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Variation in in vivo prefrontal GABA, glutamate and glutamine – effects of reproductive factors, cortisol and major depressive disorder

  • Author / Creator
    Bhardwaj, Paramjit P
  • Variations in glutamate and γ-aminobutyric acid (GABA), excitatory and inhibitory amino acid neurotransmitters in the brain, have been linked with cyclical changes across the menstrual cycle and in stress and stress-related mental disorders. We used 3.0 Tesla proton magnetic resonance spectroscopy (1H-MRS) to investigate GABA+ levels (GABA + macromolecules) in the anterior cingulate/prefrontal cortex (ACC) in relation to menstrual cycle phase and the use of hormonal birth control and in a case-control comparison of patients with major depressive disorder (MDD) and healthy matched controls. We measured ACC GABA+ using a double quantum filter with selective dual band refocusing, a method that is more selective for GABA+ than the commonly used J-difference editing method. We did not confirm the hypothesis that ACC GABA+ would decrease between the follicular (1.12 ± .30 mmol/L) and late luteal phase (1.05 ± .31 mmol/L) of the menstrual cycle (n = 20; paired t = 1.28; df = 19; p = 0.22). ACC GABA+ levels did not differ between women in the follicular phase of the menstrual cycle (n = 16; 1.11 ± .27 mmol/L) and those in the first week of pill-use of hormonal birth control (n = 14; 1.08 ± .19 mmol/L; t = 0.39; df = 28; p = 0.70). We did not confirm the hypothesis that ACC GABA+ would be lower in patients with MDD (n = 35; 1.04 ± 0.31 mmol/L) than in healthy controls (n = 42; 1.11 ± 0.22; t = 1.24; df =75; 1-tailed p = 0.11). In a post hoc analysis, MDD patients with the most severe depressive anhedonia showed lower ACC GABA+ levels (0.98 ± 0.05 mmol/L; F1,58; p = 0.04) than controls. Strengths of the GABA studies include improved measurement selectivity, quantification of ACC GABA+ with respect to brain water and the largest sample sizes for these investigations to date. The main limitation was that the quantification method did not provide estimates of fitting precision. 1H-MRS was also used to study the acute (within 30 minutes) and delayed (48 hours) effects of the administration of cortisol (40-100 mg) on glutamate and glutamine in healthy volunteers, in a double-blind, randomized, placebo-controlled design. We measured glutamate and glutamine separately, using spectrally-selective refocusing acquisitions. The administration of cortisol 40 mg (n = 6) or 100 mg (n = 8) did not lead to significant acute or delayed changes in glutamate or glutamine levels compared with placebo (n = 5). Strengths of the cortisol study were the selective measurements of glutamate and glutamine and their quantification with respect to brain water, using LCModel analysis. A major weakness was that the sample size was under-powered to test hypotheses definitively. The selective measurement of GABA+ and glutamine using 1H-MRS is technically challenging, particularly for the ACC region that was studied. The current study of MDD adds to evidence that differences in ACC GABA+ may only be large enough to be detectable in more severely ill patients.

  • Subjects / Keywords
  • Graduation date
    2017-11:Fall 2017
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3JS9HN59
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Psychiatry
  • Specialization
    • Psychopharmacology
  • Supervisor / co-supervisor and their department(s)
    • Coupland, Nicholas (Psychiatry)
    • Le Melledo, Jean-Michel (Psychiatry)
  • Examining committee members and their departments
    • Fujiwara, Esther (Psychiatry)
    • MacMaster, Frank (Psychiatry)
    • Hanstock, Chris (Biomedical Engineering)
    • Baker, Glen (Psychiatry)