Impaired Tactile Temporal Discrimination in Patients With Hepatic Encephalopathy

The sensory system constantly receives stimuli from the external world. To discriminate two stimuli correctly as two temporally distinct events, the temporal distance or stimulus onset asynchrony (SOA) between the two stimuli has to exceed a specific threshold. If the SOA between two stimuli is shorter than this specific threshold, the two stimuli will be perceptually fused and perceived as one single stimulus. Patients with hepatic encephalopathy (HE) are known to show manifold perceptual impairments, including slowed visual temporal discrimination abilities as measured by the critical flicker frequency (CFF). Here, we hypothesized that HE patients are also impaired in their tactile temporal discrimination abilities and, thus, require a longer SOA between two tactile stimuli to perceive the stimuli as two temporally distinct events. To test this hypothesis, patients with varying grades of HE and age-matched healthy individuals performed a tactile temporal discrimination task. All participants received two tactile stimuli with varying SOA applied to their left index finger and reported how many distinct stimuli they perceived (“1” vs. “2”). HE patients needed a significantly longer SOA (138.0 ± 11.3 ms) between two tactile stimuli to perceive the stimuli as two temporally distinct events than healthy controls (78.6 ± 13.1 ms; p < 0.01). In addition, we found that the temporal discrimination ability in the tactile modality correlated positively with the temporal discrimination ability in the visual domain across all participants (i.e., negative correlation between tactile SOA and visual CFF: r = −0.37, p = 0.033). Our findings provide evidence that temporal tactile perception is substantially impaired in HE patients. In addition, the results suggest that tactile and visual discrimination abilities are affected in HE in parallel. This finding might argue for a common underlying pathophysiological mechanism. We argue that the known global slowing of neuronal oscillations in HE might represent such a common mechanism

Chemical exchange saturation transfer imaging in hepatic encephalopathy

Hepatic encephalopathy (HE) is a common complication in liver cirrhosis and associated with an invasion of ammonia into the brain through the blood-brain barrier. Resulting higher ammonia concentrations in the brain are suggested to lead to a dose-dependent gradual increase of HE severity and an associated impairment of brain function. Amide proton transfer-weighted (APTw) chemical exchange saturation transfer (CEST) imaging has been found to be sensitive to ammonia concentration. The aim of this work was to study APTw CEST imaging in patients with HE and to investigate the relationship between disease severity, critical flicker frequency (CFF), psychometric test scores, blood ammonia, and APTw signals in different brain regions.Whole-brain APTw CEST images were acquired in 34 participants (14 controls, 20 patients (10 minimal HE, 10 manifest HE)) on a 3 T clinical MRI system accompanied by T1 mapping and structural images. T1 normalized magnetization transfer ratio asymmetry analysis was performed around 3 ppm after B0 and B1 correction to create APTw images. All APTw images were spatially normalized into a cohort space to allow direct comparison. APTw images in 6 brain regions (cerebellum, occipital cortex, putamen, thalamus, caudate, white matter) were tested for group differences as well as the link to CFF, psychometric test scores, and blood ammonia.A decrease in APTw intensities was found in the cerebellum and the occipital cortex of manifest HE patients. In addition, APTw intensities in the cerebellum correlated positively with several psychometric scores, such as the fine motor performance scores MLS1 for hand steadiness / tremor (r = 0.466; p = .044) and WRT2 for motor reaction time (r = 0.523; p = .022). Moreover, a negative correlation between APTw intensities and blood ammonia was found for the cerebellum (r = −0.615; p = .007) and the occipital cortex (r = −0.478; p = .045). An increase of APTw intensities was observed in the putamen of patients with minimal HE and correlated negatively with the CFF (r = −0.423; p = .013).Our findings demonstrate that HE is associated with regional differential alterations in APTw signals. These variations are most likely a consequence of hyperammonemia or hepatocerebral degeneration processes, and develop in parallel with disease severity. Keywords: Amide proton, Ammonia, Critical flicker frequency, CEST, CFF, Liver cirrhosi

Paired associative stimulation demonstrates alterations in motor cortical synaptic plasticity in patients with hepatic encephalopathy

Objective: Hepatic encephalopathy (HE) is a potentially reversible brain dysfunction caused by liver failure. Altered synaptic plasticity is supposed to play a major role in the pathophysiology of HE. Here, we used paired associative stimulation with an inter-stimulus interval of 25 ms (PAS25), a transcranial magnetic stimulation (TMS) protocol, to test synaptic plasticity of the motor cortex in patients with manifest HE. Methods: 23 HE-patients and 23 healthy controls were enrolled in the study. Motor evoked potential (MEP) amplitudes were assessed as measure for cortical excitability. Time courses of MEP amplitude changes after the PAS25 intervention were compared between both groups. Results: MEP-amplitudes increased after PAS25 in the control group, indicating PAS25-induced synaptic plasticity in healthy controls, as expected. In contrast, MEP-amplitudes within the HE group did not change and were lower than in the control group, indicating no induction of plasticity. Conclusion: Our study revealed reduced synaptic plasticity of the primary motor cortex in HE. Significance: Reduced synaptic plasticity in HE provides a link between pathological changes on the molecular level and early clinical symptoms of the disease. This decrease may be caused by disturbances in the glutamatergic neurotransmission due to the known hyperammonemia in HE patients.Comment: number of pages: 33; number of tables: 1; number of figures: 5; References: 9