade Hepatic Encephalopathy (HE) is of high importance. The aim of the study was to compare a neuropsychological with a psychophysical test on the basis of the Psychometric Hepatic Encephalopathy Score (PHES) regarding effectiveness in diagnosingminimal HE (MHE).
Methods: Patients without evidence for overt HE (OHE) according to the mental state (West-Haven criteria) with a PHES <-4 value points and no clinical symptoms were defined as having MHE. Patients were considered as HE 0 when in the PHES none of the psychometric subtest results was abnormal or with a PHES >-4 value points. Patients with clinical symptoms were considered OHE patients. For the CFF a borderline of < 39 Hz for OHE patients was seen. Different Cut-Off values were determined and their specificity and sensitivity calculated.
Results: Ninety-six of the involved patients had liver cirrhosis and 25 acted as a healthy control group. Through the creation of ROC curves, the AUCs showed that the Cut-Off time of > 224 seconds with 0.806 is the most efficientwith better sensitivity (82%) and specificity (75%) for the EncephalApp. Cases of withdrawals were seen in 10.74% of all tested patients, whereby eight of 13 patients could finish all levels with Stroop OFF but not the levels with Stroop ON. Of those eight patients, four had a MHE and four an OHE.
Conclusion: The EncephalApp has shown its limitations in the MHE as well as overt grades of HE. For these cases the test is an inacceptable method for HE grading.
... In another study, electrocorticography and direct cortical stimulation were combined to assess three patients implanted with subdural electrodes; the results also indicated that the left superior frontal gyrus plays a functional role in working memory [35]. Furthermore, the previous study demonstrated that attention, higher executive functions, and memory deficits are the main clinical presentation components of MHE patients [36]. According to the findings of an ethology and fMRI study, MHE patients debilitate spatial working memory, and neural network impairments result in spatial working memory dysfunction [37]. ...
(1) Background: Minimal hepatic encephalopathy (MHE) is an important complication of decompensated cirrhosis. Previous studies have demonstrated spontaneous brain activity alterations in cirrhotic patients with MHE. However, the reported results are inconsistent, which has limited our understanding of the potential neural mechanisms. Thus, we conducted a quantitative meta-analysis of resting-state functional imaging studies to identify the regional activity alterations consistently involved in MHE. (2) Methods: We searched six databases to include resting-state functional imaging studies and compared spontaneous brain activity patterns between MHE patients and healthy controls (HCs), and between cirrhotic patients without minimal hepatic encephalopathy (NMHE) and HCs. Then, a separate whole-brain voxel-wise meta-analysis between MHE or NMHE patients and HCs was conducted using seed-based d mapping with permutation of subject images. We further conducted the conjunction analysis to assess the distinct regional activity alterations between MHE and NMHE patients as compared to HCs. (3) Results: Thirteen studies with twenty datasets were included in this meta-analysis. Compared with HCs, MHE patients showed decreased spontaneous brain activity in the left superior frontal gyrus, left median cingulate/paracingulate gyri, and right precuneus. Compared with NMHE patients, MHE patients indicated decreased spontaneous brain activity in the left superior frontal gyrus, left median cingulate/paracingulate gyri, and right precuneus. (4) Conclusions: MHE is associated with spontaneous brain activity alterations involving the left superior frontal gyrus and median cingulate/paracingulate gyri, which may implicate primarily in spatial working memory and emotional disorders. These findings may contribute to a better understanding of the potential neural mechanisms, and guide further research.
... (Fig. 6E). We also detected the relative expression of miR-1264-5p in a high ammonia environment, and the results showed that miR-1264-5p was significantly upregulated in NH 4 Cl-treated neurons. The overexpression of lnc240 in NH 4 Cl-treated neurons significantly decreased the expression of miR-1264-5p (Fig. 6F). ...
Hepatic encephalopathy (HE) is a nervous system disease caused by severe liver diseases and different degrees of learning and memory dysfunction. Long non-coding RNA (lncRNA) is highly expressed in the brain and plays important roles in central nervous system diseases like Alzheimer’s disease. In the present work, we found that the expression of lnc240 in the hippocampus of HE mice was significantly downregulated, but its pathogenesis in HE has not been clarified. This study aimed to explore the effects of lnc240 on the cognitive function of HE. The expression of lnc240, miR-1264-5p, and MEF2C was analyzed with RNA-seq and further determined by qRT-PCR in HE mouse. Double luciferase reporter gene testing confirmed the relationship between lnc240, MEF2C, and miR-1264-5p. The functional role of lnc240 and MEF2C in vitro and in vivo was evaluated by qRT-PCR, western blot analysis, immunofluorescence staining, Golgi staining, electrophysiology, and Morris water maze. The expression of lnc240 was decreased in HE mice. The overexpression of lnc240 could significantly downregulate miR-1264-5p and upregulate MEF2C, also increasing the amplitude and frequency of mEPSC in primary cultured hippocampal neurons. The overexpression of miR-1264-5p reversed the effect of lnc240 on MEF2C. Moreover, in vivo experiments have shown that the overexpression of lnc240 could improve HE mice’s spatial learning and memory functions. Golgi staining suggested that overexpression of lnc240 could increase the density and maturity of dendritic spines in hippocampal neurons of HE mice. Lnc240 can regulate the expression of MEF2C through miR-1264-5p and regulate the synaptic plasticity of hippocampal neurons, thereby saving the learning and memory dysfunction in HE mice, suggesting that lnc240 might be a potential therapeutic target for the treatment of HE.
Graphical Abstract
... This could be due to the persistent impact of prior HE on cognitive function, which is characterized by impaired neuropsychological and perceptual motor dysfunction and which is likely to overshadow cognitive impairment alone, and the relatively small sample size. [24] Our results could also be explained by the relative short duration of the driving-simulator sequences and the focus on CCs and REEs rather than speeding and collisions compared to prior studies where cognitive performance had greater correlations with driving simulation. [9,25] Ultimately, our goal was to analyze prior HE on these outcomes compared to the remaining groups with differing simulations using goggles. ...
Abstract Driving is independently affected by cirrhosis and hepatic encephalopathy (HE) and alcohol/substance use, but their concomitant impact is unclear. We aimed to determine the impact of alcohol and other substances on driving‐simulator performance in cirrhosis with and without HE. Outpatients with cirrhosis and controls underwent cognitive testing and driving simulation for the following three conditions: baseline, wearing goggles simulating alcohol intoxication, and wearing goggles simulating opioid/benzodiazepine abuse. Outcomes were number of centerline crossings (CCs) and road‐edge excursions (REEs). We compared controls versus patients with cirrhosis then subjects with cirrhosis with and without HE for all conditions, using generalized linear modeling (GLM). Sixty subjects (17 controls, 43 with cirrhosis [Model for End‐Stage Liver Disease score, 10; 21 subjects with prior HE]) were included. Simulations showed higher CCs and REEs at baseline in patients with cirrhosis with and without HE versus controls. With alcohol‐ and substance abuse‐impairment goggles, CCs increased but REEs decreased in cirrhosis. In the GLM, a time and group interaction was seen (p
... stimulus [29,374]. Metacognition is the processes of control and monitoring of environmental stimuli allowing individuals to assess what information they have and to determine what information they still need, and to gain information if necessary [29]. Decision making is a cognitive process based on implicit/explicit individual assumptions, which results in choosing among several alternatives [130]. ...
Cognitive processes, particularly learning and memory, are crucial brain mechanisms mediating the successful adaptation of individuals to constantly changing environmental conditions. Impairments in memory performance during neurodegenerative disorders or dementias affect life quality of patients as well as their relatives and careers, and thus have a severe socio-economic impact. The last decades have viewed learning and memory as predominantly protein-mediated process at the synapses of brain neurons. However, recent developments propose a principally new, lipid-based mechanism that regulates cognition. Thereby, crucial members of cell membranes, the sphingolipids, emerged to play an outstanding role in learning and memory. The most abundant brain sphingolipids, ceramides and gangliosides, dynamically shape the composition of protein carrying cellular membranes. This, in turn, regulates protein signaling through the membranes and overall neuronal plasticity. An imbalance in sphingolipid composition and disrupted dynamics significantly affect normal functioning of cells and results in the development of multiple psychiatric and neurological disorders with cognitive impairments. Ceramides and gangliosides interact with a plethora of molecular pathways determining de novo learning and memory, as well as pathogenic pathways of neurodegenerative disorders and dementias of various origins. Considering sphingolipids as a trigger mechanism for learning and memory under physiological and pathological conditions, a principally new class of lipid-based preventive and therapeutic approaches to target cognitive impairments and dementias is emerging.
... Moreover, this study was one of the first study that investigated the relationship between muscle depletion and minimal hepatic encephalopathy (MHE). MHE is a subclinical condition in which cognitive impairment isn't detectable with physical examination, but only with psychometric tests [41,42], electrophysiological and other functional brain measures [43,44]. In this study [41] MHE was evaluated with psychometric tests and the reduction in muscle mass and muscle function were significantly associated not only with overt HE but also with MHE. ...
In the last years the link between the presence of muscular alterations and hepatic encephalopathy (HE), both minimal and overt, has been deeply studied. The pathophysiological background supporting the relationship between muscle depletion, and HE is characterized by an imbalance between the capacity of muscle in ammonia metabolism and trafficking and the inability of the liver in removing ammonia through urea synthesis due to liver failure and/or the presence of porto-systemic shunts. This review will focus on the clinical burden, the physio pathological mechanisms understanding the liver muscle axis and principles of management of muscular alterations in cirrhosis.
... Despite absence of any apparent clinical signs, minimal HE has been clearly shown to impact the quality of life of patient with chronic liver disease tremendously [9], as they had deficit in their attention, vigilance, memory, and orientation abilities [10]. The cognitive impairment also affects their ability to perform complex tasks such as driving, operation of machinery, and other work-related activities [11,12]. ...
Background
Liver transplantation (LT) helped to save the life of end stage liver disease (ESLD) patients; however, there is a debate on the persistence of cognitive impairment. The study aimed to evaluate cognitive functions in patients with ESLD before and after liver transplantation and to assess its relation to hepatic encephalopathy (HE). Thirty recipients 47.6 ± 11 years undergone living donor liver transplantation at the transplantation center of both Ain Shams Center for Organ Transplant and Egypt air organ transplant unit were prospectively assessed by Trail Making Test, Wechsler Memory Scale–Revised, Benton Visual Retention—for the evaluation of cognitive functions before and 3 months after transplantation.
Results
The mean age of the patients was 47.6 ± 11 years, 17 males and 13 females. Eight out of 30 (26.7%) had past history of hepatic encephalopathy. The study reported significant improvement in the post-operative 3 months scores of Trail Making Test part (A), the digit span forward test, digit span backward test and the correct score difference of the Benton Visual Retention, as p value was (0.02), (0.01) (0.02), and (0.01) respectively, compared to the pre-operative scores. However, there was no difference in the scores of part (B), verbal association I, II, information subtest of WMS. Cognitive performance showed no significant difference between patients with or without history of HE.
Conclusions
Patients with ESLD have significant cognitive impairment that showed improvement after LT; HE did not correlate with cognitive function. Hence, transplantation has a favorable outcome on the cognitive impairment.
... Hepatic encephalopathy (HE) is a neurological complication of the liver, which can lead to reduced quality of life and more severe outcomes in cirrhotic patients (1,2), and it is identified by cognitive deficits, personality changes, and reduced attention (3). These neuropsychiatric alterations may finally lead to coma and death (4). ...
Objectives:
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that causes brain disturbances. Thymoquinone (TQ) has a wide spectrum of activities such as antioxidant, anti-inflammatory, and anticancer. This study aimed to evaluate the effects of TQ on spatial memory and hippocampal long-term potentiation (LTP) in rats with thioacetamide (TAA)-induced liver injury and hepatic encephalopathy.
Materials and methods:
Adult male Wistar rats were divided into six groups randomly: 1) Control; 2) HE, received TAA (200 mg/kg); 3-5) Treated groups (HE+TQ5, HE+TQ10, and HE+TQ20). TQ (5, 10, and 20 mg/kg) was injected intraperitoneally (IP) for 12 consecutive days from day 18 to 29. Subsequently, spatial memory performance was evaluated by the Morris water maze paradigm and hippocampal LTP was recorded from the dentate gyrus (DG) region. Activity levels of Malondialdehyde (MDA) and superoxide dismutase (SOD) were measured in the hippocampal tissue.
Results:
Data showed that the hippocampal content of MDA was increased while SOD activities were decreased in TAA-induced HE. TQ treatment significantly improved spatial memory and LTP. Moreover, TQ restored the levels of MDA and SOD activities in the hippocampal tissue in HE rats.
Conclusion:
Our data confirm that TQ could attenuate cognitive impairment and improve LTP deficit by modulating the oxidative stress parameters in this model of HE, which leads to impairment of spatial cognition and LTP deficit. Thus, these results suggest that TQ may be a promising agent with positive therapeutic effects against liver failure and HE defects.
... These tests included the NCT type A (NCT-A; abbreviated as NCT in all text below) and the DST (Weissenborn et al., 2001). The NCT and DST are part of the Psychometric Hepatic Encephalopathy Score (Ferenci et al., 2002;Weissenborn et al., 2005) and are ideal for this study as they are supported by a variety of functional neural components given their reliance on different sensorimotor, attention, memory, and executive functions (Miyake et al., 2000). The DST and NCT have undergone repeated and rigorous psychometric validation such as test-retest reliability and discriminant validity in a range of patient samples (Matarazzo and Herman, 1984;Jaeger, 2018;Zeng et al., 2020). ...
Neurocognitive impairment is present in cirrhosis and may be more severe in cirrhosis with overt hepatic encephalopathy (OHE). Liver transplantation (LT) can restore liver function, but how it reverses the impaired brain function is still unclear. MRI of resting-state functional connectivity can help reveal the underlying mechanisms that lead to these cognitive deficits and cognitive recovery. In this study, 64 patients with cirrhosis (28 with OHE; 36 without OHE) and 32 healthy control subjects were recruited for resting-state fMRI. The patients were scanned before and after LT. We evaluated presurgical and postsurgical neurocognitive performance in cirrhosis patients using psychomotor tests. Network-based statistics found significant disrupted connectivity in both groups of cirrhotic patients, with OHE and without OHE, compared with control subjects. However, the presurgical connectivity disruption in patients with OHE affected a greater number of connections than those without OHE. The decrease in functional connectivity for both OHE and non-OHE patient groups was reversed after LT to the level of control subjects. An additional hyperconnected network (i.e., higher connected than control subjects) was observed in OHE patients after LT. Regarding the neural-behavior relationship, the functional network that predicted cognitive performance in healthy individuals showed no correlation in presurgical cirrhotic patients. The impaired neural-behavior relationship was re-established after LT for non-OHE patients, but not for OHE patients. OHE patients displayed abnormal hyperconnectivity and a persistently impaired neural-behavior relationship after LT. Our results suggest that patients with OHE may undergo a different trajectory of postsurgical neurofunctional recovery compared with those without, which needs further clarification in future studies.
... With the absence of obvious clinical evidence of HE, MHE can only be diagnosed by a detailed assessment of the patients' history and a comprehensive neurological assessment and/or electrophysiological test [38]. Additionally, MHE patients may present abnormalities in psychological tests including number connection test-A (NCT-A) and digit-symbol test (DST), as well as impairment of visual motor ability, psychomotor speed, and response selection [39]. In order to evaluate the clinical efficacy of BBD for MHE, NCT-A and DST were measured because the combination of the two was recommended to diagnose MHE and showed good consistency with PHES [32]. ...
Background and purpose
Inflammation has been considered a precipitating event that contributes to neurocognitive dysfunction in minimal hepatic encephalopathy (MHE). Inhibition TLR-4 related inflammation can effectively improve neurocognitive dysfunction of MHE. Our previous study showed that Babao Dan (BBD) effectively inhibited inflammation and ameliorated neurocognitive function in rats with acute hepatic encephalopathy (HE) and chronic HE. The mechanism may lie in the regulation of TLR4 signaling pathway. Therefore, this study aimed to evaluate the role of BBD in the treatment of MHE patients with cirrhosis and to elucidate the underlying mechanism by which BBD regulated TLR4 pathway to alleviate inflammation.
Methods
A randomized controlled trial (n = 62) was conducted to evaluate the clinical efficacy between BBD plus lactulose (n = 31) and lactulose alone (n = 31) in MHE patients by testing neurocognitive function (NCT-A and DST), blood ammonia, liver function (ALT, AST and TBIL) and blood inflammation (IL-1β, IL-6 and TNF-α). Afterward, we detected NO, inflammatory cytokines (IL-1β, IL-6 and TNF-α) and the phosphorylation of P65, JNK, ERK as well as P38 in LPS-activated rat primary bone marrow-derived macrophages (BMDMs), peritoneal macrophages (PMs), and mouse primary BMDMs/PMs/microglia/astrocytes, to investigate the underlying mechanism of BBD inhibiting inflammation through TLR4 pathway. Also, the survival rate of mice, liver function (ALT, AST), blood inflammation (IL-1β, IL-6 and TNF-α), inflammatory cytokines (IL-1β, IL-6 and TNF-α) and histopathological changes in the liver, brain and lung were measured to assess the anti-inflammatory effect of BBD on neurocognitive function in endotoxin shock/endotoxemia mice.
Results
BBD combined with lactulose significantly ameliorated neurocognitive function by decreasing NCT-A (p＜0.001) and increasing DST (p＜0.001); inhibited systemic inflammation by decreasing IL-1β (p＜0.001), IL-6(p＜0.001) and TNF-α (p＜0.001); reduced ammonia level (p = 0.005), and improved liver function by decreasing ALT(p = 0.043), AST(p = 0.003) and TBIL (p = 0.026) in MHE patients. Furthermore, BBD inhibited gene and protein expression of IL-1β, IL-6 and TNF-α as well as NO in rat primary BMDMs/PMs, and mouse primary BMDMs/PMs/microglia/astrocytes in a dose-dependent manner. BBD inhibited the activation of mouse primary BMDMs/PMs/microglia/astrocytes by regulating TLR4 pathway involving the phosphorylation of P65, JNK, ERK and P38. Also, BBD reduced the mortality of mice with endotoxin shock/endotoxemia; serum levels of ALT, AST, IL-1β, IL-6 and TNF-α; gene expression of IL-1β, IL-6 and TNF-α in the liver, brain and lung, and tissue damage in the liver and lung.
Conclusion
Our study provided for the first time clinical and experimental evidence supporting the use of BBD in MHE, and revealed that BBD could play a crucial role in targeting and regulating TLR4 inflammatory pathway to improve neurocognitive function in MHE patients.
... However, before we discuss APα′s effect in Alzheimer's disease we give a background of APα related to acute and chronic stress in non-demented and normal individuals. In addition, we discuss GAMS exposure concerning learning and memory disturbances, and take examples from disorders like chronic stress disorders Lupien et al., 2005;Wang et al., 2012a;Yaffe et al., 2010), risk of dementia in Alzheimer's disease (Sindi et al., 2017), Parkinson's dementia (Backstrom et al., 2015 and hepatic encephalopathy (HE) (Weissenborn et al., 2005;Monfort et al., 2009;Bianchi et al., 2012). We also discuss consequences these findings may have for possible treatments of memory and learning disturbances in non-demented individuals and especially Alzheimer's dementia. ...
Cognitive dysfunction, dementia and Alzheimer’s disease (AD) are increasing as the population worldwide ages. Therapeutics for these conditions is an unmet need. This review focuses on the role of the positive GABA-A receptor modulating steroid allopregnanolone (APα), it’s role in underlying mechanisms for impaired cognition and of AD, and to determine options for therapy of AD. On one hand, APα given intermittently promotes neurogenesis, decreases AD-related pathology and improves cognition. On the other, continuous exposure of APα impairs cognition and deteriorates AD pathology. The disparity between these two outcomes led our groups to analyze the mechanisms underlying the difference. We conclude that the effects of APα depend on administration pattern and that chronic slightly increased APα exposure is harmful to cognitive function and worsens AD pathology whereas single administrations with longer intervals improve cognition and decrease AD pathology. These collaborative assessments provide insights for the therapeutic development of APα and APα-antagonists for AD and provide a model for cross laboratory collaborations aimed at generating translatable data for human clinical trials
... There is no single optimal measure for diagnosis of MHE because none of the diagnostic strategies covers all aspects of deficits that are present in MHE [68,69]. Testing approaches can be divided into two major types: psychometric and neurophysiological [70,71]. ...
... About 33-55% of cirrhotic patients without obvious clinical symptoms of HE show minimal hepatic encephalopathy (MHE) with mild cognitive impairment. MHE patients present attention deficits, visuo-motor and coordination disorders, and impairments in visual perception, visual orientation and visuo-constructive abilities [3][4][5][6][7][8] . However, although many studies have evaluated the memory of these patients, the results are contradictory and do not clearly determine whether or not there is a memory alteration in MHE [9][10][11][12][13][14][15][16] . ...
BACKGROUND
Patients with minimal hepatic encephalopathy (MHE) show mild cognitive impairment associated with cognitive alterations and changes in connectivity. We assessed the relationship of abnormalities of resting-state functional connectivity (rs-FC) and gray matter (GM) volume with cognitive alterations and biochemical parameters associated to MHE. We also evaluated the relationship between memory in MHE and structural and functional connectivity (FC) changes in the hippocampal system.
METHODS
Twenty-six cirrhotic patients without MHE (NMHE), 13 with MHE, and 24 controls were cognitive assessed with a battery of psychometric tests. Atrophy was determined using Voxel-Based Morphometry and rs-FC was assessed by ICA analysis. Receiver operating characteristic (ROC) curves was performed to assess the diagnostic utility of rs-FC and GM reduction for the discrimination of patients with and without MHE. We also assessed the relationship between alterations in memory and the structural integrity and FC of the hippocampal system.
RESULTS
MHE patients showed significant decrease of GM volume and lesser degree of rs-FC in different networks related to attention and executive functions as compared to controls and NMHE. There is a progressive reduction in rs-FC in the default mode network with the progression of cognitive impairment. MHE patients showed GM reduction in right frontal lobe, right insula and right cerebellum compared to NMHE patients. Alterations in GM volume and rs-FC correlated with cognitive tests. MHE patients showed impairments in learning, memory, and recognition, compared to NMHE and controls. Cirrhotic patients showed reduced fimbria volume compared to controls. Larger volumes in hippocampus subfields were related to better memory performance in NMHE patients and controls. MHE patients presented lower FC between the L-presubiculum and L-precuneus than NMHE patients, and a reduced FC between L-presubiculum and subiculum seeds and bilateral precuneus, which correlated with cognitive impairment and memory performance.
CONCLUSIONS
Decreased cognitive performance is associated by reduced rs-FC and GM atrophy in MHE patients. These changes could have predictive value for detecting MHE. Alterations in the FC of the hippocampal system could contribute to learning and long-term memory impairments in MHE patients. This study shows the association between alterations in learning and long-term memory and structural and FC disturbances in hippocampal structures in cirrhotic patients. Supported by Ministerio Economía, Industria y Competitividad - Instituto Salud Carlos III (FIS PI15/00035; FIS PI18/00150) to CM; Consellería Educación Generalitat Valenciana (PROMETEOII/2014/033; PROMETEU/2018/051 to VF, CM; ACIF/2018/284 to JJG), co-funded with European Regional Development Funds (ERDF).
... It has a characteristic cognitive profi le that cannot be diagnosed clinically ( 1 -4 ). It is characterized by psychomotor slowing and cognitive defi cits in visual -spatial perception, attention, concentration, and constructional ability, which adversely aff ect daily activities such as driving ability, social interaction, and communication ( 4,5 ). MHE has a signifi cant impact on the health-related quality of life (HRQOL) ( 6,7 ). ...
... Minimal HE (MHE) is a subclinical cognitive impairment frequently observable in patients with cirrhosis detectable only by psychometry, (13,14) which is strongly associated with the development of overt HE. (15,16) Few studies investigated the relationship between sarcopenia and MHE (17,18) in cirrhosis, and none of them used CT scanning to define muscle quantity and quality and MHE. More recently, a retrospective study showed a correlation between muscle alteration and history of overt HE. (11) However, as MHE was not considered, the possibility that this relationship was actually due to a higher prevalence of MHE among the patients with muscle alterations cannot be ruled out. ...
Muscle alterations (myosteatosis and sarcopenia) are frequent in cirrhosis and related to some complications included overt hepatic encephalopathy. The aim of our study was to investigate the relationship between muscle alterations and minimal hepatic encephalopathy (MHE) and their role on the risk of overt HE. 64 cirrhotics were submitted to Psychometric Hepatic Encephalopathy Score (PHES) and to Animal Naming Test (ANT) to detect MHE. CTscan was used to analyse the skeletal muscle index (SMI) and attenuation. The incidence of the first episode of HE, taking into account the competing risk nature of the data, was estimated. Myosteatosis was observed in 24 patients (37.5%), sarcopenia in 37 (58%) and MHE in 32 (50%). Both myosteatosis (62.5vs12.5%;p<0.001) and sarcopenia (84vs31%;p<0.001) were more frequent in patients with MHE. The variables independently associated to the presence of MHE were: sarcopenia, previous overt HE and myosteatosis. Thirty‐one (48%) patients developed overt HE during 16.1±13 months; myosteatosis was detected in 68% and sarcopenia in 84% of them. Sarcopenia and myosteatosis were also independently associated to the development of overt HE. Venous ammonia was significantly higher in sarcopenic patients (62.6±17.7 vs 41.4±16.1 μg/dl; p<0.001) and in myosteatosic patients (65.2±19.2 vs 46.7±17.1 μg/dl; p<0.001) and inversely correlated to both parameters. Survival was significantly lower in malnourished patients compared with patients without myosteatosis or sarcopenia (p<0.001). Myosteatosis and sarcopenia, probably by reducing the handling of ammonia in the muscle, are independently associated to MHE and to the risk of overt HE in cirrhotics. In malnourished patients, the amelioration of nutritional status may be a possible goal to decrease both the prevalence oh MHE and the incidence of overt HE. This article is protected by copyright. All rights reserved.
... As the disease progresses, motor function and mental abilities become impaired. Patients show a reduced ability in terms of attention, learning, memory, and cognition, and may also suffer from motion and visual perception impairment [5,6]. These changes affect the quality of life in patients with HE and can lead to impairment in performing daily activities [7]. ...
Hepatic encephalopathy (HE) is a brain disorder as a result of liver failure. Previous studies have indicated that erythropoietin (EPO) has neuroprotective effects in different neurological diseases. This study addressed the therapeutic effect of a four-week treatment with EPO on neuronal damages in bile duct-ligated rats. Forty male Wistar rats (250–280 g) were used in the present study. The animals were randomly divided into four groups consisting of 10 animals each, including sham, sham + EPO, bile duct ligation (BDL), and BDL + EPO. EPO was intraperitoneally administered every other day (5,000 U/Kg) in the last four weeks after BDL. Biochemical and histological studies were performed to evaluate neurodegeneration. The results revealed that BDL increases the level of hepatic enzymes and total bilirubin. Furthermore, neurodegeneration was significantly increased in the BDL group compared to sham groups. EPO preserved hepatic enzymes and total bilirubin in the treated group. In addition, EPO significantly decreased the neurodegeneration in BDL + EPO compared to the BDL group. Results of this study showed that EPO has neuroprotective effects in the rat model of HE, possibly due to its anti-inflammatory and anti-oxidant properties. Complementary studies are required to clarify the exact mechanisms.
... Hepatic encephalopathy (HE) is the disturbance of CNS due to liver failure [1]. HE is characterized by several symptoms including cognitive, psychiatric, and motor deficits [2]. Although the clear mechanism (s) involved in the pathogenesis of HE remain to be determined, there is agreement that ammonia is the primary molecule responsible for HEinduced CNS complications [3]. ...
... On the other hand, based on time-consuming neuropsychological tests, hepatologists rarely spend time to screen patients with MHE. [14][15][16] What has been mentioned above shows the importance of diagnosing MHE in patients with cirrhosis. Different studies have presented various prevalence of MHE among patients with cirrhosis. ...
BACKGROUND
Minimal hepatic encephalopathy (MHE) is the mildest type of hepatic encephalopathy in patients with cirrhosis. Patients with MHE have normal clinical and physical examination but they show some neurocognitive dysfunctions that affect their quality of life negatively. The aim of the current study is to diagnose MHE in patients with cirrhosis and its associated factors.
METHODS
This is a cross-sectional study on 120 known cases of cirrhosis referred to hospitals affiliated to Isfahan University of Medical Sciences during 2014-17. The patients’ cirrhosis severity was evaluated using laboratory tests and physical examinations based on MELD (Model for End-stage Liver Disease) and Child-Pugh criteria. The patients’ demographics were filled in a checklist. All included patients with cirrhosis were asked to respond to the questions of Psychometric Hepatic Encephalopathy Score (PHES) test.
RESULTS
Mean age of the patients was 51.2 ± 9.7 years. 62 (51.7%) patients were men and 58 (48.3%) patients were women. The mean score of the patients based on MELD criteria was 14.03 ± 6.09. 26.7% of the patients presented MHE. Mean age of the patients with MHE was statistically less than the patients without MHE (p value < 0.001). Mean score of MELD criteria among the patients with diagnosis of MHE was significantly higher than the other group (p value < 0.001). The patients’ Child class was statistically associated with MHE (p value < 0.001). Men were significantly more affected than women (p value = 0.03).
CONCLUSION
MHE was associated with MELD score and Child class of the patients with cirrhosis. The noticeable point was reversible association of age with MHE. Further studies are recommended.
... MHE impairs patient's daily functioning and quality of life, patients with MHE have difficulties with attention, response inhibition and working memory [28]. In our study we diagnosed MHE in 60 cirrhotic patients without overt encephalopathy by using combination of minimental state examination, EEG and VEP P100 event-related potential and this is close to the results of recent reports by Mina et al. [29]. ...
... Neurocognitive impairment induced by biliary cirrhosis is a serious health problem in patients with chronic or acute liver diseases, which considerably affects the quality of life and ability to perform daily life tasks in these patients [1][2][3][4][5][6][7][8]. The molecular mechanisms leading to cognitive impairment following biliary cirrhosis is largely unknown and, as a result, currently there are no effective treatments available [9]. ...
Objective:
Memory impairment induced by biliary cirrhosis is associated with abnormalities in the function of different neurotransmitter systems. However, the exact molecular mechanisms involved in the learning and memory dysfunctions following biliary cirrhosis is largely unknown. This study set out to determine whether activation of transient receptor potential vanilloid type 1 (TRPV1) in the CA1 area of the hippocampus in rats improve memory impairment induced by biliary cirrhosis.
Methods:
To assess learning and memory, passive avoidance task was carried out using a shuttle box. The mRNA expression of TRPV1 and cAMP response element binding (CREB) protein in the hippocampus were also evaluated by qT-PCR.
Results:
Our results indicated that activation of TRPV1 channels by capsaicin significantly decreased memory impairment and increased mRNA expression of the TRPV1 and CREB in the hippocampus of rats with biliary cirrhosis. Our findings also demonstrated that a positive correlation existed between mRNA expression of TRPV1 and CREB, and between memory function and TRPV1 expression.
Discussion:
Taken together, the results of this study support the view that TRPV1 receptor may play an important role in the regulation of learning and memory functions, and suggest that activation of TRPV1 channels seems to be a promising therapeutic target for learning and memory impairments following biliary cirrhosis.
... About 33-55% of cirrhotic patients without obvious clinical symptoms of HE show minimal hepatic encephalopathy (MHE) with mild cognitive impairment. MHE patients present attention deficits, visuo-motor and coordination disorders, and impairments in visual perception, visual orientation and visuo-constructive abilities [3][4][5][6][7][8] . However, although many studies have evaluated the memory of these patients, the results are contradictory and do not clearly determine whether or not there is a memory alteration in MHE [9][10][11][12][13][14][15][16] . ...
Patients with minimal hepatic encephalopathy (MHE) show mild cognitive impairment associated with alterations in attentional and executive networks. There are no studies evaluating the relationship between memory in MHE and structural and functional connectivity (FC) changes in the hippocampal system. This study aimed to evaluate verbal learning and long-term memory in cirrhotic patients with (C-MHE) and without MHE (C-NMHE) and healthy controls. We assessed the relationship between alterations in memory and the structural integrity and FC of the hippocampal system. C-MHE patients showed impairments in learning, long-term memory, and recognition, compared to C-NMHE patients and controls. Cirrhotic patients showed reduced fimbria volume compared to controls. Larger volumes in hippocampus subfields were related to better memory performance in C-NMHE patients and controls. C-MHE patients presented lower FC between the L-presubiculum and L-precuneus than C-NMHE patients. Compared to controls, C-MHE patients had reduced FC between L-presubiculum and subiculum seeds and bilateral precuneus, which correlated with cognitive impairment and memory performance. Alterations in the FC of the hippocampal system could contribute to learning and long-term memory impairments in C-MHE patients. This study demonstrates the association between alterations in learning and long-term memory and structural and FC disturbances in hippocampal structures in cirrhotic patients.
... К числу последних относятся нарушения активности и динамики психических процессов по ригидному типу, сужение объема внимания и памяти, лабильность волевых усилий и изменения мыслительной деятельности церебрастенического типа. Для описания феноменологии нейрокогнитивных нарушений в литературе последних лет [7][8][9][10][11] используется термин «печеночная энцефалопатия» (hepaticencephalopathy). ...
Aim:
To study the efficacy of nooclerin (deanoli aceglumas) in alcohol withdrawal syndrome assessed by clinical and biochemical characteristics.
Material and methods:
A multicenter, open, randomized, comparative study of nooclerin in the complex treatment of alcohol withdrawal syndrome included 90 patients. The patients were randomized into nooclerin group (n=55) and control group (n=35).
Results and conclusion:
Nooclerin reduced alcohol withdrawal symptoms more significantly throughout the whole study period. There were significant between-group differences on the Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA-Ar) and the Multidimensional Fatigue Inventory (МFI-20). However, patients exhibited no excessive activity. No adverse side-effects were observed.
... The cognitive dysfunction related to HE can detrimentally affect individuals' ability to drive and work, which may lead to a negative impact on their socioeconomic status (Sidhu et al, 2011;Chaney et al, 2015). Furthermore, it is well established that patients with HE have a very poor quality of life, as described by quality-of-life scoring systems that show that most of these patients' physical, mental and social domains are severely compromised (Marchesini et al, 2001;Weissenborn et al, 2005). Patients who have experienced HE have expressed the following concerns (Grønkjaer et al, 2016). ...
This article provides an overview of the metabolic brain dysfunction hepatic encephalopathy (HE). HE is caused by severe liver cirrhosis and patients will often be treated in a liver unit, but patients with symptoms of HE may require nursing care anywhere in the healthcare system. Therefore it is beneficial for all nurses to have a basic knowledge of HE and this article explains the symptoms and treatment. Possible differential diagnoses are presented, as well as factors that can trigger episodes of HE. Both patients' and relatives' experiences are examined. Finally, the nurse's role in caring for patients with HE is described, along with the dilemmas and challenges involved. © MA Healthcare Ltd. Downloaded from magonlinelibrary.com by 203.056.241.128 on August 14, 2017.
It is known that patients with covert hepatic encephalopathy (CHE) exhibit working memory abnormalities, but to date there is no study comparing patients with cirrhosis with/without CHE and controls with both electrophysiological and hemodynamic data collected at the same time.
Here we collected behavioral [accuracy and reaction times (RTs), electrophysiological (evoked potentials) and hemodynamic (oxygenated and deoxygenated haemoglobin) correlates of an n-back task [formed by a control (0-back) condition, a low (1-back) and a high (2-back) working memory load conditions] in patients with cirrhosis with/without CHE: (1) at baseline (n = 21, males = 15, 58±8 yrs), and by comparison with controls (n = 21, males = 15, 57±11 yrs) and (2) after a 3-month course of rifaximin (n = 18, males = 12, 61±11 yrs), and by comparison to baseline.
All patients showed slower RTs (p < 0.0001) and lower P2 amplitude compared with controls (p = 0.018); moreover, patients with CHE showed reduced accuracy (p < 0.0001) compared with controls, and patients without CHE showed higher oxygenated haemoglobin in the central dorsolateral prefrontal cortex in the 2-back compared with patients with CHE. Post-rifaximin, oxygenated haemoglobin increased in the central frontopolar cortex. In addition, in patients without CHE the RTs of the 2-back became comparable to those of the 0-back and P3 showed higher amplitude.
In conclusion, the presence of cirrhosis seemed to have more effects than CHE on working memory at baseline. A course of treatment with rifaximin was more beneficial to patients without CHE, who probably had more room for improvement in this complex task.
A 70-year-old woman with liver cirrhosis presented with gastric varices and recurrent hepatic encephalopathy. Magnetic resonance imaging (MRI) showed a splenorenal shunt, and balloon-occluded retrograde transvenous obliteration (B-RTO) was indicated but could not be performed due to iodine allergy. We then performed B-RTO using gadoteridol, an MRI contrast medium, instead of iodine contrast and successfully occluded the shunt vessel. After the procedure, hepatic encephalopathy did not recur, and the size of the gastric varices was reduced. This experience may aid in the management of iodine-allergic patients requiring interventional radiological treatment.
Minimal hepatic encephalopathy (MHE) is a subtle form of hepatic encephalopathy (HE), a reversible syndrome of impaired brain function occurring in patients with advanced liver dysfunction, often culminating in a hepatic coma and consequently death. Although most patients who develop HE first present the typical abnormalities of MHE, sometimes this stage goes unnoticed by psychometric tests focused on diagnosing it. Therefore, there is a need for the development of more efficient diagnostic tests to improve the patient’s quality of life and thus increase the prognosis for survival. The main objective of this study was to analyze the existence of parameters extracted from the P300 wave that are useful for differentiating between control subjects and cirrhotic patients with and without MHE in accordance with the diagnosis by Psychometric Score of Hepatic Encephalopathy (PSHE) and Critical Flicker Frequency (CFF). For this, the evoked potentials of 40 controls, 51 cirrhotic patients without MHE, and 20 with MHE were examined. Thirty statistical, temporal, frequency, and uncertainty indicators characteristics were extracted from the P300 wave. Statistically significant differences (\(p < 0.05\)) were found in the Hjorth parameter of complexity and an evident reduction in the latency and amplitude of the evoked potentials in the groups studied.KeywordsMinimal hepatic encephalopathyEvoked potentialsEmpirical decomposition into modesAmplitudeLatencyComplexityMobilityActivity
Gut microbiota dysbiosis plays a significant role in the progression of liver disease, and no effective drugs are available for the full spectrum. In this study, we aimed to explore the dynamic changes of gut microbiota along the liver disease spectrum, together with the changes in cognition and brain metabolism. Sprague-Dawley rats were divided into four groups reflecting different stages of liver disease: control diet (NC); high-fat, high-cholesterol diet (HFHC), emulating non-alcoholic steatohepatitis; control diet + thioacetamide (NC + TAA), simulating acute liver failure; and high-fat, high-cholesterol diet + thioacetamide (HFHC + TAA) to assess the effect of the superimposed damages. The diet was administered for 14 weeks and the thioacetamide was administrated (100 mg/kg day) intraperitoneally over 3 days. Our results showed changes in plasma biochemistry and liver damage across the spectrum. Differences in gut microbiota at the compositional level were found among the experimental groups. Members of the Enterobacteriaceae family were most abundant in HFHC and HFHC + TAA groups, and Akkermansiaceae in the NC + TAA group, albeit lactobacilli genus being dominant in the NC group. Moreover, harm to the liver affected the diversity and bacterial community structure, with a loss of rare species. Indeed, the superimposed damage group (HFHC + TAA) suffered a loss of both rare and abundant species. Behavioral evaluation has shown that HFHC, NC + TAA, and HFHC + TAA displayed a worsened execution when discriminating the new object. Also, NC + TAA and HFHC + TAA were not capable of recognizing the changes in place of the object. Furthermore, working memory was affected in HFHC and HFHC + TAA groups, whereas the NC + TAA group displayed a significant delay in the acquisition. Brain oxidative metabolism changes were observed in the prefrontal, retrosplenial, and perirhinal cortices, as well as the amygdala and mammillary bodies. Besides, groups administered with thioacetamide presented an increased oxidative metabolic activity in the adrenal glands. These results highlight the importance of cross-comparison along the liver spectrum to understand the different gut-microbiota-brain changes. Furthermore, our data point out specific gut microbiota targets to design more effective treatments, though the liver-gut-brain axis focused on specific stages of liver disease.
T-cell receptor (TCR) analysis is relevant for the study of immune system diseases. The expression of TCRs is usually measured with targeted sequencing approaches where TCR genes are selectively amplified. However, many non-targeted RNA-seq experiments also contain reads of TCR genes, which could be leveraged for TCR expression analysis while reducing sample requirements and costs. Moreover, a step-by-step pipeline for the processing of transcriptome RNA-seq reads to deliver immune repertoire data is missing, and these types of analyses are usually not included in RNA-seq studies of immunological conditions. This represents a missed opportunity for complementing them with the analysis of the immune repertoire.
We present a Nextflow pipeline for CD4 T-cell receptor repertoire reconstruction and analysis from RNA sequencing data. We used a case study where TCR repertoire profiles were recovered from bulk RNA-seq of isolated CD4 T cells from control patients, cirrhotic patients without and with Minimal Hepatic Encephalopathy (MHE). MHE is a neuropsychiatric syndrome, mediated by peripheral inflammation, that may affect cirrhotic patients. After the recovery of 498-1,114 distinct TCR beta chains per patient, repertoire analysis of patients resulted in few public clones, high diversity and elevated within-repertoire sequence similarity, independently of immune status. Additionally, TCRs associated with celiac disease and inflammatory bowel disease were significantly overrepresented in MHE patient repertoires. The provided computational pipeline functions as a resource to facilitate TCR profiling from RNA-seq data boosting immunophenotype analyses of immunological diseases.
Introduction/Aim
Muscle alterations, portosystemic shunts (SPSS) and minimal hepatic encephalopathy (MHE) are related to hepatic encephalopathy (HE), however no studies have investigated the relative role of all these risk factors detected in the same patients. The aim of the study was to assess the prognostic impact of muscle alterations, MHE and SPSS on hepatic encephalopathy and transplant free survival.
Patients/Methods
114 cirrhotics were submitted to Psychometric Hepatic Encephalopathy Score (PHES) and Animal Naming Test (ANT) to detect MHE. CT scan was used to analyze the skeletal muscle index (SMI), muscle attenuation and SPSS. The incidence of the first episode of HE and survival were estimated.
Results
Previous HE was present in 47 patients (41%). The variables independently associated to previous HE were: sarcopenia, MHE and SPSS. 44 patients (39%) developed overt HE during 14±11 months; MHE and SPSS were the only variables significantly asociated to overt HE. During the same follow-up, 42 patients died (37%); MELD and sarcopenia were the only variables significantly asociated to transplant free survival.
Conclusions
MHE, sarcopenia and SPSS are clinically relevant and should be sought for in cirrhotics. In particular, MHE and SPSS are the only risk factors significantly associated to the development of HE while MELD and sarcopenia are independently associated to overall mortality.
Background
Minimal hepatic encephalopathy (MHE) is considered a risk factor for falls in patients with liver cirrhosis. However, MHE is prevalent in patients with muscle alterations (sarcopenia and myosteatosis) probably due to the role of muscle in ammonia handling.
Aim
To assess the respective role of muscle alterations and MHE on the risk of falls in cirrhotic patients.
Methods
Fifty cirrhotics were studied for MHE detection by using Psychometric Hepatic Encephalopathy Score (PHES) and Animal Naming Test (ANT). CT scan was used to quantify the skeletal muscle index (SMI) and muscle attenuation, as a measure of myosteatosis. The risk of falls was evaluated by the Timed Up&Go test (TUG). The occurrence of falls during follow up was also detected.
RESULTS
32 patients (64%) had an abnormal TUG (< 14 s). In the group with TUG ≥ 14 s, MHE (72vs31%, p<0.005) and myosteatosis (94vs50%, p = 0.002) were significantly more frequent than in patients with TUG<14 s. At multivariate the variables independently associated to TUG ≥ 14 s were myosteatosis, MHE and chronic beta-blockers use. During a mean follow-up of 25±16.9 months, 12 patients fell; the percentage of falls was significantly higher in patients with TUG ≥ 14 s (50%vs9%, p = 0.001) as well as in patients with myosteatosis (33%vs6%, p = 0.03), but similar in patients with or without MHE (35%vs15%, NS).
Conclusion
In cirrhotic patients both muscle alterations and cognitive impairment, as well as chronic beta-blockers use, are associated to the risk of falls.
Cərrahiyyə və hepatologiyanın vacib mövzularından biri olan portal hipertenziyaya həsr olunan bu kitabda portal hipertenziyanın etiologiyası, patogenezi, diaqnostika və müalicəsi haqqında müasir məlumatlar yer almışdır. Portal hipertenziyanın ağırlaşmalarının, xüsusən, varikoz və qanaxma, assit, hepatorenal sindrom və hepatik ensefalopatiyanın patogenezi, diaqnostika və müalicəsi haqqında məlumatlar verilmişdir. Bu patologiyaların diaqnostik və müalicə taktikaları aydın şəkildə təqdim edilmişdir. Portal hipertenziyaya səbəb olan bir çox xəstəliklərin müalicə xüsusiyyətləri də ayrıca verilmişdir. Mövzuların asan qavranılması üçün orjinal olaraq 28 şəkil və sxem, 13 cədvəl, 47 izahlı və 31 test sualları hazırlanmışdır. Kitabda 195 yerli və xarici ədəbiyyatdan istifadə edilmişdir. Kitab tədqiqatçılar, gənc cərrahlar və qastroenteroloqlar, müəllimlər və tələbələr üçün nəzərdə tutulmuşdur.
Background and aims:
Liver health professionals have difficulty discussing liver cirrhosis and its prognosis with patients and families. Question Prompt Lists (QPLs), which are evidence-based lists of "recommended questions," may improve communication but need to be designed specifically for the target population. This study aimed to develop and pilot a QPL for patients with cirrhosis.
Methods:
A mixed-methods design in 3 phases. In phase 1 (item generation), potential questions for inclusion in the QPL were identified from 3 sources-a scoping literature review; an online survey; and interviews with patients, family members, and health professionals. In phase 2 (QPL construction), a multidisciplinary expert panel finalized the selection of questions and the format of the QPL. In phase 3 (pilot study), the QPL was assessed for acceptability and feasibility in a hepatology outpatient clinic population.
Results:
From 258 topics initially identified, 30 questions were included in the first draft of the QPL. After review by a multidisciplinary expert panel including patients, the QPL was reduced to 22 questions. In the pilot study, 133/215 eligible patients consented to participate, although only 67/133 used the QPL in their clinic appointment. Among those who used the QPL, all questions were asked at least once. The most commonly asked question related to life expectancy. Most participants expressed support for the content of the QPL.
Conclusions:
A QPL, suitable for use in patients with liver cirrhosis attending hepatology outpatient clinics, has been developed and piloted. The QPL seems to be feasible to use and acceptable to patients and clinicians. Further work is needed to evaluate its effectiveness and to determine optimum delivery in clinical practice.
INTRODUCCIÓN Multitud de causas sistémicas producen encefalopatías (tabla 12-1), es decir, cuadros de disfunción encefálica difusa que clínicamente suelen manifestarse de dos maneras: alteracio-nes del nivel de conciencia y síndromes confusionales; ambas situaciones pueden acompañarse de défi cits focales, movimien-tos involuntarios, crisis comiciales y disautonomía (1, 2). Las encefalopatías agudas constituyen la primera causa de demanda de asistencia neurológica inmediata. Hasta un 40% de los ingre-sados en unidades de cirugía pueden sufrir un síndrome confu-sional; tasas similares se encuentran en unidades de cuidados intensivos. Privación de sueño, inmovilidad y exceso o falta de estimulación actúan como factores desencadenantes, sobre todo en pacientes ancianos y con deterioro cognitivo previo (1). El oxígeno y la glucosa son el soporte principal de la actividad encefálica, de ahí que, ante un paciente con sospecha de encefa-lopatía, la primera medida será valorar su función cardiorrespi-ratoria y glucemia, para proceder inmediatamente a su restable-cimiento si se hallasen perturbadas. Posteriormente se realizará una historia clínica detallada, anotando ordenadamente el esta-do de conciencia, orientación, memoria, contenido y curso del pensamiento, situación emocional y actividad psicomotora. También se prestará especial atención a signos de disfunción hemisférica y de tronco cerebral, así como a la presencia o ausen-cia de respuestas de descerebración y decorticación, mioclonias, asterixis y otros movimientos involuntarios (1, 2). ENCEFALOPATÍAS ISQUÉMICA, ANÓXICA E HIPERTENSIVA Una interrupción o disminución crítica del fl ujo sanguíneo cerebral, con el consiguiente desabastecimiento encefálico Encefalopatías metabólicas, carenciales y tóxicas Manuel Arias Gómez ÍNDICE DEL CAPÍTULO Introducción 237 Encefalopatías isquémica, anóxica e hipertensiva 237 Encefalopatía hepática 241 Encefalopatía urémica 244 Encefalopatía secundaria a septicemia 245 Encefalopatías endocrinas 246 Encefalopatías por trastornos hidroelectrolíticos 249 Encefalopatías carenciales 250 Encefalopatía alcohólica 254 Encefalopatías tóxicas 256 Bibliografía 258 12 MATEOS 12 (237-260).indd 237 MATEOS 12 (237-260).indd 237
Several million patients with liver cirrhosis suffer minimal hepatic encephalopathy (MHE), with mild cognitive and coordination impairments that reduce their quality of life and life span. Hyperammonemia and peripheral inflammation act synergistically to induce these neurological alterations. We propose that MHE appearance is due to changes in peripheral immune system, which are transmitted to brain, leading to neuroinflammation that alters neurotransmission leading to cognitive and motor alterations.
We summarize studies showing that MHE in cirrhotic patients is associated with alterations in the immune system and that patients died with HE show neuroinflammation in cerebellum, with microglial and astrocytic activation and Purkinje cell loss.
We also summarize studies in animal models of MHE on the role of peripheral inflammation in neuroinflammation induction, how neuroinflammation alters neurotransmission and how this leads to cognitive and motor alterations. These studies identify therapeutic targets and treatments that improve cognitive and motor function.
Rats with MHE show neuroinflammation in hippocampus and altered NMDA and AMPA receptor membrane expression, which impairs spatial learning and memory. Neuroinflammation in cerebellum is associated with altered GABA transporters and extracellular GABA, which impair motor coordination and learning in a Y maze.
These alterations are reversed by treatments that reduce peripheral inflammation (anti‐TNFα, ibuprofen), neuroinflammation (sulforaphane, p38 inhibitors), GABAergic tone (bicuculline, pregnenolone sulfate) or increase extracellular cGMP (sildenafil or cGMP).
The mechanisms identified would also occur in other chronic diseases associated with inflammation, aging and some mental and neurodegenerative diseases. Treatments that improve MHE may also be beneficial to treat these pathologies.
This article is protected by copyright. All rights reserved.
Background:
Increasing numbers of patients over the age of 60 are undergoing liver transplantation.
Objective:
We sought to determine whether age or clinical morbidities were associated with pre- and post-transplant executive and memory performance using the Brief Test of Adult Cognition by Telephone (BTACT).
Methods:
Participants included 36 recipients with n = 20 in the older group (>60 y) and n = 16 in the younger group (≤60 years). The BTACT was administered an average of 3 months before transplant, and at follow-up post-transplant intervals of 3, 6, and 9 months. BTACT composite scores for memory and executive function with age and education norms were obtained.
Results:
Older recipients were more likely to have hepatocellular carcinoma, a lower biological MELD score at transplant, less cellular rejection, and fewer post-operative hospital days. Older and younger recipients showed comparable pre-transplant executive and memory function and comparable post-transplant improvement. Both older and younger patients showed statistically significant improvement in executive function scores at 3 months post-transplant and maintained improvement at 6 and 9 months. Memory function improved significantly in older patients by 6 months post-transplant but did not improve significantly in the younger group.
Conclusion:
Older liver transplant recipients were more likely to have hepatocellular carcinoma and a lower biological MELD score than younger recipients, but both age groups showed comparable pre-transplant cognitive performance and post-transplant cognitive improvement. Additionally, a normed telephone test can be used to effectively screen and track executive and memory function post-transplant.
In the intersection of alcohol ingestion with the law, medical ethics, and public safety, physicians are often unsure about how to proceed. Physicians' primary focus should be on patient education with an ethical and legal duty to warn the patient of the adverse effects of alcohol. Warning third parties of potential harm related to alcohol-related impairment may involve a breach of patient confidentiality; therefore it should only be undertaken after careful analysis suggests that the risk for significant harm exceeds the burden that results to the patient from warning others. The law remains vague in this area.
Background:
Minimal hepatic encephalopathy (MHE) is a subclinical cognitive impairment frequently observable in cirrhotics. Proton pump inhibitors (PPIs) can contribute to small-bowel bacterial overgrowth but no study investigated the link between PPIs and MHE.
Aim:
to investigate the relationship between minimal HE and PPIs use as well as the role of PPIs use in the development of overt HE and survival.
Patients and methods:
310 consecutive cirrhotic patients were included in the study and followed up for 14.1±12.3 months. At entry, MHE was diagnosed when the Psychometric Hepatic Encephalopathy Score (PHES) was ≤ -4. Data were analyzed by logistic regression for the factors associated to MHE and by time related models for overt HE development and survival .
Results:
at inclusion, 131 out of 310 cirrhotic patients (42%) were affected by MHE. One hundred and twenty-five patients (40%) were using PPIs. The variables independently associated to the presence of MHE were: PPIs use, previous overt HE, low albumin, low sodium and age. During follow-up, the development of overt HE was higher (64% vs 25%; p<0.001) and overall survival lower (41% vs 81%; p<0.001) in PPIs users than in non-users. Variables independently associated to the development of overt HE were: PPIs, history of overt HE, low albumin, MHE and age while variables independently associated to mortality were: PPIs, development of overt HE, MELD score, age, low sodium and age.
Conclusion:
the study identifies a potentially removable factor associated to the presence of minimal HE and related to the development of overt HE and survival in patients with liver cirrhosis. This article is protected by copyright. All rights reserved.
Learning pathways in spatial navigation has been a subject of the literature in the last decade, one must bear about decision making and situation management. Column models were characterized few years ago and current implementations of the prefrontal brain cortex (PFC) simulated the rat behavior in a 3x3 maze given a Goal-Driven task. In this work, the simulation was adapted to study learning variables and goal task processing. The model was adapted to study different situations such a (1) 'µ' parameter value (for learning enhancement or degeneration) and different limits between a half and the entire amplitude of the threshold parameter, and (2) size of the maze (3x3, 3x4, 3x6 and 3x8 in tabulated simulations) related with the initial position of the rat and the goal condition (reward position). The initially position did not increment the average number of step to learn the way, but the when vertical size was increased to more than 4/3 the horizontal maze size, the number of steps was increased to learn the optimal pathway to reach to reward. Then, the larger size maze the more difficult to the PFC model to learn the optimal pathway and this was discussed in the current view of the entorhinal cortex and how this model process a different number of goals for a Goal-Driven task, especially considering modelling of adquisition and learning variables in the minicolumn model. A short discussion is extended about studies of situation management.
This chapter reviews clinical and research applications of electroencephalography (EEG) tools for the aging mind and brain. It addresses age-related changes in electrophysiological measures of oscillatory activity essential for neuronal communication. The chapter examines studies on age-related changes of evoked potentials. Waveforms constructed from signal averaging methods are characterized by sequentially alternating positive and negative deflections in EEG voltages - colloquially referred to as event-related potential (ERP) components - that track emerging neural activity associated with stimulus-evoked cognitive processes. According to current ERP studies, age-related compensatory mechanisms occur during relatively later working memory updating stages of cognitive processing, approximately 300 milliseconds after stimulus presentation. The chapter concludes with a discussion of remaining clinical challenges in application of EEG, particularly in delineating normal and abnormal electrographic findings in healthy elderly adults. It also concludes that there are ample opportunities for further experimental and applied neuroscience research in cognitive aging.
Aim:
To evaluate the efficacy of non-invasive multichannel electrical stimulation (sympathetic correction) in patients with alcohol amnesic (Korsakoff's) psychosis.
Material and methods:
Thirty-seven men, aged 33-48 years, with Korsakoff's (amnestic) psychosis were studied. The duration of disease varied from 12 to 24 month. The device of electrical stimulation of neck nerve structures was used for neuroelectrostimulation. Treatment included 15 sessions within 3 weeks. During this period, patients did not receive pharmacological therapy. The Frontal Assessment Battery (FAB), the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE) were used to determine changes in cognitive state of patients. Electroencephalography with qEEG analysis and spectral analysis of heart rate variability (HRV) were carried out as well.
Results and conclusion:
Positive effects of treatment were observed in all patients that suggested the high therapeutic potential of the neuroelectrostimulation method.
In many areas of the world, driving is an essential part of life and for reasons of comfort, convenience, and security remains the primary mode of transportation among older adults. Both normal aging and diseases that are more prevalent in advanced age can substantially reduce older drivers' functional abilities, elevating their risk of involvement in motor vehicle accidents and serious injury or death. Identifying and intervening with older drivers at increased crash risk is an important aspect of preventive medicine. The authors discuss the specific driving risks adults face as they age and how nurses can raise older patients' awareness of these risks. They also discuss the importance of connecting older adults to community resources that may help them continue driving safely for a longer period or find alternative transportation options.
The efficacy of game-like computerised adaptive training programmes for intensity aspects of attention (alertness and vigilance) and selectivity aspects of attention (selective and divided attention) was studied in patients with left or right focal brain damage of vascular aetiology. Each patient received consecutive training in the two most impaired of the four attention domains. Control tests were performed by means of a standardised computerised attention test battery comprising tests for the four attention functions. Assessment was carried out at the beginning and after each of two training periods of 14 one-hour sessions each. There were significant specific training effects for both intensity aspects (alertness and vigilance), and also for response time in the selective attention and error rate in the divided attention task. For selectivity aspects of attention, reaction time also improved after training of basic attention domains. The application of inferential single case procedures revealed not only a high degree of specific training effects in individual cases but also a substantial number of deteriorations in performance after non-specific training of basic attention problems by tasks requiring selectivity of attention. The results are discussed in the light of a hierarchical organisation of attention functions.
This chapter first reviews efforts to develop a cognitive model of executive control and considers how experimental methods can be used to explore conditions in which executive attention operates. In the 2nd section, neuroimaging studies that employ those cognitive methods to explore the anatomy and circuitry of executive attention are examined. The 3rd section considers evidence from lesion, schizophrenia, and developmental studies that provide further tests of which areas are involved in executive attention. Finally, future opportunities for dissociating components of executive function are considered. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
: The concept of attention as central to human performance extends back to the start of experimental psychology, yet even a few years ago, it would not have been possible to outline in even a preliminary form a functional anatomy of the human attentional system. New developments in neuroscience have opened the study of higher cognition to physiological analysis, and have revealed a system of anatomical areas that appear to be basic to the selection of information for focal (conscious) processing. The importance of attention is its unique role in connecting the mental level of description of processes used in cognitive science with the anatomical level common in neuroscience. Sperry describes the central role that mental concepts play in understanding brain function. As is the case for sensory and motor systems of the brain, our knowledge of the anatomy of attention is incomplete. Nevertheless, we can now begin to identify some principles of organization that allow attention to function as a unified system for the control of mental processing. Although many of our points are still speculative and controversial, we believe they constitute a basis for more detailed studies of attention from a cognitive-neuroscience viewpoint. Perhaps even more important for furthering future studies, multiple methods of mental chronometry, brain lesions, electrophysiology, and several types of neuro-imaging have converged on common findings.
The ability to image the human brain has provided a new perspective for neuropsychologists in their efforts to understand, diagnose, and treat insults to the human brain that might occur as the result of stroke, tumor, traumatic injury, degenerative disease, or errors in development. These new findings are the major theme of this special issue. In our article, we consider brain networks that carry out the functions of attention. We outline several such networks that have been studied in normal and pathological states. These include networks for orienting to sensory stimuli, for maintaining the alert state, and for orchestrating volitional control. There is evidence that these networks have a certain degree of anatomical and functional independence, but that they also interact in many practical situations. Damage to each of these networks, irrespective of the source, produces distinctive neuropsychological deficits. We consider the links between the etiology of the injury and changes in cognition and behavior and examine the role of brain imaging in the study of rehabilitation.
Attention is a complex neurobehavioral domain that is essential for all higher functions. Large areas of the brain are devoted to attention, reflecting its importance in the entire range of mental operations. Currently, two major distributed neural networks are recognized as mediating complementary aspects of attentional function. One is a diffuse system that distributes attention globally. This attentional system is subserved by a widespread network of thalamic and bihemispheric structures in which the frontal lobes are particularly important. The second network, a focal system that distributes attention to salient aspects of spatial experience, is lateralized to frontal and parietal regions of the right hemisphere. Both attentional networks are comprised of cortical and subcortical gray matter structures, as well as connecting white matter tracts that integrate these regions into functional ensembles. Neurological disorders frequently produce dramatic syndromes reflecting dysfunction of these networks. Among these syndromes are the acute confusional state, which results from disturbance of the diffuse system, and left neglect, which follows disruption of the right hemisphere system. The neuroanatomy of attention is crucial for understanding important neurobehavioral syndromes and their treatment.
The parietal lobe forms about 20% of the human cerebral cortex and is divided into two major regions, the somatosensory cortex and the posterior parietal cortex. Posterior parietal cortex, located at the junction of multiple sensory regions, projects to several cortical and subcortical areas and is engaged in a host of cognitive operations. One such operation is selective attention, the process where by the input is filtered and a subset of the information is selected for preferential processing. Recent neuroimaging and neuropsychological studies have provided a more fine-grained understanding of the relationship between brain and behavior in the domain of selective attention.
A differentiation of memory is possible on the basis of chronological and contents-related aspects. Furthermore, it is possible to make process-specific subdivisions (encoding, transfer, consolidation, retrieval). The time-related division on the one hand refers to the general differentiation into short-term and long-term memory, and, on the other, to that between anterograde and retrograde memory ("new" and "old memory"; measured from a given time point, usually that when brain damage occurred). Anterograde memory means the successful encoding and storing of new information; retrograde the ability to retrieve successfully acquired and/or stored information. On the contents-based level, memory can be divided into five basic long-term systems-episodic memory, the knowledge system, perceptual, procedural and the priming form of memory. Neural correlates for these divisions are discussed with special emphasis of the episodic and the knowledge systems, based both on normal individuals and brain-damaged subjects. It is argued that structures of the limbic system are important for encoding of information and for its transfer into long-term memory. For this, two independent, but interacting memory circuits are proposed-one of them controlling and integrating primarily the emotional, and the other primarily the cognitive components of newly incoming information. For information storage principally neocortical structures are regarded as important and for the recall of information from the episodic and semantic memory systems the combined action of portions of prefrontal and anterior temporal regions is regarded as essential. Within this fronto-temporal agglomerate, a moderate hemispheric-specificity is assumed to exist with the right-hemispheric combination being mainly engaged in episodic memory retrieval and the left-hemispheric in that of semantic information. Evidence for this specialization comes from the results from focally brain-damaged patients as well as from that functional brain imaging in normal human subjects. Comparing results from imaging studies in memory disturbed patients with brain damage and from patients with a psychiatric diagnosis (e.g., psychogenic amnesia) revealed that both patient groups demonstrate comparable metabolic changes on the brain level. It can therefore be concluded that in neurological patients distinct, identifiable tissue damage is existent, while in psychiatric patients changes in the brain's biochemistry (release of stress hormones, and transmitters) constitute the physiological bases for the memory disturbances.
brain structures that are of critical importance for the transmission of information for long-term storage or for retrieval are reviewed; it is emphasized that in addition to the partition of memory along the dimension time, a contents-based division is necessary to describe the processing of information within brain circuits / this review emphasizes the importance of the major telencephalic nuclei, probably together with the cerebellum, for the processing of priming and procedural memory / here, the basal ganglia have a central role for skill memories, while certain forms of priming or affective-autonomous information processing may involve nonprimary cortical regions and the amygdala as well (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Although no neuron is exclusively devoted to attention, all areas of the cerebral cortex display attentional modulations, which are more prominent in downstream components of sensory pathways and within limbic and heteromodal association areas. Through attentional modulations, the mental representation of experience transcends surface appearances and becomes sensitive to behavioral relevance. Domain-specific attentional responses are under the bottom-up influence of the ascending reticular activating system and the top-down influence of frontoparietal and limbic cortices. Lesions that interfere with the bottom-up or top-down regulation of attention or disruption of attentional modulations give rise to the clinical syndrome of acute confusional states. Contralesional neglect represents a domain-specific impairment of spatial attention. A large-scale distributed network with cortical epicenters in the posterior parietal cortex, frontal eye field, and cingulate gyrus mediates the transformation of extrapersonal events into internal representations that can then be targeted for attentional shifts. Damage to any cortical or subcortical component of this network leads to contralesional neglect. The topic of functional anatomy of unilateral neglect is also discussed. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Administered Kimura's Recurring-Figures-Test to 427 normal Ss from Germany. A Kuder-Richardson test reliability of rtt = .94 was obtained. T-scale norms are given for two subgroups of different educational level.
We report experience with a modification of the Wada test used before temporal lobe resection in patients with drug-resistant epilepsy. Our procedure consists of injection of amytal via a microcatheter into the anterior choroidal artery or the P2 segment of the posterior cerebral artery and simultaneous presentation of verbal and figural memory test material before, during and after the injection. Pros and cons of the modification and inherent shortcomings of the amytal test are discussed on the basis of the results in ten patients.
The rapid visual information processing (RVIP) task, a test of sustained attention which also requires working memory for its successful execution, has been used in a number of human psychopharmacological studies. Single digits are presented in quick succession (100 or 200 digits/min) on a computer screen, and target sequences of numbers must be detected with a button press. Although previous neuroimaging studies have implicated the frontal and parietal cortices in performance of simple sustained attention tasks, the neuroanatomical substrates of RVIP performance are not yet known. This information would prove invaluable in the interpretation of drug effects on this task, possibly delineating a neuronal network for neurotransmitter action. Therefore, this study investigated the functional anatomy of the RVIP task using positron emission tomography (PET) derived measures of regional cerebral blood flow (rCBF) in eight healthy volunteers. Subjects were required to perform variants of the RVIP task which manipulated both the level of working memory load and the speed of stimulus presentation. Compared with a rest condition (eyes closed), the RVIP task increased rCBF bilaterally in the inferior frontal gyri, parietal cortex and fusiform gyrus, and also in the right frontal superior gyrus rostrally. In comparison with a simple sustained attention control condition, the aforementioned right frontal activations were no longer apparent. We suggest that these data are consistent with the existence of a right fronto-parietal network for sustained, and possibly selective, attention, and a left fronto-parietal network for the phonological loop component of working memory.
Experiments were conducted to elucidate the role of the noradrenergic neurotransmitter system in arousal and the orienting of attention. Rhesus monkeys were trained to perform a peripherally cued, covert orienting task for juice reward, and their manual reaction times (RTs) to visual stimuli were measured. The effects of parenteral injections of the alpha-2 adrenergic agonists clonidine and guanfacine, and normal saline were compared on the covert task. We assessed 1) overall error rates, 2) the difference in RTs between validly and invalidly cued trials (validity effect), 3) the difference in RTs between neutral and no-cue trials (alerting effect), 4) target location (visual field), and 5) cue-target interval. Changes in noradrenaline levels produced by clonidine (and to a lesser extent guanfacine) significantly decreased the alerting effect, and lowered RTs to stimuli in the left visual field, but did not change the validity effect, suggesting that noradrenaline is involved in maintaining non-spatial, sensory readiness to external cues but not in the shifting of the attentional focus.
Attentional dysfunction, which influences overall cognitive productivity, is not well characterized in cirrhotic patients. The aim of this study was to clarify the features of covert visual attention orienting in cirrhotics without overt hepatic encephalopathy. One hundred consecutive cirrhotic patients and 40 controls were enrolled. Visual covert attention orienting was assessed by the Posner test, which evaluates the effect of a cue on visual reaction times. Patients were characterized by the number connection test (NCT) and electroencephalographic (EEG) spectral analysis. The severity of liver disease was graded using standard laboratory parameters and the Child-Pugh's classification. Fifty-five psychometric and EEG evaluations were performed in the follow-up of 17 patients to assess the relationship between the variations of psychometric and neurophysiological findings. NCT and quantified-EEG parameters (altered in 19% and 40% of cirrhotic patients, respectively) were linked to each other and to the severity of liver disease. The Posner test showed a delay of visual reaction times in class B-C cirrhotic patients. Reaction times were correlated with ammonia and EEG parameters. The effect of the cue was higher in cirrhotic patients than in controls, particularly in the invalid position. This study suggests that cirrhotic patients have a reduced activity rate and reduced capacity to disengage attention previously focused on a cue. Such alterations are linked to NCT and EEG findings.
Currently, diagnoses of attention deficit hyperactivity disorder (ADHD) and hyperkinetic disorder (HKD) are made on the basis of phenomenology, but information is accumulating from the neurosciences about the biological bases of these disorders. Recent studies addressing the neuropsychology, neuroanatomy, neurochemistry, and molecular biology of ADHD/HKD document abnormalities in well-defined neuroanatomical networks and neurochemical pathways. Magnetic resonance imaging (MRI) studies have shown that some regions of the frontal lobes (anterior superior and inferior) and basal ganglia (caudate nucleus and globus pallidus) are about 10% smaller in ADHD groups than in control groups of children, and molecular genetic studies have shown that diagnosis of ADHD is associated with polymorphisms in some dopamine genes (the dopamine D4 receptor gene and the dopamine transporter gene).
The anterior cingulate cortex has been activated by color Stroop tasks, supporting the hypothesis that it is recruited to mediate response selection or allocate attentional resources when confronted with competing information-processing streams. The current study used the newly developed "Counting Stroop" to identify the mediating neural substrate of cognitive interference. The Counting Stroop, a Stroop variant allowing on-line response time measurements while obviating speech, was created because speaking produces head movements that can exceed those tolerated by functional magnetic resonance imaging (fMRI), preventing the collection of vital performance data. During this task, subjects report by button-press the number of words (1-4) on the screen, regardless of word meaning. Interference trials contain number words that are incongruent with the correct response (e.g., "two" written three times), while neutral trials contain single semantic category common animals (e.g., "bird"). Nine normal right-handed adult volunteers underwent fMRI while performing the Counting Stroop. Group fMRI data revealed significant (P < or = 10(-4) activity in the cognitive division of anterior cingulate cortex when contrasting the interference vs. neutral conditions. On-line performance data showed 1) longer reaction times for interference blocks than for neutral ones, and 2) decreasing reaction times with practice during interference trials (diminished interference effects), indicating that learning occurred. The performance data proved to be a useful guide in analyzing the image data. The relative difference in anterior cingulate activity between the interference and neutral conditions decreased as subjects learned the task. These findings have ramifications for attentional, cognitive interference, learning, and motor control mechanism theories.
There is accumulating evidence to suggest that cholinergic neurotransmission may play an important role in visuospatial attention, but the brain sites at which acetylcholine modulates attention are not well understood. The present work tested the hypothesis that the cholinergic influences within the intraparietal cortex are necessary for normal attentional shifting (covert orienting) in nonhuman primates. Two rhesus monkeys were trained to perform a visual, cued target detection task for liquid reinforcement. The animals pressed a lever to produce a visual display in which a central fixation point was flanked by two circles. Shortly after fixation was established, one of the circles brightened (cue), and a target appeared subsequently within one of the circles. Detection was signaled by a manual response and the reaction time to the appearance of the target was recorded. Four types of trials were presented. For valid cue trials, the cue and target were at the same spatial location; for invalid cues, cue and target were in opposite hemifields; for double cues, both cues were brightened but the target appeared in either the left or right circle; in no-cue trials, the cue was omitted. We localized the intraparietal region by recording attention-related, cellular activity with intracerebral microelectrodes. Among visually responsive cells in this area, valid cues presented to the receptive fields of visual neurons enhanced the responses to target stimuli in about half the cells and inhibited those responses in the remainder. In addition, some cells showed longer response latencies to invalid cues than to valid cues. We then infused scopolamine into attention-related activity sites and assessed its effect on performance. Scopolamine produced a dose-dependent increase in reaction times and decrease in performance accuracy that lasted more than 1 h. Neither vehicle injections in the same locations nor scopolamine outside the physiologically defined area produced any significant change in behavior. Under our conditions of measurement, we conclude that activity mediated by muscarinic cholinergic receptors within the intraparietal cortex is necessary for normal covert orienting.
Recent neurobiological studies have begun to reveal the cognitive and neural coding mechanisms that underlie declarative memory--our ability to recollect everyday events and factual knowledge. These studies indicate that the critical circuitry involves bidirectional connections between the neocortex, the parahippocampal region and the hippocampus. Each of these areas makes a unique contribution to memory processing. Widespread high-order neocortical areas provide dedicated processors for perceptual, motor or cognitive information that is influenced by other components of the system. The parahippocampal region mediates convergence of this information and extends the persistence of neocortical memory representations. The hippocampus encodes the sequences of places and events that compose episodic memories, and links them together through their common elements. Here I describe how these mechanisms work together to create and re-create fully networked representations of previous experiences and knowledge about the world.
Minimal hepatic encephalopathy (HE) is characterized by a decrease of psychomotor speed, and deficits in visual perception, visuo-spatial orientation, and visuo-constructive abilities. Attention deficits have also been proposed to be part of the syndrome. Several attempts were made in the past to elaborate suitable psychometric means for the assessment of minimal HE. However, there is still no "gold standard" for the diagnosis of minimal HE. We recently evaluated the so called "PSE-Test" for the assessment of minimal HE, a test battery which does not include a test predominantly aimed at the assessment of attention. We therefore presented a battery of attention tests in addition to the PSE-Test to a group of cirrhotics without clinical signs of HE compared to a healthy control group matched for age and education to determine whether the addition of special attention tests would increase the diagnostic sensitivity of the PSE-Test. It was shown that the patients with a pathological PSE-Test result differed significantly from controls in all attention tests applied, while the patients with normal PSE-Test results achieved attention test results similar to that of the controls. Thus, the PSE-Test results represent attention deficits as well as deficits in motor skills, visuo-spatial orientation, and visual construction.
Research on hepatic encephalopathy is hampered by the imprecise definition of this disabling complication of liver disease. Under this light, the Organisation Mondiale de Gastroentérologie commissioned a Working Party to reach a consensus in this area and to present it at the 11th World Congress of Gastroenterology in Vienna (1998). The Working Party continued its work thereafter and now present their final report. In summary, the Working Party has suggested a modification of current nomenclature for clinical diagnosis of hepatic encephalopathy; proposed guidelines for the performance of future clinical trials in hepatic encephalopathy; and felt the need for a large study to redefine neuropsychiatric abnormalities in liver disease, which would allow the diagnosis of minimal (subclinical) encephalopathy to be made on firm statistical grounds. In the interim, it proposes the use of a psychometric hepatic encephalopathy score, based on the result of 5 neuropsychologic tests. Finally, the need for a careful evaluation of the newer neuroimaging modalities for the diagnosis of hepatic encephalopathy was stressed.
Many cirrhotics have abnormal neuropsychological test scores. To define the anatomical-physiological basis for encephalopathy in nonalcoholic cirrhotics, we performed resting-state fluorodeoxyglucose positron emission tomographic scans and administered a neuropsychological test battery to 18 patients and 10 controls. Statistical parametric mapping correlated changes in regional glucose metabolism with performance on the individual tests and a composite battery score. In patients without overt encephalopathy, poor performance correlated with reductions in metabolism in the anterior cingulate. In all patients, poor performance on the battery was positively correlated (p < 0.001) with glucose metabolism in bifrontal and biparietal regions of the cerebral cortex and negatively correlated with metabolism in hippocampal, lingual, and fusiform gyri and the posterior putamen. Similar patterns of abnormal metabolism were found when comparing the patients to 10 controls. Metabolic abnormalities in the anterior attention system and association cortices mediating executive and integrative function form the pathophysiological basis for mild hepatic encephalopathy.
A differentiation of memory is possible on the basis of chronological and contents-related aspects. Furthermore, it is possible to make process-specific subdivisions (encoding, transfer, consolidation, retrieval). The time-related division on the one hand refers to the general differentiation into short-term and long-term memory, and, on the other, to that between anterograde and retrograde memory ("new" and "old memory"; measured from a given time point, usually that when brain damage occurred). Anterograde memory means the successful encoding and storing of new information; retrograde the ability to retrieve successfully acquired and/or stored information. On the contents-based level, memory can be divided into five basic long-term systems--episodic memory, the knowledge system, perceptual, procedural and the priming form of memory. Neural correlates for these divisions are discussed with special emphasis of the episodic and the knowledge systems, based both on normal individuals and brain-damaged subjects. It is argued that structures of the limbic system are important for encoding of information and for its transfer into long-term memory. For this, two independent, but interacting memory circuits are proposed--one of them controlling and integrating primarily the emotional, and the other primarily the cognitive components of newly incoming information. For information storage principally neocortical structures are regarded as important and for the recall of information from the episodic and semantic memory systems the combined action of portions of prefrontal and anterior temporal regions is regarded as essential. Within this fronto-temporal agglomerate, a moderate hemispheric-specificity is assumed to exist with the right-hemispheric combination being mainly engaged in episodic memory retrieval and the left-hemispheric in that of semantic information. Evidence for this specialization comes from the results from focally brain-damaged patients as well as from that functional brain imaging in normal human subjects. Comparing results from imaging studies in memory disturbed patients with brain damage and from patients with a psychiatric diagnosis (e. g., psychogenic amnesia) revealed that both patient groups demonstrate comparable metabolic changes on the brain level. It can therefore be concluded that in neurological patients distinct, identifiable tissue damage is existent, while in psychiatric patients changes in the brain's biochemistry (release of stress hormones, and transmitters) constitute the physiological bases for the memory disturbances.
Early hepatic encephalopathy (HE) is characterized by deficits in motor performance, visual perception, visuo-constructive abilities and attention. Whether defective memory is a feature of early HE is controversial.
To analyze memory function in patients with early HE.
Memory tests were applied to cirrhotic patients with grade 0 HE, minimal HE and grade I HE (n=45) and controls (n=52). The battery included short and long term memory tests requiring free recall or recognition. Minimal HE was diagnosed by assessing the psychometric hepatic encephalopathy score using the PSE-Syndrom-Test and by carrying out a neurological examination. Group differences of the test results were analyzed using analysis of covariance.
HE 0 patients achieved test results similar to the controls in all but two tests. Patients with early HE (minimal and grade I HE) scored lower than the controls in all tests applied. A detailed analysis of test performance showed that the patients' deficits were in attention and visual perception, rather than memory.
Patients with early HE score lower than controls in memory tasks predominantly because of deficits in attention and visual perception.
PSE-Syndrom-Test. Psychodi-agnostisches Verfahren zur quantitativen Erfassung der (minimalen) portosystemischen Enzephalopathie Portal-systemic encephalopathy. Neuro-logical complications of liver disease
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Schomerus, H., Weissenborn, K., Hamster, W., Rü, N., and Hecker, H. (1999). PSE-Syndrom-Test. Psychodi-agnostisches Verfahren zur quantitativen Erfassung der (minimalen) portosystemischen Enzephalopathie. Swets Test Services, Frankfurt. Sherlock, S., Summerskill, W.H.J., White, L.P., and Phear, E.A. (1954). Portal-systemic encephalopathy. Neuro-logical complications of liver disease. Lancet I:453–457.
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Le test de copie d'une figure complexe
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