A longitudinal pilot proton MRS investigation of the manic and euthymic states of bipolar disorder

Abstract

Several lines of evidence implicate dysfunction in brain energy production as a key component of bipolar disorder. In particular, elevated brain lactate levels observed in this condition suggest a shift from aerobic to anaerobic metabolism, possibly as a result of mitochondrial abnormalities. Most prior imaging studies of brain metabolites were performed in either euthymic or depressed bipolar patients or compared different populations in different mood states. We sought to measure brain metabolite concentrations in the same patients in both manic and euthymic states. Given the dramatic changes in clinical state of bipolar disorder patients, we hypothesized that previously observed abnormalities in lactate concentrations in bipolar disorder might show state dependent changes. In this study 15 patients (mean age 36.1 years) diagnosed with bipolar I disorder underwent proton magnetic resonance spectroscopy of the anterior cingulate cortex and parieto-occipital cortex during hospitalization for acute mania (mean Young Mania Rating Scale (YMRS) 22.1). Seven of these subjects returned (mean interval 21.16 months) to have imaging repeated while euthymic (mean YMRS 2.0). A group of age- and gender-matched control participants (N=6) were scanned as well. We report that during mania, bipolar disorder subjects had lactate levels comparable to healthy control subjects but during euthymia these levels were significantly reduced. No significant change was observed for other metabolites. These results implicate mood dependent alterations in energy metabolism in the biology of bipolar disorder. Additionally, this finding has potential use as a biomarker for both evaluating novel treatments as well as diagnostic clarification between mood disorders.

Figure 1

Placement of the anterior cingulate cortex (ACC) (left) and parietal occipital cortex (POC) (right) voxels.

Figure 2

Contour plots of real two-dimensional (2-D) spectra from the anterior cingulate cortex (ACC) in a control (top) and bipolar disorder (BD) subject (bottom). In each case, the X axis is frequency (F2 in p.p.m.) and the Y axis is J (F1 in Hz). The spectral region from about −35 to +35 Hz is shown. The main metabolite resonances recognizable in the plots are labeled. Although the lactate resonance is not well-resolved in these plots, its approximate location at 1.33 p.p.m. is highlighted. The additional information available from 2-D magnetic resonance spectroscopy (MRS) allows improved fitting of this metabolite as discussed in the text. Note the variable nature of water suppression, and of the macromolecule signal profile (highlighted in a box in the top panel) in the two spectra. Lac, lactate; H₂O, water; GSH, glutathione; MMs, macromolecules.

Figure 3

Brain lactate concentrations measured as lactate/creatinine ratios in the parietal occipital cortex (POC) and anterior cingulate cortex (ACC) for bipolar patients in a manic state (left), bipolar patients in a euthymic state (middle), and healthy control subjects (right). Identical voxel locations in the same subjects are connected by gray lines. The group mean (error bars=s.d.) is shown at the side for each time point. *P=0.002; **P=0.049.