A longitudinal study of patients with cirrhosis treated with L-ornithine L-aspartate, examined with magnetization transfer, diffusion-weighted imaging and magnetic resonance spectroscopy.

The presence of overt hepatic encephalopathy (HE) is associated with structural, metabolic and functional changes in the brain discernible by use of a variety of magnetic resonance (MR) techniques. The changes in patients with minimal HE are less well documented. Twenty-two patients with well-compensated cirrhosis, seven of whom had minimal HE, were examined with cerebral 3 Tesla MR techniques, including T1- and T2-weighted, magnetization transfer and diffusion-weighted imaging and proton magnetic resonance spectroscopy sequences. Studies were repeated after a 4-week course of oral L-ornithine L-aspartate (LOLA). Results were compared with data obtained from 22 aged-matched healthy controls. There was no difference in mean total brain volume between patients and controls at baseline. Mean cerebral magnetization transfer ratios were significantly reduced in the globus pallidus and thalamus in the patients with cirrhosis irrespective of neuropsychiatric status; the mean ratio was significantly reduced in the frontal white matter in patients with minimal HE compared with healthy controls but not when compared with their unimpaired counterparts. There were no significant differences in either the median apparent diffusion coefficients or the mean fractional anisotropy, calculated from the diffusion-weighted imaging, or in the mean basal ganglia metabolite ratios between patients and controls. Psychometric performance improved in 50 % of patients with minimal HE following LOLA, but no significant changes were observed in brain volumes, cerebral magnetization transfer ratios, the diffusion weighted imaging variables or the cerebral metabolite ratios. MR variables, as applied in this study, do not identify patients with minimal HE, nor do they reflect changes in psychometric performance following LOLA.

Frontoparietal cognitive control of verbal memory recall in Alzheimer's disease.

OBJECTIVE: Episodic memory retrieval is reliant upon cognitive control systems, of which 2 have been identified with functional neuroimaging: a cingulo-opercular salience network (SN) and a frontoparietal executive network (EN). In Alzheimer's disease (AD), pathology is distributed throughout higher-order cortices. The hypotheses were that this frontoparietal pathology would impair activity associated with verbal memory recall; and that central cholinesterase inhibition (ChI) would modulate this, improving memory recall. METHODS: Functional magnetic resonance imaging was used to study normal participants and 2 patient groups: mild cognitive impairment (MCI) and AD. Activity within the EN and SN was observed during free recall of previously heard sentences, and related to measures of recall accuracy. RESULTS: In normal subjects, trials with reduced recall were associated with greater activity in both the SN and EN. Better recall was associated with greater activity in medial regions of the default mode network. By comparison, AD patients showed attenuated responses in both the SN and EN compared with either controls or MCI patients, even after recall performance was matched between groups. Following ChI, AD patients showed no modulation of activity within the SN, but increased activity within the EN. There was also enhanced activity within regions associated with episodic and semantic memory during less successful recall, requiring greater cognitive control. INTERPRETATION: The results indicate that in AD, impaired responses of cognitive control networks during verbal memory recall are partly responsible for reduced recall performance. One action of symptom-modifying treatment is partially to reverse the abnormal function of frontoparietal cognitive control and temporal lobe memory networks.

Auditory cortical function during verbal episodic memory encoding in Alzheimer's disease.

OBJECTIVE: Episodic memory encoding of a verbal message depends upon initial registration, which requires sustained auditory attention followed by deep semantic processing of the message. Motivated by previous data demonstrating modulation of auditory cortical activity during sustained attention to auditory stimuli, we investigated the response of the human auditory cortex during encoding of sentences to episodic memory. Subsequently, we investigated this response in patients with mild cognitive impairment (MCI) and probable Alzheimer's disease (pAD). METHODS: Using functional magnetic resonance imaging, 31 healthy participants were studied. The response in 18 MCI and 18 pAD patients was then determined, and compared to 18 matched healthy controls. Subjects heard factual sentences, and subsequent retrieval performance indicated successful registration and episodic encoding. RESULTS: The healthy subjects demonstrated that suppression of auditory cortical responses was related to greater success in encoding heard sentences; and that this was also associated with greater activity in the semantic system. In contrast, there was reduced auditory cortical suppression in patients with MCI, and absence of suppression in pAD. Administration of a central cholinesterase inhibitor (ChI) partially restored the suppression in patients with pAD, and this was associated with an improvement in verbal memory. INTERPRETATION: Verbal episodic memory impairment in AD is associated with altered auditory cortical function, reversible with a ChI. Although these results may indicate the direct influence of pathology in auditory cortex, they are also likely to indicate a partially reversible impairment of feedback from neocortical systems responsible for sustained attention and semantic processing.

The visual word form system in context.

According to the "modular" hypothesis, reading is a serial feedforward process, with part of left ventral occipitotemporal cortex the earliest component tuned to familiar orthographic stimuli. Beyond this region, the model predicts no response to arrays of false font in reading-related neural pathways. An alternative "connectionist" hypothesis proposes that reading depends on interactions between feedforward projections from visual cortex and feedback projections from phonological and semantic systems, with no visual component exclusive to orthographic stimuli. This is compatible with automatic processing of false font throughout visual and heteromodal sensory pathways that support reading, in which responses to words may be greater than, but not exclusive of, responses to false font. This functional imaging study investigated these alternative hypotheses by using narrative texts and equivalent arrays of false font and varying the hemifield of presentation using rapid serial visual presentation. The "null" baseline comprised a decision on visually presented numbers. Preferential activity for narratives relative to false font, insensitive to hemifield of presentation, was distributed along the ventral left temporal lobe and along the extent of both superior temporal sulci. Throughout this system, activity during the false font conditions was significantly greater than during the number task, with activity specific to the number task confined to the intraparietal sulci. Therefore, both words and false font are extensively processed along the same temporal neocortical pathways, separate from the more dorsal pathways that process numbers. These results are incompatible with a serial, feedforward model of reading.

A comparison of sensory-motor activity during speech in first and second languages.

A foreign language (L2) learned after childhood results in an accent. This functional neuroimaging study investigated speech in L2 as a sensory-motor skill. The hypothesis was that there would be an altered response in auditory and somatosensory association cortex, specifically the planum temporale and parietal operculum, respectively, when speaking in L2 relative to L1, independent of rate of speaking. These regions were selected for three reasons. First, an influential computational model proposes that these cortices integrate predictive feedforward and postarticulatory sensory feedback signals during articulation. Second, these adjacent regions (known as Spt) have been identified as a "sensory-motor interface" for speech production. Third, probabilistic anatomical atlases exist for these regions, to ensure the analyses are confined to sensory-motor differences between L2 and L1. The study used functional magnetic resonance imaging (fMRI), and participants produced connected overt speech. The first hypothesis was that there would be greater activity in the planum temporale and the parietal operculum when subjects spoke in L2 compared with L1, one interpretation being that there is less efficient postarticulatory sensory monitoring when speaking in the less familiar L2. The second hypothesis was that this effect would be observed in both cerebral hemispheres. Although Spt is considered to be left-lateralized, this is based on studies of covert speech, whereas overt speech is accompanied by sensory feedback to bilateral auditory and somatosensory cortices. Both hypotheses were confirmed by the results. These findings provide the basis for future investigations of sensory-motor aspects of language learning using serial fMRI studies.

Perceptual systems controlling speech production.

It is proposed that the acquisition and maintenance of fluent speech depend on the rapid temporal integration of motor feedforward and polysensory (auditory and somatosensory) feedback signals. In a functional magnetic resonance imaging study on 21 healthy right-handed, English-speaking volunteers, we investigated activity within these motor and sensory pathways and their integration during speech. Four motor conditions were studied: two speech conditions (propositional and nonpropositional speech) and two silent conditions requiring repetitive movement of the principal articulators (jaw and tongue movements). The scanning technique was adapted to minimize artifact associated with overt speech production. Our result indicates that this multimodal convergence occurs within the left and right supratemporal planes (STPs), with peaks of activity at their posteromedial extents, in regions classically considered as unimodal auditory association cortex. This cortical specialization contrasted sharply with the response of somatosensory association cortex (SII), in which activity was suppressed during speech but not during the silent repetitive movement of the principal articulators. It was also clearly distinct from the response of lateral auditory association cortex, which responded to auditory feedback alone, and from that within a left lateralized ventrolateral temporal and inferior frontal system, which served lexical- and sentence-level language retrieval. This response of cortical regions related to speech production is not predicted by the classical model of hierarchical cortical processing, providing new insights into the role of the STP in polysensory integration and into the modulation of activity in SII during normal speech production. These findings have novel implications for the acquisition and maintenance of fluent speech.

Diagnosing and treating hepatic encephalopathy.

Hepatic encephalopathy is a complex condition. This article considers the efficacy of the methods used in its diagnosis and management and discusses the impact of minimal hepatic encephalopathy on patients and the ethics of its treatment.

Modulation of neural activation following treatment of hepatic encephalopathy.

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.

Changes in brain size in hepatic encephalopathy: a coregistered MRI study.

Magnetic resonance imaging (MRI) coregistration techniques can be used to track changes in brain volume. We aimed to determine whether treatment in chronic liver disease altered brain size. The study group comprised nine patients with cirrhosis (7 Child's grade B and 2 Child's grade C). Six had minimal and three had overt hepatic encephalopathy on clinical, psychometric, and electrophysiological testing. Cerebral MRI was performed in seven patients before and 6 weeks after starting lactulose. A further two patients underwent transjugular intrahepatic portosystemic stent shunting with MRI performed before and 24 h afterwards. One patient had a further scan 3 months after TIPSS. Brain size was measured using a semiautomated contour/thresholding technique. Measurable changes were found after treatment intervention, but there was no correlation with severity of encephalopathy (West Haven criteria) or liver dysfunction (Child's score). Three patients improved on lactulose, the brain size decreased with an increase in ventricular volume. Two patients deteriorated; the brain size increased with a concomitant decrease in ventricular volume. Two stable patients had small changes, one with an increase in brain size and a decrease in ventricular volume and the other showing the converse. Following TIPSS, there was an increase in brain size in both patients, evident within 24 h in one patient and at 3 months in the other. Coregistered MRI demonstrates easily detectable changes in brain size following treatment intervention. Our results support the hypothesis that low-grade brain swelling is present, even in minimal hepatic encephalopathy.