Functional Imaging Studies of Speech and Verbal Memory in Healthy Adults and Patients with Alzheimer’s Disease

Alzheimer’s disease (AD) results in a diffuse, but characteristic impairment of cognitive function, with early involvement of verbal episodic memory. A prodromal phase of amnestic mild cognitive impairment (MCI) consists of patients with a mild, isolated impairment of episodic memory. In this thesis, I have described experiments performed on these patients and healthy volunteers using functional magnetic resonance imaging (fMRI). I aimed to investigate changes in neural activity associated with the breakdown in verbal episodic memory. Initially, I established the feasibility of using fMRI to investigate spoken responses in a study of speech production in healthy volunteers. This was important for investigating spoken retrieval of episodic memory. I also demonstrated integration of perceptual feedback and motor feedforward responses during propositional speech production within the medial planum temporale, associated with suppression of activity in secondary somatosensory cortex within the parietal operculum. In the verbal memory study, I demonstrated that successful encoding of heard sentences was associated with greater activity in cortical regions associated with semantic processing, but lower activity within early auditory cortex; implying a “top-down” effect on early perceptual cortex, related to sustained auditory attention. Patients with AD did not show this top-down effect. In addition, less activity was observed during encoding in AD patients, compared to MCI patients or controls, in regions associated with motivation. In the medial temporal lobes, there was less activity in AD compared to controls, but higher activity in MCI, consistent with previous reports. During retrieval, there was less activity in frontal executive control systems in AD compared to controls. This was seen in both performance-matched comparisons and in the neural response to a reduction in retrieval performance. MCI patients showed early changes in parietal lobe retrieval performance-related activity. Overall, the reduced verbal encoding performance in AD was related to impairments in the function of both MTL memory-related systems and sustained auditory attention, and was associated with reduced motivation. During free recall, lower performance in AD was associated with impairment of frontal cognitive control. Therefore, I have shown that verbal episodic memory impairment in AD is the consequence of altered activity in multiple cognitive networks, in addition to the well-recognised impairments in the MTL-memory network. These results have implications for future therapeutic interventions to improve memory function in this patient group, highlighting the potential use of drugs that enhance attention, motivation and frontal executive function

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

Functional imaging studies of speech and verbal memory in healthy adults and patients with Alzheimer's disease

Alzheimer’s disease (AD) results in a diffuse, but characteristic impairment of cognitive function, with early involvement of verbal episodic memory. A prodromal phase of amnestic mild cognitive impairment (MCI) consists of patients with a mild, isolated impairment of episodic memory. In this thesis, I have described experiments performed on these patients and healthy volunteers using functional magnetic resonance imaging (fMRI). I aimed to investigate changes in neural activity associated with the breakdown in verbal episodic memory. Initially, I established the feasibility of using fMRI to investigate spoken responses in a study of speech production in healthy volunteers. This was important for investigating spoken retrieval of episodic memory. I also demonstrated integration of perceptual feedback and motor feedforward responses during propositional speech production within the medial planum temporale, associated with suppression of activity in secondary somatosensory cortex within the parietal operculum. In the verbal memory study, I demonstrated that successful encoding of heard sentences was associated with greater activity in cortical regions associated with semantic processing, but lower activity within early auditory cortex; implying a “top-down” effect on early perceptual cortex, related to sustained auditory attention. Patients with AD did not show this top-down effect. In addition, less activity was observed during encoding in AD patients, compared to MCI patients or controls, in regions associated with motivation. In the medial temporal lobes, there was less activity in AD compared to controls, but higher activity in MCI, consistent with previous reports. During retrieval, there was less activity in frontal executive control systems in AD compared to controls. This was seen in both performance-matched comparisons and in the neural response to a reduction in retrieval performance. MCI patients showed early changes in parietal lobe retrieval performance-related activity. Overall, the reduced verbal encoding performance in AD was related to impairments in the function of both MTL memory-related systems and sustained auditory attention, and was associated with reduced motivation. During free recall, lower performance in AD was associated with impairment of frontal cognitive control. Therefore, I have shown that verbal episodic memory impairment in AD is the consequence of altered activity in multiple cognitive networks, in addition to the well-recognised impairments in the MTL-memory network. These results have implications for future therapeutic interventions to improve memory function in this patient group, highlighting the potential use of drugs that enhance attention, motivation and frontal executive function.EThOS - Electronic Theses Online ServiceRoyal College of Physicians of London and the Dunhill Medical Trust and Medical Research Council of the United KingdomGBUnited Kingdo

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

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