Structural Magnetic Resonance Imaging in Bipolar Disorder: An International Collaborative Mega-Analysis of Individual Adult Patient Data

Published brain volumetric studies in bipolar disorder were identified by a systematic search of the databases MedLine, PsychLIT, and EMBASE for articles published between 1980 and 2009 in any language using the following medical subject heading categories; magnetic resonance imaging or MRI and bipolar affective disorder, bipolar disorder, or mania. We cross-referenced all relevant original research and review articles relating to imaging of affective disorders to search for additional published articles. A systematic literature search using the medical subject heading categories magnetic resonance imaging or MRI and schizophrenia or schizoaffective disorder was also conducted, because some studies have compared bipolar disorder, schizophrenia, and other comparison groups.

We invited research groups that had employed robust methodology in data acquisition by setting certain minimum requirements, and we used similar inclusion criteria to our previous aggregate data meta-analysis (13): 1) an MRI scanner strength of 1T or greater, 2) regional brain structure measurement based on contiguous slices, 3) included individuals aged 16 to 55 years, 4) brain structures independently examined by three or more research groups, and 5) patients with bipolar disorder only—data contributed by research groups including individuals with schizoaffective disorder, schizo-phrenia, or unipolar depression alone were not included.

We identified 22 research groups meeting these criteria. Senior representatives from each group were invited to participate and submit to us their relevant individual raw data for this mega-analysis. Data requested included participant diagnosis, relevant brain volumetric measurements, demographic details including age and gender, clinical details about the age of onset and course of illness, and medication use. Researchers from 11 groups submitted data on 321 individuals with bipolar I disorder and 442 healthy subjects. Data on a further 29 individuals with bipolar II disorder were submitted; however due to this limited data, we only examined individuals with bipolar I disorder. The majority of these data have been previously published (Table S1 in Supplement 1) (4–9, 24–43). Projects from each research center were approved by the respective ethical committees. Data from the different research centers were merged into a single spreadsheet and corrected for inaccuracies, duplications, and inclusion criteria (e.g., adolescents under 16 years and individuals with bipolar II disorder were excluded from further analysis).

Linear mixed effects regression models were used where the research center was incorporated as a random effect to account for the correlation due to individuals within each research center and possible heterogeneity between research centers. As the factor, gender, and covariates, age + brain slice thickness, could be potential confounders, these were forced into each model in addition to the primary diagnostic group variable. Summary statistics and point and 95% confidence interval (CI) estimates of the difference in the mean adjusted response variables across the levels of diagnostic group were reported. The level of statistical significance was set at α = .05, and effect sizes using Cohen's d were also reported. Model diagnostics were performed using suitable residual plots. Ventricular volume distributions were normalized through log transformation. All analysis was performed using the Statistical Package for Social Sciences 15.0 for Windows (SPSS 15.0 for Windows, SPSS, Inc., Chicago, Illinois) and R (version 2.6.1) (The R project for statistical computing; http://www.rproject.org). We corrected for multiple testing using the technique described by Holm (44).

Our principal analysis compared regional brain volumes between groups (bipolar I individuals vs. healthy subjects). We also performed analyses to ascertain the effect of medication between subgroups (e.g., bipolar disorder individuals treated with lithium vs. bipolar disorder individuals not treated with lithium vs. healthy subjects) and any effect on brain volume or duration of illness and number of hospitalizations.

Similar to meta-analyses of aggregate data (13–15), we found that bipolar I disorder is associated with increased right lateral ventricular volume, which suggests a subtle anatomical laterality difference in pathogenesis compared with schizophrenia, where left-sided ventriculomegaly is more prominent (45). Our findings comparing the entire bipolar group with healthy subjects are also consistent with previous meta-analyses that found a preservation of global cerebral volume and hippocampal volume in bipolar disorder (13, 14), although a recent meta-analysis noted a global reduction in brain volume (15). However, the present study provides strong evidence for a substantial contribution of lithium treatment to medial temporal lobe enlargement in patients with bipolar disorder and reveals this phenomenon as a potential source of heterogeneity in published magnetic resonance bipolar studies. The apparent trophic effect of lithium was present across research centers and age and was anatomically specific, most prominently evident in the neuroplastic hippocampus and the amygdala. No such lithium effect was detected for anterior cingulate, lateral ventricular, thalamic, basal ganglia, or temporal lobe volume.

First-episode bipolar disorder patients had reduced cerebral volume and amygdala volume and individuals with bipolar disorder who were not taking lithium had reduction in cerebral and hippocampal volumes compared with healthy comparison subjects—findings consistently reported in the related syndromes of unipolar depression and schizophrenia (45–49). This finding raises the intriguing possibility that bipolar disorder may indeed share with schizophrenia and depression the pathogenetic mechanisms associated with medial temporal lobe volume reduction, perhaps induced by glucocorticoid excess (50, 51), but that these changes are reversed in patients with bipolar disorder alone by the differential use of lithium in this patient group.

Our finding of increased hippocampal volume in individuals treated with lithium compared with those bipolar individuals not treated with lithium (and healthy subjects) is consistent with some other cross-sectional studies not included in the mega-analysis (21–23, 52, 53) and two recent longitudinal studies of 1 to 8 weeks and 2 to 4 years duration (43, 54). Although the mechanism of action of lithium is poorly understood (55), an important role in neuroprotection and neurogenesis has been suggested (56, 57). The hippocampus is a particularly plastic brain region (58) and is one of the few areas to produce neurons postnatally (59); therefore, it may be more likely than other brain regions to be affected by medication induced neurogenesis (60). The mechanism of lithium-induced neurogenesis has not been fully elucidated; however, proposed mechanisms include an effect on signal pathways including its ability to upregulate the cytoprotective protein Bcl-2 (58, 60) and its effect on growth factors including nerve growth factor (57) and brain-derived neurotrophic factor (57, 61, 62). Our finding of increased amygdala volume in individuals treated with lithium is consistent with the findings from another recent study (21) and suggests that the amygdala may also be modified by lithium. Interestingly, these structures are closely interconnected and form part of the anterior limbic system known to be involved in mood regulation and that demonstrate task-related hyperactivity in functional imaging studies of bipolar disorder, possibly related to impaired prefrontal modulation of these regions (63, 64). In contrast, there was no apparent effect of lithium on striatum, temporal lobes, or lateral ventricular volumes. However, almost all patients in the sample were taking medications and it may well be that alternative mood stabilizing agents had differential effects on other brain volumes. For example, taking lithium or any other mood stabilizer could be related to the temporal lobe and putamen volume increase identified in the present study, as there were insufficient psychotropic naive patients in the sample to assess this. The inclusion of medication-free patients with bipolar disorder and careful longitudinal studies assessing homogenous samples of patients on different medications will be required to elucidate such propositions.

There are some other limitations to this study. It was only possible to acquire individual data from 11 of the 22 research groups identified who satisfied our inclusion and exclusion criteria. Due to this, we were unable to examine anterior cingulate gyrus and intracranial volume between treatment groups. Not all research sites had acquired data on sociodemographic or clinical variables of interest such as socioeconomic class, medication use (two sites did not supply data in relation to medication use; however, these two sites contributed the fewest individuals to the mega-analysis and did not analyze the amygdala or hippocampus), treatment adherence, severity of depression or mania at time of scanning (most individuals were euthymic), and psychotic symptoms. All research sites did, however, supply data in relation to subjects' age, gender, and illness duration. We did not have sufficient data to analyze the duration of medication exposure or medication levels and regional brain volumes. We were also unable to control for intracranial or cerebral volume in our analysis of brain subregions, as not all research groups had acquired these data. We did not have sufficient data to examine if a history of psychosis significantly affected regional brain volumes in bipolar disorder. The different MRI datasets analyzed used different MRI field strengths and pulse sequences and different techniques to delineate anatomical brain regions. While mega-analysis has the advantage of being specifically able to control for research center and thus control for differences in MRI techniques between research centers, it would, of course, be preferable if identical techniques were used by each research center.

Our finding of increased amygdala volume in individuals with bipolar disorder treated with lithium may help to explain some of the inconsistencies in the published literature. Previous studies demonstrating increased amygdala volume in individuals with bipolar disorder have predominantly included individuals treated with lithium (71% and 63%) (5, 6), whereas studies demonstrating a reduction in amygdala volume included fewer individuals treated with lithium (20%–40%) (8–11).

We noted increased temporal lobe volume in individuals with bipolar disorder, with left temporal lobe volume increased in bipolar individuals both on and off lithium. Although this is not a well documented finding, three of the five studies included in our analysis had nonsignificant increases in temporal lobe volume in bipolar individuals compared with healthy subjects (4–6). Other studies have noted an increase in left temporal lobe volume (65, 66). Wilke et al. (65) suggested that their finding of increased left temporal lobe volume was due to increased volume of the superior temporal gyrus, and an association between left temporal lobe volume and increasing duration of illness has been reported (66).

While we had fairly modest power in relation to the putamen, we detected an increased volume of this region in individuals with bipolar disorder, which is consistent with some (3, 7, 37) but not all previous findings (26, 67, 68). This increased volume was only noted for the right putamen and may reflect previous findings where shape differences (increased radii) in the right putamen but not left side were noted in drug-naive bipolar subjects compared with control subjects (69).

Our finding of a reduction in cerebral volume with duration of illness is consistent with a number of studies that have demonstrated reduced total gray matter volume with illness duration in bipolar disorder (69–72) and suggests that a neurodegenerative process may be involved in the pathophysiology of bipolar disorder. Further prospective longitudinal studies are necessary to comprehensively elucidate this proposition.

In this study, we demonstrated that adults with established bipolar I disorder display right lateral ventricle enlargement and increased mean left temporal lobe and right putamen volume. The main source of heterogeneity identified by this large individual level analysis of clinical and demographic factors was medication usage. Lithium treatment was differentially associated with a regionally specific increased mean volume of the hippocampus and amygdala. This increased mean brain volume associated with lithium may be due to the neuroprotective effects of lithium, which are possibly mediated by its effect on neurotrophic growth factors.