In vivo imaging of oxidative stress and fronto-limbic white matter integrity in young adults with mood disorders
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Fronto-limbic connectivity is compromised in mood disorders, as reflected by impairments in white matter (WM) integrity revealed by diffusion tensor imaging. Although the underlying mechanisms remain unclear, disruption to normal myelination due to oxidative stress is thought to play a key role. We aimed to determine whether fronto-limbic WM integrity is compromised, and associated with in vivo antioxidant levels (indexed by glutathione; GSH), in young adults with unipolar depression (DEP) and bipolar (BD) disorders. Ninety-four patients with DEP, 76 with BD and 59 healthy controls (18–30 years) underwent diffusion tensor and proton magnetic resonance spectroscopy imaging. Fractional anisotropy (FA) was calculated from the cingulum bundle (cingulate, hippocampus), fornix, stria terminalis (ST) and uncinate fasciculus tracts. GSH concentration was measured in anterior cingulate cortex (ACC) and hippocampus (HIPP). Compared to controls, DEP showed significantly reduced FA in ST, whereas BD did not significantly differ in FA across the five tracts. There were significant positive correlations between ST-FA and HIPP-GSH across groups. Regression analysis revealed that having DEP or BD and reduced HIPP-GSH were significantly associated with reduced ST-FA. Similarly, decreased ST-FA was associated with poorer neuropsychological performance in conjunction with having DEP. Our findings suggest a structural disconnectivity specific to the limbic region of young adults with DEP. Decreased WM integrity was associated with depleted levels of hippocampal GSH suggesting that this particular disruption may be linked to oxidative stress at early stages of illness. Young adults with BD do not have the same degree of impairment.
KeywordsDiffusion tensor imaging Hippocampus Depression Bipolar disorder Magnetic resonance spectroscopy Glutathione
This study was supported by grants from the National Health & Medical Research Council (NHMRC) including: Centre of Research Excellence (No. 1061043), Australia Fellowship (No. 511921 awarded to IBH), Clinical Research Fellowship (No. 402864 awarded to SLN) and Senior Research Fellowship (No. 1080963 awarded to GPA). We would like to express our gratitude to individuals who participated in this study.
Compliance with ethical standards
Conflict of interest
The authors declare that there are no competing financial interests in relation to the work described. Potential conflicts of interest may arise from the following: DFH has received honoraria for educational seminars from Janssen-Cilag and Eli Lilly. SLN has received honoraria for an educational seminar for Lundbeck (cognition in depression). IBH has led a range of community-based and pharmaceutical industry-supported depression awareness and education and training programs. He has led depression and other mental health research service evaluation or investigator-initiated research projects that have been supported by a variety of pharmaceutical partners. Servier and Pfizer support current investigator-initiated studies. He has received honoraria for his contributions to professional educational seminars related to depression, youth mental health and circadian-rhythms research. He has received travel support from Servier to attend scientific meetings related specifically to circadian-rhythm disorders. The authors report no other biomedical financial interests or potential conflicts of interest.
- 1.Andersson JLR, Jenkinson M, Smith S (2007) Non-linear optimisation. FMRIB technical report tr07ja1. University of Oxford FMRIB Centre, OxfordGoogle Scholar
- 2.Andersson JLR, Jenkinson M, Smith S (2007) Non-linear registration, aka spatial normalisation fmrib technical report tr07ja2. FMRIB Analysis Group of the University of Oxford, OxfordGoogle Scholar
- 11.Corcoba A, Steullet P, Duarte JM, Van de Looij Y, Monin A, Cuenod M, Gruetter R, Do KQ (2015) Glutathione deficit affects the integrity and function of the fimbria/fornix and anterior commissure in mice: relevance for schizophrenia. Int J Neuropsychopharmacol 19:pyv110CrossRefPubMedPubMedCentralGoogle Scholar
- 12.de Diego-Adelino J, Pires P, Gomez-Anson B, Serra-Blasco M, Vives-Gilabert Y, Puigdemont D, Martin-Blanco A, Alvarez E, Perez V, Portella MJ (2014) Microstructural white-matter abnormalities associated with treatment resistance, severity and duration of illness in major depression. Psychol Med 44:1171–1182CrossRefPubMedGoogle Scholar
- 17.Frodl T, Schaub A, Banac S, Charypar M, Jager M, Kummler P, Bottlender R, Zetzsche T, Born C, Leinsinger G, Reiser M, Moller HJ, Meisenzahl EM (2006) Reduced hippocampal volume correlates with executive dysfunctioning in major depression. J Psychiatry Neurosci 31:316–323PubMedPubMedCentralGoogle Scholar
- 25.Jahanshad N, Kochunov PV, Sprooten E, Mandl RC, Nichols TE, Almasy L, Blangero J, Brouwer RM, Curran JE, de Zubicaray GI, Duggirala R, Fox PT, Hong LE, Landman BA, Martin NG, McMahon KL, Medland SE, Mitchell BD, Olvera RL, Peterson CP, Starr JM, Sussmann JE, Toga AW, Wardlaw JM, Wright MJ, Hulshoff Pol HE, Bastin ME, McIntosh AM, Deary IJ, Thompson PM, Glahn DC (2013) Multi-site genetic analysis of diffusion images and voxelwise heritability analysis: a pilot project of the enigma-dti working group. Neuroimage 81:455–469CrossRefPubMedPubMedCentralGoogle Scholar
- 39.Monin A, Baumann PS, Griffa A, Xin L, Mekle R, Fournier M, Butticaz C, Klaey M, Cabungcal JH, Steullet P, Ferrari C, Cuenod M, Gruetter R, Thiran JP, Hagmann P, Conus P, Do KQ (2015) Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients. Mol Psychiatry 20:827–838CrossRefPubMedGoogle Scholar
- 41.Olvet DM, Delaparte L, Yeh FC, DeLorenzo C, McGrath PJ, Weissman MM, Adams P, Fava M, Deckersbach T, McInnis MG, Carmody TJ, Cooper CM, Kurian BT, Lu H, Toups MS, Trivedi MH, Parsey RV (2016) A comprehensive examination of white matter tracts and connectometry in major depressive disorder. Depress Anxiety 33:56–65CrossRefPubMedGoogle Scholar
- 43.Rickert P, Senior G (1998) Wms-iii list learning test and the rey auditory verbal learning test: Comparisons and australian normative data. In: 4th Annual Conference of the College of Clinical Neuropsychologists Loren, Victoria, AustraliaGoogle Scholar
- 49.Shungu DC, Weiduschat N, Murrough JW, Mao X, Pillemer S, Dyke JP, Medow MS, Natelson BH, Stewart JM, Mathew SJ (2012) Increased ventricular lactate in chronic fatigue syndrome. Iii. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed 25:1073–1087CrossRefPubMedPubMedCentralGoogle Scholar
- 52.Strauss E, Sherman EMS, Spreen O (2006) A compendium of neuropsychological tests: administration, norms, and commentary. Oxford University Press, New YorkGoogle Scholar
- 53.Tombaugh TN, Kozak J, Rees L (1998) Normative data for the trail making test (1996). In: Strauss E, Spreen O (eds) A compendium of neuropsychological tests. Oxford University Press, New YorkGoogle Scholar
- 56.Wechsler D (2001) Wechsler test of adult reading. Psychological Corporation, San AntonioGoogle Scholar