Investigation Of Brain GABA Levels In Patients With Premenstrual Dysphoric Disotder By Proton MR Spectroscopy

Most women of reproductive age may experience a broad spectrum of psychosomatic and behavioral symptoms in the luteal phase before menses, which is called premenstrual syndrome (PMS). Premenstrual dysphoric disorder (PMDD) is a severe form of PMS, which affects 3-8% of menstruating women. American Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-Ⅳ) classifies PMDD as a separate strictly defined psychiatric diagnosis. Rigorous and specific diagnostic criteria for PMDD were specified in DSM-Ⅳ. PMDD was formly included in newly published DSM-V under the category of mood disorder in 2013.The burden of PMDD is significant and can disrupt family life, relationships with significant others, career roles and work productivity. The etiology of PMDD is multifactorial. Elucidation of the pathophysiologic mechanisms of the disorder should allow for a more precise diagnosis, and provide direction for targeted therapeutic interventions. γ-aminobutyric acid (GABA), the predominant inhibitory neurotransmitter in human brain, is related to various physiological processes, particularly mood regulation and cognition function. Abnormalities of brain GABA levels have been suggested to be relevant to a number of psychiatric disorders, for instance, depression disorder, anxiety disorder. Increasing evidence indicated that dysregulation of inhibitory GABAergic neurotransmitter system is associated with the pathogenesis of PMDD. Researchers focus mostly on gonadal hormones, their metabolites and interactions with neurotransmitters (GABA). Neurosteroids have modulatory effects on GABA synthesizing enzyme-- glutamic acid decarboxylase (GAD) and GABA receptors. Plasma GABA levels in PMDD have been found to be lower than healthy women in luteal phase. However, research on GABA levels in PMDD or PMS seems to be limited.Proton magnetic resonance spectroscopy (1H-MRS) enables the non-invasive in vivo measurement of major neurometabolite levels and has been successfully used to evaluate brain regional N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myo-inositol (ml), glutamate (Glu) and lactate (Lac). Recent developments involving 1H-MRS editing PRESS-based techniques, such as MEGA-Point Resolved Spectroscopy (PRESS), provide an opportunity to isolate and evaluate brain GABA levels. The MEGA-PRESS sequence has been successfully applied to measure GABA level in neuroscience and clinical studies. Thus, in the present study, the MEGA-editing technique was used to compare brain GABA levels between PMDD women and matched controls during the late luteal phase of the menstrual cycle. Moreover, the assessment of brain GABA levels between PMDD and PMS patients was also performed.This study contains three parts, as follows:Part 1. In vivo detection of brain GABA levels using MEGA-PRESS technique:A reproducibility studyObjective:To detect brain GABA levels in frontal lobe and left basal ganglia of healthy volunteers using MEGA-PRESS editing sequence, and investigate the intra-reproducibility and inter-reproducibility of simple quantification, relative quantification and absolute quantification.Material and Methods:10 right-handed healthy volunteers (mean age:26.5+2.3 y. age range:23-30 y), consisting of 5 male and 5female, participated in this study. Scans were performed using a 3T Philips MRI scanner (Achieva, TX, Best, The Netherlands), equipped with an eight-channel phased-array head coil. For each subject, a T1-weighted 3D TFE scan was acquired for MRS voxel placement and tissue segmentation. Spectra were recorded from the frontal lobe (FL) and left basal ganglia (ltBG) using MEGA-PRESS sequence. A reference water spectrum was also collected from the same voxel without water suppression, which was later used for absolute quantification. All subjects were scanned at least twice. In three subjects, four continuous scans were conducted within a period of four weeks. Each voxel in the 3D T1-weighted structural images was segmented using FSL package (Oxford University, Oxford, UK). Post-processing of the MRS data was carried out using jMRUI v.4.0. GABA+levels were quantified by simple quantification (GABA+), relative quantification (GABA+/Cr) and absolute quantification ([GABA+]). Coefficient of variation was calculated, accordingly.Results:GABA+difference spectra were successfully quantified from all 52 voxels of 10 subjects. For both the intra-individual and inter-individual reproducibility, coefficient of variation of [GABA+] was lower than GABA+/Cr, and GABA+was the highest.Conclusion:The MEGA-PRESS technique was stable to resolve and detect GAB A signals in human brain. For both the intra-individual and inter-individual reproducibility, absolute quantification was more reliable than relative quantification and simple quantification.Part 2. Alteration of brain GABA levels in patients with premenstrual dysphoric disorderObjective:MEGA-editing technique was used to compare GABA levels between PMDD women and matched healthy controls in two brain regions, the frontal lobe and the left basal ganglia.Material and Methods:40 right-handed, regularly menstruating women consisting of 20 PMDD (23.0±1.6 y) and 20 age matched controls (HCs) (23.6±1.4 y) were recruited from local medical school. Daily Record of Severity of Problems (DRSP) was used to record severity of mood and physical symptoms. Scans were performed during the late luteal phase using a 3T Philips MRI scanner. For each subject, a T1-weighted 3D TFE scan was acquired for MRS voxel placement and tissue segmentation. Spectra were recorded from the frontal lobe (FL) and left basal ganglia (ltBG) using MEGA-PRESS sequence. A reference water spectrum was also collected from the same voxel without water suppression for absolute quantification. Post-processing of the MRS data was carried out using jMRUI v.4.0.software. GABA+levels were quantified by referencing to tissue water. The absolute concentration [GABA+] was deemed as the primary results. The glutamate-glutamine complex/creatine (Glx/Cr), N-Acetyl-aspartate/creatine (NAA/Cr) and Choline/ceatine (Ch/Cr) ratios were also measured. One-way analysis of variance (ANOVA) was performed to compare group differences in metabolite levels. Pearson correlation coefficients were computed to assess the associations between [GABA+] and Glx/Cr levels in each region and PMDD severity (ADRSP).Results:In the FL VOI, the absolute GABA+concentrations were significantly lower (p=0.02) in PMDD women (1.35±0.10) compared to HCs (1.43±0.11). And Glx/Cr levels were significantly higher (p= 0.01) in PMDD women compared to HCs. In the ltBG VOI, the absolute GABA+concentrations were significantly lower (p= 0.01) in PMDD women (1.22±0.09) compared to HCs (1.30±0.10). There were no significant group differences in NAA/Cr and Cho/Cr ratios in both regions. In women with PMDD, the absolute GABA+concentrations and Glx/Cr ratios were not correlated with PMDD severity as rated by ADRSP scores (all p> 0.05).Conclusion:In this study, we found reduced GABA+levels existing in the FL and ltBG regions of PMDD women. Menstrual cycle-related dysregulation of the GAB A neurotransmitter system may be an important neurobiological mechanism contributing to the pathophysiology of PMDD. We hope our results as well as future research will provide new insights into treatment strategies for affected women.Part 3. Comparative study of brain GABA levels in patients with premenstrual dysphoric disorder and premenstrual syndromeObjective:In this part, we used MEGA-PRESS editing technique to detect the brain GABA levels of frontal lobe (FL), left Basal Ganglia (ltBG) regions in patients with premenstrual syndrome (PMS), and to assess whether there are brain GABA differences among PMS, PMDD patients and matched healthy controls.Material and Methods:20 clinically diagnosed PMS patients participated in this study. Daily Record of Severity of Problems (DRSP) was used to record severity of PMS symptoms. All participants underwent T1-FFE sequence and MEGE-PRESS sequence to get structural images and GABA spectroscopic data. Spectra were recorded from the FL and ItBG regions using a 3T Philips MRI scanner. Post-processing of the MRS data was carried out using jMRUI v.4.0.software. The absolute concentration [GABA+] was deemed as the primary results. The Glx/Cr ratios were also calculated. The MRI and MRS data of the 20 patients with PMDD and matched healthy controls collected in part-two were also recruited. One-way analysis of variance (ANOVA) was performed to compare group differences in metabolite levels. Pearson correlation coefficients were computed to assess the associations between [GABA+] levels in each region and PMS severity as rated by ΔDRSP.Results:In FL VOI, decreased [GABA+] levels were detected in both PMS (p=0.03) and PMDD (p=0.02) patients, compared with matched controls. However, there was no group difference in [GABA+] levels between PMS and PMDD group. PMDD patients have significant higher Glx/Cr levels than HCs (p=0.04). There were no group differences in Glx/Cr levels between PMS and HCs (p=0.71), and between PMS and PMDD (p= 0.21). In ItBG VOI, PMDD patients have significant lower [GABA+] levels than HCs (p=0.02). And there were no group differences in [GABA+] levels between PMS and HCs (p=0.71), and between PMS and PMDD (p =0.13). With regard to the Glx/Cr levels, there were no significant differences among three groups (p=0.26). In addition, no significant correlation between [GABA+] levels and ΔDRSP scores were detected (all p> 0.05).Conclusion:Decreased GABA+levels were found in FL region of patients with PMS and PMDD. PMS and PMDD may constitute a continuous pathphysiological process, and dysregulation of GABAergic system may be a common neurobiological mechanism in PMS and PMDD.