These maps provide novel information regarding regionally specific gray matter enlargement associated with lithium treatment in bipolar patients. Cortical pattern matching methods revealed significantly greater gray matter concentration, particularly within the medial walls of the cerebral hemispheres, in the anterior cingulate, ventral prefrontal cortex, and paralimbic association cortex in lithium-treated patients with bipolar disorder, as compared with healthy control subjects. These brain regions are part of a complex interconnected neural circuitry involved in mood and cognitive regulation, memory, and the pathophysiology of both unipolar and bipolar mood disorders (Brambilla et al. 2005
; Phan et al. 2002
). Given that this effect was not found in unmedicated bipolar patients, these results suggest changes in regional gray matter brain content related to lithium treatment and may reflect its postulated effect of neuropil increase manifested as increases in gray matter volume (Moore et al. 2000b
). Further corroborating these data in a prospective MRI study with healthy volunteers, we found significant increases in gray matter concentration in the left cingulate, left precuneus, and right superior frontal gyrus after 4 weeks of lithium treatment (Monkul et al. 2004
These findings are also consistent with a recent voxel-based morphometry investigation (Adler et al. 2005
) that observed areas of significantly greater gray matter in several brain regions, including portions of the anterior cingulate, ventral prefrontal cortex, fusiform gyrus, and primary and supplementary motor cortex, in a sample of adult bipolar patients on a variety of medications. Although the authors interpret their findings as possibly reflective of preapoptotic osmotic changes or hypertrophy, they did not explicitly investigate differential medication effects, leaving open the question of the etiology of these neuroanatomic differences. In contrast, using similar methods, Lyoo et al. (2004)
found reduced gray matter density in left anterior cingulate and right inferior frontal gyrus in bipolar patients relative to comparison subjects. In this study, only 25% of patients were currently taking lithium, while a slight majority (39%) were unmedicated.
While very little is currently known regarding the functional significance of lithium-associated brain changes, functional neuroimaging studies offer preliminary evidence that mood-stabilizing medications may normalize functional abnormalities within frontotemporal neural systems in bipolar illness (Blumberg et al. 2005
). In addition, two recent functional neuroimaging studies have reported decreases in task-associated physiological activity following 2 weeks of lithium treatment in both euthymic bipolar patients (Silverstone et al. 2005
) and healthy volunteers (Bell et al. 2005
). The relationship of such physiological changes to structural neuroanatomic changes is unknown and clearly warrants further investigation.
We did not detect an effect of lithium dosage or a significant linear correlation between duration of lithium usage and GMD. However, in this naturalistic study, a quadratic (inverted U-shaped) relationship was observed between overall GMD and weeks of lithium treatment. The onset of lithium’s neuroprotective action appears to require about 7 days of treatment, at least in cultured cells (Manji and Lenox 2000
). Moreover, the therapeutic effects of mood stabilizers are generally not immediately reversed on discontinuation, suggesting a progressive and complex biological response (Manji et al. 2000a
). In rats treated by diet for 2 or 4 weeks, lithium at therapeutic doses has been shown to increase the activity of two prominent transcription factors, AP-1 and cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB), in cultured cerebellar granule cells and in distinct brain regions, including the frontal cortex, amygdala, hippocampus, and cerebellum (Ozaki and Chuang 1997
However, it is difficult to infer from these animal studies what might be predicted over a longer time course in humans. While prior studies in human subjects have detected effects of lithium treatment on gray matter volume within 4 weeks (Moore et al. 2000a
), it is unsurprising that the relationship between duration of treatment and brain changes is complex and nonlinear. Although gray matter increases attributable to lithium treatment would be expected to reach asymptote at some point, the inverted U-shaped function is somewhat unexpected and may possibly reflect a complex interaction between effects of lithium treatment and normal aging processes. Because these questions cannot be addressed in this naturalistic, cross-sectional study, we are actively investigating neuroanatomic, as well as neurocognitive, effects of duration and dosage of lithium treatment in a longitudinal follow-up study.
Our findings suggest that some of the inconsistencies between prior neuroanatomic studies of patients with bipolar disorder may be attributable to competing processes of disease-related atrophy and/or tissue reduction pitted against possible neurotrophic or neuroprotective effects of mood-stabilizing medication. Consistent with this possibility, Drevets et al. (1997)
previously reported that a small subregion of the anterior cingulate, the subgenual prefrontal cortex (SGPFC), was about 40% smaller in patients with bipolar disorder than in matched control subjects; however, they subsequently found that the patients treated with lithium or valproate had significantly higher SGPFC volumes than nontreated patients and did not differ from control subjects.
Although the mechanism of action of lithium is still largely unknown, recent animal and human studies have provided converging evidence for its potential neuroprotective and neurotrophic effects (e.g., Manji et al. 2000a
). At the molecular level, both lithium and valproate robustly increase levels of the neuroprotective protein B-cell lymphoma protein-2 (bcl-2) in the frontal cortex (Chen et al. 1999
) and inhibit the proapoptotic protein glycogen synthase kinase-3β (GSK-3β) in the central nervous system (CNS) (Chen et al. 1999
; Manji et al. 2000a
). B-cell lymphoma protein-2 is part of a well-characterized protein family that regulates apoptotic cell death, acting on mitochondria to stabilize membrane integrity and prevent release of apoptogenic factors (Manji et al. 2000b
). Glycogen synthase kinase-3β is implicated in regulation of various cytoskeletal processes and disease-related neuronal death (Chen et al. 1999
; Jope 1999
; Manji et al. 2000a
). Its inhibition by lithium is thought to be protective against processes of programmed cell death (Hetman et al. 2000
). It is unclear which of these cellular actions is related to lithium’s therapeutic effects; an increasing number of studies are now attempting to elucidate the processes that convert these second messenger-mediated events into long-term cellular phenotypic changes.
Notably, recent postmortem neuropathologic studies have documented reduced neuronal density in brain regions in which we found evidence for robustly increased gray matter density in lithium-treated patients, particularly the anterior cingulate (Benes et al. 2001
; Bouras et al. 2001
). Although effects of mood-stabilizing medications were not explicitly examined in these studies, the question of whether lithium treatment has long-term neuroprotective benefits that persist following termination of treatment is also of fundamental importance.
Certain limitations of the current study must be noted. Because we did not specifically design this study to examine the effects of lithium treatment, we were unable to match the patient groups on all clinical variables; specifically, there was a nonsignificant trend toward higher depression severity scores in the untreated group at the time of scanning. However, given that prior studies have not reported structural anatomic differences as a function of current mood state (Brambilla et al. 2005
), we do not believe that this presents a significant confound. Further, while patients with bipolar II disorder were proportionally overrepresented in the untreated group, bipolar II disorder patients did not significantly differ from bipolar I disorder patients in terms of GMD [means: bipolar I disorder = .38 ± .03 versus .38 ± .06 for bipolar II disorder; F
(1,26) = .12, p
= .73]. Thus, the higher proportion of bipolar II disorder patients in the untreated group cannot account for this pattern of findings. With regard to medication treatment, our sample included patients who had been on lithium for varying time periods and dosages were not uniform across subjects. In the context of a clinical trial, such variables could be better controlled. In addition, while some subjects were taking more than one medication, results did not change when these subjects were excluded from analysis. These limitations notwithstanding, as this study is, to our knowledge, the first to characterize the pattern of gray matter differences across the cortical surface in lithium-treated bipolar patients, replication with a larger homogenous group of subjects may serve to confirm the results observed here.
Given the small sample size in the lithium-untreated group and the cross-sectional nature of this investigation, these findings do not conclusively demonstrate that greater gray matter concentration in the lithium-treated group results from medication effects alone. Although robust differences were detected between the lithium-treated group and normal control subjects, the group difference comparison for lithium-treated versus untreated bipolar patients reached statistical significance only for the right anterior cingulate after permutation analysis to correct for multiple comparisons. Thus, it cannot be ruled out that these regional increases were present prior to initiation of lithium and instead reflect neuronal pathology intrinsic to bipolar illness, perhaps resulting from a selective failure of these systems to myelinate, which could result in more tissue segmenting as gray matter in these brain regions. However, this explanation is unlikely, given the clear absence of differences between the untreated group and normal control subjects, as well as converging evidence demonstrating gray matter increases resulting from short-term lithium treatment in healthy volunteers (Monkul et al. 2004
; Moore et al. 2000b
). In addition, while we cannot exclude the possibility that the observed gray matter differences in the lithium-treated group are related to osmotic effects of lithium leading to changes in water content in the brain, a purely osmotic action would be unlikely to be restricted to gray matter alone (Sassi et al. 2002
); the absence of any differences in white matter argues against this interpretation. Notably, other psychotropic agents, including valproate (Chen et al. 1999
) and atypical antipsychotics (Braus et al. 2001
), may also affect neuronal viability. These observations demonstrate the importance of taking medication effects into account when interpreting data from in vivo neuroimaging studies and postmortem reports. Furthermore, other factors that may contribute to GMD increases in bipolar patients should be systematically examined in future investigations.
In conclusion, the sensitive cortical pattern matching methods employed in this study were able to detect prominent gray matter enlargement, most pronounced in bilateral cingulate and paralimbic cortices, in lithium-treated patients with bipolar disorder relative to healthy control subjects. It is tempting to infer that the observed gray matter increases may suggest a mechanism of action for lithium’s therapeutic effects, but these findings clearly need to be replicated in other studies. The pattern of results observed here, combined with those of prior studies indicating structural and neurochemical differences as a function of lithium treatment, suggest that reanalysis of previously collected neuroimaging data may be an efficient way to substantially increase our current understanding of the magnitude and time course of lithium’s effects on the brain. Future studies should also assess whether valproate or other medications that effectively treat bipolar disorder lead to similar increases in brain gray matter in vivo and further investigate the clinical and functional relevance of these results.