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Reduced QSM values in the caudate and amygdala of first episode mania patients1Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada, 2Pediatrics, University of British Columbia, Vancouver, BC, Canada, 3Medicine (Neurology), University of British Columbia, Vancouver, BC, Canada, 4Laboratory of Molecular Psychiatry, Centro de Pesquisas Experimentais, Hospital de Clínicas de Porto Alegre, Porto Algre, Brazil, 5Mood Disorders Centre, University of British Columbia, Vancouver, BC, Canada, 6Psychiatry, University of British Columbia, Vancouver, BC, Canada
Synopsis
Bipolar I disorder is characterized by recurrent manic and depressive episodes. Both, dopamine and oxidative stress, resulting from mitochondrial dysfunction, have been implicated in BD and volumetric and metabolic changes have been reported. Nevertheless, it remains unknown whether changes result from treatment or ongoing disease, or if they are present at first episode mania. We used R2* and quantitative susceptibility mapping (QSM) to assess differences in brain iron and myelination in a cohort of first episode mania patients compared to controls. Patients exhibited lower QSM values than controls in the caudate and amygdala, possibly linked to iron loss or hypermyelination.
Introduction
Bipolar I disorder (BD) is characterized by recurrent manic and depressive episodes, which are interspersed by euthymic periods. The typically adolescent onset significantly impacts patient's lives, leaving them prone to substance abuse1 and suicide2. The etiology of BD remains unknown, although genetic and environmental factors are believed to play a role. Volumetric3-5 and metabolic changes6,7, increased dopamine receptor density8 and decreased presynaptic dopamine metabolism with treatment9, have been reported. However, it is unclear whether these findings express neurobiological changes that initiated before or at the time of the first episodes or if these are the result of ongoing disease or treatment. Recently, mitochondrial dysfunction has been implicated in BD10,11 as part of a potential oxidative stress cascade, which may contribute to neuroprogression12. Quantitative susceptibility mapping (QSM)13,14 and R2*15 allow to assess tissue iron concentrations that could amplify oxidative stress levels, but also yield information about the role of iron and myelin in brain health. Here, we assessed QSM and R2* in first episode mania (FEM) patients compared to age and sex-matched healthy individuals in brain regions previously implicated in BD16,17.Methods
30 euthymic FEM patients (15 male/15 female, age 23.8±5.3 years) and age and sex-matched healthy controls (age 24.4±5.5 years) were scanned at 3T (Philips Achieva) using an 8-channel head coil. Enrolled patients had their first manic episode within the two years prior to MRI. Average time between first episode and MRI was 3.5 month and the average number of previous episodes was 1.72±3.07, median 1. Patient co-morbidities included learning disability, anxiety, substance abuse, attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder. MRI included a 3DT1 at 1 mm3 isotropic resolution and a 3D gradient-echo, five echoes, TE1/ΔTE/TR=13/7/46 ms at 0.42x0.41x1 mm3 resolution. R2* maps were computed by single exponential fitting after background field correction. QSM maps were obtained by in-house dipole inversion14, after Laplacian unwrapping and V-SHARP. Median QSM values were normalized to white matter (WM) QSM values. Regions-of-interest (ROI) included the genu, body and splenium of the corpus callosum, the anterior and posterior cingulate gyrus, frontal pole, thalamus, caudate, putamen, globus pallidus, superior temporal gyrus, precuneus cortex, nucleus accumbens, ventral striatum, hippocampus and amygdala16,17. These were obtained by FSL FIRST18 and MNI atlas registration (Harvard-Oxford, striatal, JHU DTI WM) to age-specific group templates, created from the acquired control data using ABSORB19. Group differences were assessed by mixed effects modelling (R), including the effects of ROI volumes, age, sex, co-morbidities, time since first episode and number of previous episodes. P-values <0.025 were considered significant, Bonferroni-adjusted for the use of QSM and R2* in this hypothesis-generating study.Results
Example QSM, R2* and T1w images from one patient, indicating some ROIs, are displayed in Fig. 1. The number of previous episodes correlated positively with R2* in the amygdala, but not with QSM. Time since first episode had no significant effect on R2* nor QSM. Both, R2* and QSM, correlated positively with age in most regions, without a significant group-by-age interaction (Fig. 2, p>0.027). The linear regression model detected significantly lower QSM values in the caudate (p=0.0016) and the amygdala (p=0.008) of FEM patients compared to controls, after adjusting for sex, age, co-morbidities and ROI volume differences (Fig. 3). There were no significant group-by-sex, group-by-age or group-by-volume interactions. However, the amygdala and the genu showed significant sex differences, demonstrating higher QSM values in females than males (Fig. 4A &C). Moreover, the caudate QSM values were significantly linked to caudal volumes (p=0.0002, Fig. 4B). No significant group differences were found for R2* (p>0.08). Although neither in- nor out-of-episode co-morbidities directly affected R2* and QSM measurements when all regions were considered (p > 0.4), the mixed effects model showed a decrease in caudal QSM values in patients with co-morbidities (Fig. 4D).Discussion
Reduced QSM values in patients compared to controls may indicate lower iron concentrations, due to either iron loss, or dilution of iron by structural enlargement. The reduction was independent of age, suggesting differences may be present at FEM, not developing with disease duration. Enlargement of the amygdala and caudate has been reported in some studies20,21. However, the lack of group-by-volume interactions on R2* and QSM measurements suggests that tissue changes other than volume contribute to the observed group differences, although some link between caudal volume and caudal QSM exists. Iron deficiency has been described in restless leg syndrome22, ADHD23 and in patients suffering from migraines, depression and anxiety24 and may relate to a downregulation of dopaminergic activity. Independent of iron, our findings may also be explained by hypermyelination. Studies have reported increased activity in both the caudate and amygdala25,26, which is believed to link to WM integrity and myelination, although the relationship is not fully understood.Conclusion
We observed localized QSM reductions in the amygdala and caudate of patients following their first manic episode, compared to matched healthy controls. Both of these regions are frequently implicated in BD and have important functions in the pathways of emotional behaviour. The reduction in QSM values may suggest iron deficiency or hypermyelination in FEM patients. Both of these hypotheses find support in existing literature20-26, but further work is needed to discern them.Acknowledgements
This study was funded by a Canadian Institute of Health Research (CIHR) operating grant. VW has been supported by the MS Society of Canada. AR is supported by Canada Research Chairs.References
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