Lin, Yan
(2011)
Investigating stimulus induced metabolic changes in human visual cortex using functional magnetic resonance spectroscopy at 7T.
PhD thesis, University of Nottingham.
Abstract
This thesis concerns the investigation of metabolic changes in 1H metabolite levels in the human visual cortex due to visual stimulation using proton magnetic resonance spectroscopy (1H-MRS) at 7T. The work described in this thesis has been undertaken by the author and collaborators at the Sir Peter Mansfield Magnetic Resonance Centre at the University of Nottingham.
Detection of functional changes in 1H metabolites may enable a greater understanding of neurotransmitter activity and metabolic pathways used for energy synthesis during activation of brain tissue. Previous 1H MRS studies of the activated human brain mainly focused on observing lactate (Lac) changes. More recent studies by Mangia et al, taking advantage of the increased signal and spectral resolution at 7T, have investigated the change in the level of Lac, glutamate (Glu), Aspartate (Asp) and Glucose (Glc) during activation. However, Mangia, did not measure significant change in the level of gamma aminobutyric acid (GABA) and Glutamine (Gln), which might be expected to change due to increased neurotransmitter cycling rates during activation.
Given that the metabolite changes observed due to visual stimulation were relatively small. We used a long, intense visual stimulus, designed to retain attention, to confirm and quantify the changes in the levels of Glu, GABA, and Gln, and to further investigate the Lac and Asp response to visual stimulation. Our present results using a moving stimulus of full-screen flickering contrast-defined wedges, have demonstrated many more metabolic changes throughout two different time scales of stimulation. Small (2~11%) but significant stimulation induced increases in Lac, Glu and glutathione (GSH) were observed along with decreases in Asp, GIn and glycine (Gly). In addition, decreases in (intracellular) Glc and increases in GABA were seen but did not reach significance. The opposite changes in Glu and Asp are indicative of increased activity of the malate-aspartate shuttle, which taken together with the opposite changes in Glc and Lac reflect the expected increase in brain energy metabolism. The increases in Glu and GABA coupled with the decrease in GIn can be interpreted in terms of increased activity of the Glu/Gln and Gln/Glu/GABA neurotransmitter cycles. An entirely new observation is the increase of GSH during prolonged visual stimulation. The similarity of its time course to that of Glu suggests that it may be a response to the increased release of Glu or to the increased production of reactive oxygen species. Gly is also a precursor of GSH and a decrease on activation is consistent with increased GSH synthesis. Together these observations constitute the most detailed analysis to date of functional changes in human brain metabolites.
Interestingly, the Lac response was confined to the first visual stimulus. It is possible that processes triggered during the first period of visual stimulation, could continue for a while after stimulation has ended. If this is an important mechanism of the activity-stimulated brain Lac response, shortening the duration of the first stimulus might lead to an increase in Lac response during the second period of stimulation. With this in mind, we designed a repeated visual stimulation paradigm, varying the duration of the first stimulation (shorter than 9.9-min, based on our previous results), to see the effect on the Lac response during the second visual stimulation period. A gradual increase in Lac under the prolonged stimulation, following the first brief stimulation (1s, 16s and 48s, respectively), was observed and maintained until the end of these periods. Lac responses during the second stimulation period looked similar whether the first stimulation was 1s or 16s. With the increase of first visual stimulus duration (48s), the Lac response under the second stimulation period was slightly diminished. No significant Lac accumulation can be evident to the second stimulation, when the initial stimulation was 288s. The averaged Lac level was considerably below baseline after cessation of the first 288s stimulus. It is possible that the increased glycolytic flux, triggered during the initial longer stimulation, would still continue for a while during recovery, accounting for the decreased brain Lac level during resting periods from stimulation. Further experiments are ongoing, varying the duration of the second resting periods, to see the effect on the Lac response to the second stimulation.
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