Modulation of neural activation following treatment of hepatic encephalopathy

Abstract

Objective: To measure changes in psychometric state, neural activation, brain volume (BV), and cerebral metabolite concentrations during treatment of minimal hepatic encephalopathy.

Methods: As proof of principle, 22 patients with well-compensated, biopsy-proven cirrhosis of differing etiology and previous minimal hepatic encephalopathy were treated with oral l-ornithine l-aspartate for 4 weeks. Baseline and 4-week clinical review, blood chemistry, and psychometric evaluation (Psychometric Hepatic Encephalopathy Score and Cognitive Drug Research Score) were performed. Whole-brain volumetric and functional MRI was conducted using a highly simplistic visuomotor task, together with proton magnetic resonance spectroscopy of the basal ganglia. Treatment-related changes in regional BV and neural activation change (blood oxygenation level dependent) were assessed.

Results: Although there was no change in clinical, biochemical state, basal ganglia magnetic resonance spectroscopy, or in regional BV, there were significant improvements in Cognitive Drug Research Score (+1.2, p = 0.003) and Psychometric Hepatic Encephalopathy Score (+1.5, p = 0.003) with treatment. This cognitive amelioration was accompanied by changes in blood oxygenation level-dependent activation in the posterior cingulate and ventral medial prefrontal cortex, 2 regions that form part of the brain's structural and metabolic core. In addition, there was evidence of greater visual cortex activation.

Conclusions: These structurally interconnected regions all showed increased function after successful encephalopathy treatment. Because no regional change in BV was observed, this implies that mechanisms unrelated to astrocyte volume regulation were involved in the significant improvement in cognitive performance.

Figure 1. Activation evoked by the motor and visual tasks across all patients both before and after 4 weeks of oral l-ornithine l-aspartate therapy

Warm colors are regions that activate significantly for task, whereas blue colors are regions that activate more during the rest baseline (all results cluster-corrected for multiple comparisons, p < 0.05), (A) motor and (B) visual.

Figure 2. Regions that were more active in all patients

Common areas of increased activation after 4 weeks of oral l-ornithine l-aspartate therapy (cluster-corrected for multiple comparisons, p < 0.05).

Figure 3. Relationship between change in evoked activation (motor [A/C] and visual [B/D]) and change in psychometric performance (Speed of Memory [A/B] and Quality of Episodic Memory [C/D])

Warm colors indicate a significant positive relationship between activation (“after-before” 4 weeks of oral l-ornithine l-aspartate therapy) and behavioral performance, while cold colors indicate a negative relationship.