1716
Modulation of left anterior cingulate myo-Inositol in Lithium treatment of bipolar disorder1Cleveland Clinic Foundation, Cleveland, OH, United States, 2Brigham and Women’s Hospital, Boston, MA, United States
Synopsis
Keywords: Psychiatric Disorders, Spectroscopy
Motivation: There is limited information on anterior cingulate cortex (ACC) myo-inositol (m)I level in medication-free bipolar disorder (BD) patients in depressed state, which can explore role of neuro-inflammation in BD.
Goal(s): Investigate modulation of ACC mI level during Li monotherapy.
Approach: Patients with BD (depressed state) and healthy controls were scanned at 7-tesla MRI with a semi-LASER sequence at baseline and 2, 8 and 26 weeks from onset of Li monotherapy, and ACC mI level was measured at each time point.
Results: mI level decreased in 1st 2 weeks of onset of therapy but the reduction was not observed after 8 weeks.
Impact: The preliminary results suggest that decrease in neuro-inflammatory/microglial marker mI during Li monotherapy of depressed BD may be a short term effect. Future studies can investigate if this is specific to depressed state by investigating during manic state also.
Introduction
Bipolar disorder (BD) is characterized by periods of uncharacteristically elevated mood and depression.[1,2] Microglial activation and cytokine inflammation are suggested biomarkers of BD.[3,4] mI has been suggested to be a marker of glial activation [5-7] and neuro-inflammation.[8-10] BD has been associated with modulation in mI concentrations in frontal and temporal lobes, cingulate gyrus and basal ganglia.[11]Investigation of mI modulation at anterior cingulate cortex (ACC) is important because of its involvement in pathophysiology of BD.[12-14] However, no differences in ACC mI were observed between medication-free BD (depressed and different mood states) and healthy controls. [15,16]
Lithium (Li), having anti-inflammatory properties, is a commonly prescribed mood stabilizing drug in BD[17]. Higher ACC mI and brain Li levels have been reported to be related in older patients with BD.[18] Reduction in ACC (i) mI in healthy individuals 2 hours after Li administration,[19] (ii) mI/creatine (Cr) ratio ~7 days after acute lithium treatment in children with BD [20] and (iii) mI/Cr after 6-week of Li-induced euthymia[21] have been reported in BD.
Investigation of ACC mI level in medication-free patients in depressed state, which can explore role of neuro-inflammation in BD, is largely lacking. We investigated modulation of left dorsal/rostral ACC mI level during 26 weeks of Li therapy in medication-free patients with BD in depressed state.
Methods
Seventeen patients with BD (30±9 y, 3 M, fulfilling DSM-V criteria for BD with current depressive episode, 15<HAM-D<25, YMRS<8, ≥2 weeks without any psychotropic (medication-free for 5 weeks in case previously on fluoxetine), no Li therapy for past 6 months, 1 week without alcohol consumption) and 9 healthy controls (29±10 y, 3 M) were scanned at Siemens 7T Magnetom scanner with a 32-channel receive head coil under an IRB-approved protocol. Subjects were scanned at baseline (pre-therapy), and after 2, 8 and 26 weeks of Li monotherapy (started at 300 mg po bid and increased aiming for a blood level of 0.6 meq/l or as tolerated). MRI scans consisted of (i) localizer, T1-weighted MPRAGE anatomical scan (TR/TE=2250/2.97ms, matrix=256×256, FOV=204×204mm2, scan time 4-min 38-s) and (iii) semi-LASER (sLASER)[22] scan with VAPOR for water suppression[23] (TR/TE1/TE2/TE3=8000/9/11/9ms, 32 transients, scan time 4-min 24-s) scan of a 20×30×20mm3 voxel at left dorsal/rostral ACC (Fig. 1). In addition, unsuppressed water signals with RF off and on were acquired for eddy current correction and quantification respectively. MRspa (https://www.cmrr.umn.edu/downloads/mrspa/) was used to analyze sLASER data, which consisted of (i) Eddy current correction, (ii) frequency correction, (iii) phase correction, (iv) signal averaging, and (v) quantification using LCModel corrected for tissue voxel composition. Voxel segmentation was performed using BET and FAST algorithm[24] of FSL software library.[25] Data with >20% CRLB of mI fit were not used in analysis.Mean ACC mI levels of patients and controls at baseline were compared using unpaired t-test. Longitudinal mI data were analyzed using a linear mixed-effects model including visit (4 time-points), group (patients and controls) and their interaction as fixed effects, and a Gaussian random intercept at t participant level. Linear contrasts were applied to estimate changes in mI level at different visits and their difference. Statistical significance was established at two-sided P-value<0.05. %Coefficient of variation (%CV) of mI levels over 4 weeks was determined for healthy controls using data from 6 subjects with all 4 time-points.
Results and Discussion
A sample LCModel fitted spectrum is shown in Fig. 2. Two patients dropped out after 2 visits, and 3 patients and 1 control dropped out after 3 visits. After accounting for data with poor fit, baseline mI level were not significantly different between patients (N=16; 6.00±1.05 mM) and controls (N=9; 5.71±0.78 mM). %CV of mI for healthy controls was determined to be 10.46%. Evolution of mI levels over 4 visits for patients and controls are shown in Fig. 3. mI levels in patients decreased significantly change during 1st 2 weeks of Li therapy (P=0.003); however mI levels at 8 and 26 weeks did not differ significantly from baseline level. In addition, there was significant difference in changes in mI level (from baseline) to 2-week between patients and controls (P=0.02). Results from this preliminary study addressing depressed state of BD are in line with that observed in acute Li treatment and Li-induced euthymia.[20,21] However, this study suggests that reduction in mI is not a long-term effect and is reverted sometime between 2 and 8 weeks.Conclusion
Li-monotherapy decreases mI level at left dorsal/rostral ACC in otherwise medication-free patients with BD in depressed state in 1st 2 weeks of onset of therapy and the reduction is not observed after 8 weeks.Acknowledgements
This work was supported, in part, by the National Institutes of Health. We thank Sineyob Ahn, Siemens Healthineers, for support with sLASER sequence used in this study.References
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Figures
Fig. 1. 20×30×20 mm3 voxel prescribed at left dorsal/rostral ACC.
Fig. 2. Representative single subject LC Model fitted spectrum.
Fig. 3. (a) Evolution of left dorsal/rostral ACC mI level in healthy controls and patients during 4 visits over 26 weeks, p-values of (b) changes in mI level and (c) difference in changes in mI level between healthy controls and patients (*p<0.05, ** p<0.005).