Browsing by Subject "Cerebral Cortex"
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Item Human Brain Metabolic Imaging by ¹H MR Spectroscopy at 3T and 7T: Application in Cancers(2014-11-21) Ganji, Sandeep Kumar; DeBerardinis, Ralph J.; Choi, Changho; Maher, Elizabeth; Merritt, Matthew E.; Ren, JiminProton MR spectroscopy (MRS) provides an effective tool for measuring metabolites in human brain noninvasively. Precise measurement of several clinically important metabolites such as glycine (Gly), 2-hyroxyglutarate (2HG), gamma-aminobutyric acid (GABA), and glutamate (Glu) remains challenging primarily due to their relatively small signal strengths and spectral overlap with adjacent large signals. The present study aims to develop new MRS techniques for reliable imaging of these metabolites and apply in brain tumor patients at 3T and 7T. The transverse relaxation times (T₂) of brain metabolites are needed for absolute quantitation. As the first topic, the T₂s of metabolites in healthy brain were measured using point-resolved spectroscopy (PRESS) at 3T. The T₂s of Glu, myo-inositol, NAA-aspartate, and N-acetyl-aspartyl-glutamate were evaluated in addition to large singlet signals. The second topic was to measure Gly in human brain with MRS imaging at 3T. An optimized PRESS TE=160 ms scheme was used to measure Gly in healthy brain and brain tumors. The data indicated the presence of a regional variation of Gly in healthy brain, with estimates ∼1 mM and ∼0.3 mM in gray and white matter dominant regions, respectively. The Gly level was significantly increased in tumors compared to the contralateral brain. Gly elevation was more extensive with higher tumor grade. Mutations in isocitrate dehydrogenase (IDH) 1 and 2 result in production of 2HG and as a result, 2HG is elevated by orders of magnitude in IDH-mutated gliomas. As the third topic, 2HG was estimated in subjects with IDH-mutated gliomas using MRS imaging. PRESS TE=97 ms and 78 ms were used for detection of 2HG at 3T and 7T, respectively. The reproducibility of 2HG MRS was evaluated at 3T. The MRS measurement of 2HG was reliable and highly reproducible, suggesting that the methods can be used as a noninvasive diagnostic/prognostic tool in brain tumors. GABA, a primary inhibitory neurotransmitter, is implicated in a variety of neuropsychiatric disorders. As the fourth topic, GABA level in healthy brain was evaluated using PRESS TE=92 ms at 7T, which was optimized for separating the GABA and Glu signals between 2.2 and 2.4 ppm. The data from multiple brain regions indicated that GABA is higher by 7 - 8 fold in gray matter regions than in white matter regions.Item Role of the Transient Receptor Potential Channels in Modulating Prefrontal Cortical Excitability and the Behavioral Responses to Cocaine(2009-09-04) Fowler, Melissa Ann; Cooper, Donald C.Drug addiction is a disease that is influenced by both genetic and environmental factors that result in altered excitability in the key brain regions associated with reward and decision-making. The prefrontal cortex (PFC) processes reward-related information; and pathologies in PFC excitability resulting from prolonged drug use may lead to the loss of control over drug intake associated with drug addiction. We show that layer 5 pyramidal neurons in the PFC exhibit a prolonged depolarizing response to Gq-coupled receptor activation, which produces a period of heightened excitability of the cell following brief bursts of action potential activity. This burst triggered delayed depolarization enables the cell to convert subthreshold inputs into persistent firing output and may be a way for the cell to hold information in a short term memory buffer. The delayed after-depolarization (dADP) is reduced by dopamine and chronic cocaine, which may serve to bias the cell towards very strong inputs, such as those associated with drug cues, while preventing the cell from responding to smaller, subthreshold inputs. The dADP is induced by activation of Gq-coupled receptors, such as metabotropic glutamate receptors or muscarinic acetylcholine receptors and is mediated by subsequent activation of a non-selective cation channel, which pharmacological data suggested to be a canonical transient receptor potential (TRPC) channel. We used in situ hybridization, immunoblots, and real-time PCR to examine the expression of the TRPC channels and found dense expression of TRPC5 in the pyramidal cell layers of the PFC. Using adeno-associated viral mediated knock-down of TRPC5 in the prefrontal cortex of TRPC5flx mice, we show that TRPC5 channels are necessary for induction of the dADP in the PFC. We show that loss of TRPC5 in the PFC increases the locomotor activating and rewarding effects of cocaine. Knock-out of TRPC1 channels, on the other hand, has no effect on the dADP and does not alter behavioral responses to cocaine, suggesting that TRPC5 homomultimeric complexes rather than TRPC1/5 heteromultimeric complexes underlie the dADP in the PFC. These studies identify the TRPC5 channels as important for modulating neuronal excitability in the PFC and the behavioral responses to cocaine.Item [UT News](1986-08-22) Rutherford, Susan