Neural mechanism underlying impaired visual judgement in the dysmetabolic brain: an fMRI study
Introduction
Hepatic encephalopathy (HE) as a consequence of liver dysfunction in both acute and chronic hepatic diseases is a disorder frequently observed in association with changes of personality, motor coordination, and altered sleep patterns followed by shortened attention span Butterworth, 1996, Sherlock et al., 1954, Summerskill et al., 1956. Early after the onset, HE is accompanied by an impairment of the ability to cope with daily decision-demanding situations Groeneweg et al., 1998, Rikkers et al., 1978.
Positron emission tomography (PET) studies observed an altered glucose metabolism in patients without clinically overt HE (Lockwood et al., 1991) and described a correlation between brain activity and psychologic performance variables Lockwood, 1998, Lockwood, 2002b, Lockwood et al., 1993, Lockwood et al., 1998 via methods of statistical parametric mapping (Frackowiak et al., 1997). In these studies, poor performance in a variety of neuropsychologic tests was particularly related to a reduction of glucose metabolism in parietal and prefrontal regions in nonmanifest hepatic encephalopathy (nmHE) patients.
To quantify the severity of HE in patients via a single psychologic performance variable, a psychophysical procedure was derived from the neuropsychologic Vienna Test System Eberhardt, 1994, Kircheis et al., 2002, Vienna Test System (WINWTS), 1999. During the test, subjects viewed an initially constant light source and were required to detect and indicate the apparent transition from the steady light to the onset of a flickering of the light, that is, the critical flicker frequency (CFF).
The relation between the simple but practicable accessible performance variable CFF and the clinical staging of HE patients performed with a standardized set up is illustrated in Fig. 1A. To explore the neural mechanism underlying the impaired performance of patients during a very early stage of HE (nmHE patients), we designed a functional magnetic resonance imaging (fMRI)-compatible version of the visual motion inducing flicker light test (Fig. 1B) as applied to patients suffering from HE (Kircheis et al., 2002; Fig. 1).
In previous neuroimaging studies, the characterization of the functional architecture underlying attention to changes in visual motion has been explored as a network and in its subparts (e.g., Büchel et al., 1998, Kleinschmidt et al., 2002, Tootell and Maunsell, 1996, Tootell et al., 1995, Zeki et al., 1991), and interactions between parietal and prefrontal areas with the visual system were identified at the level of V5/MTL Beauchamp and DeYoe, 1995, Beauchamp and DeYoe, 1996, Büchel and Friston, 1997, Chawla et al., 1999a, Chawla et al., 1999b, Friston and Büchel, 2000, Friston et al., 1997.
Our first hypothesis was that alterations of the blood oxygenation level-dependent (BOLD) signal are detectable in the parietal and/or prefrontal cortex of nmHE patients in comparison to control subjects, since alterations of these cortical regions were observed in PET studies using 18F-fluoro-deoxyglucose Lockwood, 1998, Lockwood, 2002b, Lockwood et al., 1993, Lockwood et al., 1998. This hypothesis is further supported by the concept of the “neuron–lactate–astrocyte trafficking” Magistretti and Pellerin, 1999a, Magistretti and Pellerin, 1999b, Magistretti et al., 1999, Tsacopoulos and Magistretti, 1996. It relates the metabolic and vascular correlates of brain activation registered as BOLD-signal activity in fMRI (Raichle, 2001) to an interaction between neurons and astrocytes. Under the pathologic conditions of HE (for a review, see Lockwood, 2002a), an accumulation of neurotoxic substances, especially of ammonia normally metabolized by the liver, leads to a gradual dysmetabolism affecting neurons Raabe, 1987, Szerb and Butterworth, 1992 and astrocytes Butterworth et al., 1987, Norenberg, 1987. Especially astrocytes build a structural part of the blood–brain barrier that regulates glucose uptake (Butterworth, 1993) and in turn influences the signal in PET studies.
Our second hypothesis was that the coupling between parietal or prefrontal regions and motion-sensitive areas such as area V5/MTL is increasingly impaired as the severity of HE progresses. We therefore operationalized “HE severity” in a design of psychophysiologic interaction (PPI; Friston et al., 1997, Frith and Friston, 1996), assuming a modulation of the interaction between cortical regions by the pathophysiologic impairment in the patients. We defined “HE severity” by CFF in a design for PPI according to the experimentally measured relation illustrated in Fig. 1A. Moreover, it has been shown (Kircheis et al., 2002) that degradation of the status of patients with preexisting HE after transjugular intrahepatic portosystemic stent shunt (TIPS) implantation was accompanied by a decrease of CFF in contrast to an increase of CFF when the status improved temporarily. Due to its diagnostic and prognostic relevance Lockwood, 1998, Lockwood, 2000, we focused on this controversially discussed group of patients with the nonmanifest or low-graded form of HE (Ferenci et al., 2002). This group of patients is supposed to be categorizable between normality and overt metabolic encephalopathy induced by liver dysfunction and has been reported to show impaired performance on neuropsychologic tasks such as visuopractic capacity, learning, memory, language, attention, and executive function tests Srivastava et al., 1994, Tarter et al., 1984, Watanabe et al., 1997, Weissenborn et al., 2001.
Section snippets
Material and methods
This study was approved by the ethics committee of the University Hospital of Düsseldorf according to the Declaration of Helsinki, and the subjects' informed consent was obtained. Nine patients [age = 52.3 ± 3.5 (mean ± SE)] with nmHE and 10 control subjects [age = 49.6 ± 3.8 (mean ± SE)] were scanned. All participants were right-handed, three subjects of the nonmanifest and control group were female, and all others were male. There were no significant differences between the ages (t = −0.523, P
Task performance
The mean values of critical flicker frequency were averaged over all subjects of a group for a common imaging trial and plotted against the trial sequence in the scanner (Fig. 2). The percentage of button responses during an experimental run of the control subject group was 96.2% ± 1.9% (mean ± SE), the percentage of button response of the patients suffering from nmHE was 97.43% ± 2.5% (mean ± SE). There was no statistically significant difference in the number of button responses between both
Discussion
Results from previous neuroimaging studies using different motion detection paradigms Beauchamp and DeYoe, 1995, Beauchamp and DeYoe, 1996, Büchel and Friston, 1997, Büchel et al., 1998, Chawla et al., 1999a, Chawla et al., 1999b, Friston and Büchel, 2000, Friston et al., 1997, Kleinschmidt et al., 2002, Tootell and Maunsell, 1996, Tootell et al., 1995, Zeki et al., 1991 enabled specific predictions concerning activated networks during the detection of the transition from a constant light to
Acknowledgements
We owe a special thank to N. Palomero-Gallagher, K. E. Stephan, A. Ritzl, U. Pietrzyk, M. Zaitsev, and B. Elghawaghi for technical assistance. The work was supported by Programme Grants from the SFB Nr. 575 to K. Z., D. H., and G. K.
References (89)
- et al.
Brain areas for processing motion and their modulation by selective attention
NeuroImage
(1996) - et al.
Polymodal motion processing in posterior parietal and premotor cortex: a human fMRI study strongly implies equivalencies between humans and monkeys
Neuron
(2001) - et al.
Speed-dependent responses in V5: a replication study
NeuroImage
(1999) - et al.
Hepatic encephalopathy—Definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998
Hepatology
(2002) - et al.
Deriving numerosity and shape from identical visual displays
NeuroImage
(2001) - et al.
Degeneracy and redundancy in cognitive anatomy
Trends. Cogn. Sci.
(2003) - et al.
Psychophysiological and modulatory interactions in neuroimaging
NeuroImage
(1997) - et al.
The role of the thalamus in “top down” modulation of attention to sound
NeuroImage
(1996) - et al.
Modeling regional and psychophysiologic interactions in fMRI: the importance of hemodynamic deconvolution
NeuroImage
(2003) - et al.
Proton magnetic resonance spectroscopy studies on human brain myo-inositol in hypoosmolarity and hepatic encephalopathy
Gastroenterology
(1994)
Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema?
J. Hepatol.
Neuronal–astrocytic and cytosolic–mitochondrial metabolite trafficking during brain activation, hyperammonemia and energy deprivation
Neurochem. Int.
Critical flicker frequency for quantification of low-grade hepatic encephalopathy
Hepatology
Neural correlates of visual-motion perception as object- or self-motion
NeuroImage
“What's in a name?” Improving the care of cirrhotics
J. Hepatol.
Hepatic encephalopathy
Neurol. Clin.
Effective connectivity and intersubject variability: using a multisubject network to test differences and commonalities
NeuroImage
Regional cerebral blood flow and cognitive function in patients with chronic liver disease
Lancet
Voluntary attention modulates fMRI activity in human MT-MST
Neuron
Spatial dependence of the nonlinear BOLD response at short stimulus duration
NeuroImage
Degeneracy and cognitive anatomy
Trends Cogn. Sci.
Subclinical hepatic encephalopathy: detection, prevalence, and relationship to nitrogen metabolism
Gastroenterology
Portal-systemic encephalopathy. Neurological implications of liver disease
Lancet
Fitness to drive in patients with cirrhosis and portal-systemic shunting: a pilot study evaluating driving performance
J. Hepatol.
Effect of ammonium ions on synaptic transmission in the mammalian central nervous system
Prog. Neurobiol.
Nonalcoholic cirrhosis associated with neuropsychological dysfunction in absence of overt evidence of hepatic encephalopathy
Gastroenterology
Mu rhythm modulation during changes of visual percepts
Neuroscience
Clinical efficacy of lactulose in cirrhotic patients with and without non-manifest hepatic encephalopathy
Hepatology
Neuropsychological characterization of hepatic encephalopathy
J. Hepatol.
FMRI reveals feature-specific attentional modulation of area MT, V3/V3a and parietal visual areas
Soc. Neurosci. Abstr.
Modulation of connectivity in visual pathways by attention: cortical interactions evaluated with structural equation modelling and fMRI
Cereb. Cortex
The functional anatomy of attention to visual motion. A functional MRI study
Brain
Portal-systemic encephalopathy: a disorder of neuron–astrocytic metabolic trafficking
Dev. Neurosci.
The neurobiology of hepatic encephalopathy
Semin. Liver Dis.
Metabolic encephalopathies
Pathophysiology of hepatic encephalopathy: a new look at ammonia
Metab. Brain Dis.
Ammonia: key factor in the pathogenesis of hepatic encephalopathy
Neurochem. Pathol.
The physiological basis of attentional modulation in extrastriate visual areas
Nat. Neurosci.
BrainWeb: online interface to a 3D MRI simulated brain database
NeuroImage
Quantifying the severity of hepatic encephalopathy
Parietal neglect and visual awareness
Nat. Neurosci.
Investigating temporal pole function by functional imaging
Epileptic Disord.
Flimmerfrequenz-Analysator. Automatische Messmethode. Version 3.00
Subclinical hepatic encephalopathy—Does it exist?
Cited by (0)
- 1
Present address: Department of Psychiatry, University of Bonn, Roemerstr. 164, D-53117 Bonn, Germany.