Greater Cortical Gray Matter Density in Lithium-Treated Patients with Bipolar Disorder

University of Udine, Udine, Friuli Venezia Giulia, Italy
Biological Psychiatry (Impact Factor: 10.26). 08/2007; 62(1):7-16. DOI: 10.1016/j.biopsych.2006.10.027
Source: PubMed


The neurobiological underpinnings of bipolar disorder are not well understood. Previous neuroimaging findings have been inconsistent; however, new methods for three-dimensional (3-D) computational image analysis may better characterize neuroanatomic changes than standard volumetric measures.
We used high-resolution magnetic resonance imaging and cortical pattern matching methods to map gray matter differences in 28 adults with bipolar disorder, 70% of whom were lithium-treated (mean age = 36.1 +/- 10.5; 13 female subject), and 28 healthy control subjects (mean age = 35.9 +/- 8.5; 11 female subjects). Detailed spatial analyses of gray matter density (GMD) were conducted by measuring local proportions of gray matter at thousands of homologous cortical locations.
Gray matter density was significantly greater in bipolar patients relative to control subjects in diffuse cortical regions. Greatest differences were found in bilateral cingulate and paralimbic cortices, brain regions critical for attentional, motivational, and emotional modulation. Secondary region of interest (ROI) analyses indicated significantly greater GMD in the right anterior cingulate among lithium-treated bipolar patients (n = 20) relative to those not taking lithium (n = 8).
These brain maps are consistent with previous voxel-based morphometry reports of greater GMD in portions of the anterior limbic network in bipolar patients and suggest neurotrophic effects of lithium as a possible etiology of these neuroanatomic differences.

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    • "Adler et al. (2007) found increased GM density in bilateral ACC of first-episode bipolar patients compared to healthy controls. Another VBM study reported greater GM density in the ACC of bipolar patients than in controls and lithium-treated patients showed significantly greater GM density in the right ACC than patients not-taking lithium (Bearden et al., 2007). Decreased (Atmaca et al., 2007; Chiu et al., 2008; Kaur et al., 2005; Lochhead et al., 2004; Lyoo et al., 2004) or unchanged (Biederman et al., 2008; Brambilla et al., 2002; Zimmerman et al., 2006) GM density/volume in the ACC of bipolar patients have also been reported. "
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    ABSTRACT: Bipolar disorder (BD) is a highly heritable mental illness which is associated with neuroanatomical abnormalities. Investigating healthy individuals at high genetic risk for bipolar disorder may help to identify neuroanatomical markers of risk and resilience without the confounding effects of burden of illness or medication. Structural magnetic resonance imaging scans were acquired from 30 euthymic patients with BD-I (BP), 28 healthy first degree relatives of BD-I patients (HR), and 30 healthy controls (HC). Data was analyzed using DARTEL for voxel based morphometry in SPM8. Whole-brain analysis revealed a significant main effect of group in the gray matter volume in bilateral inferior frontal gyrus, left parahippocampal gyrus, left lingual gyrus and cerebellum, posterior cingulate gyrus, and supramarginal gyrus (alphasim corrected (≤0.05 FWE)). Post-hoc t-tests showed that inferior frontal gyrus volumes were bilaterally larger both in BP and HR than in HC. BP and HR also had smaller cerebellar volume compared with HC. In addition, BP had smaller left lingual gyrus volume, whereas HR had larger left parahippocampal and supramarginal gyrus volume compared with HC. This study was cross-sectional and the sample size was not large. All bipolar patients were on medication, therefore we were not able to exclude medication effects in bipolar group in this study. Our findings suggest that increased inferior frontal gyrus and decreased cerebellar volumes might be associated with genetic predisposition for bipolar disorder. Longitudinal studies are needed to better understand the predictive and prognostic value of structural changes in these regions. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of Affective Disorders 07/2015; 186:110-118. DOI:10.1016/j.jad.2015.06.055 · 3.38 Impact Factor
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    • "Lithium has been suggested to be neuro-protective in the context of other psychiatric disorders, as studies have indicated that lithium may change disease progress in Alzheimer's patients with early symptoms (Forlenza et al., 2012; Diniz et al., 2013). It has also been suggested that lithium may stimulate increases in gray matter volume and density in bipolar patients (Moore et al., 2000, 2009; Sassi et al., 2002; Bearden et al., 2007), particularly hippocampal volume increases (Yücel et al., 2007; Hallahan et al., 2011; Hajek et al., 2012a, 2012b, 2014). However, research into the effects of lithium on the brain in bipolar disorder, particularly psychotic bipolar disorder (PBD), remains unclear and inconsistent (Kato et al., 1996; Davanzo et al., 2001; Brambilla et al., 2004; Friedman et al., 2004; Patel et al., 2008; Dickstein et al., 2009; Selek et al., 2013). "
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    ABSTRACT: Relative to healthy controls, lithium free bipolar patients exhibit significant gray matter abnormalities. Lithium, the long-time reference standard medication treatment for bipolar disorder, has been proposed to be neuro-protective against these abnormalities. However, its effects on cortical thickness and hippocampal subfield (HSF) volumes remain unstudied and unclear, respectively, in bipolar disorder. This study included 342 healthy controls (HC), 51 lithium free PBD patients (NoLi), and 51 PBD patients taking lithium (Li). Regional gray matter thickness and HSF volume values were extracted from 3T MRI images. After matching NoLi and Li samples, regions where HC differed from either Li or NoLi were identified. In regions of significant or trending HC-NoLi difference, Li-NoLi comparisons were made. No significant HC-Li thickness or HSF volume differences were found. Significantly thinner occipital cortices were observed in NoLi compared to HC. In these regions, Li consistently exhibited non-significant trends for greater cortical thickness relative to NoLi. Significantly less volume was observed in NoLi compared to both HC and Li in right HSFs. Our results suggest that PBD in patients not treated with Li is associated with thinner occipital cortices and reduced HSF volumes compared with HC. Patients treated with Li exhibited significantly larger HSF volumes than NoLi, and those treated with Li were no different from HC in cortical thickness or hippocampal volumes. This evidence directly supports the hypothesis that Li may counteract the locally thinner and smaller gray matter structure found in PBD.
    Journal of Psychiatric Research 12/2014; 61. DOI:10.1016/j.jpsychires.2014.12.008 · 3.96 Impact Factor
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    • "Our results suggest that the GSK-3β inhibitor lithium acts on these areas and increases their GM volumes proportionally to the duration of treatment. This observation in 150 patients with BD is in agreement with preliminary studies showing that 6 patients on chronic lithium had a higher subgenual PFC volume than 15 patients off lithium (Drevets et al. 1997), that 20 patients on lithium had a higher volume than 8 patients off lithium in right ACC including subgenual ACC (Bearden et al. 2007), and that in 28 patients, lithium increased PFC and subgenual PFC volumes proportional to treatment response (Moore et al. 2009). Moreover, our results suggest that inhibition of GSK-3β activity, as determined by a functional genetic polymorphism in its promoter gene (Kwok Table 1 Clinical and demographic characteristics of the sample divided according to GSK-3β rs334558 genotype "
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    ABSTRACT: Rationale Lithium is the mainstay for the treatment of bipolar disorder (BD) and inhibits glycogen synthase kinase-3β (GSK-3β). The less active GSK-3β promoter gene variants have been associated with less detrimental clinical features of BD. GSK-3β gene variants and lithium can influence brain gray and white matter structure in psychiatric conditions, so we studied their combined effect in BD. Objectives The aim of this study is to investigate the effects of ongoing long-term lithium treatment and GSK-3β promoter rs334558 polymorphism on regional gray matter (GM) volumes of patients with BD. Materials and methods GM volumes were estimated with 3.0 Tesla MRI in 150 patients affected by a major depressive episode in course of BD. Duration of lifetime lithium treatment was retrospectively assessed. Analyses were performed by searching for significant effects of lithium and rs334558 in the whole brain. Results The less active GSK-3β rs334558*G gene promoter variant and the long-term administration of lithium were synergistically associated with increased GM volumes in the right frontal lobe, in a large cluster encompassing the boundaries of subgenual and orbitofrontal cortex (including Brodmann areas 25, 11, and 47). Effects of lithium on GM revealed in rs334558*G carriers only, consistent with previously reported clinical effects in these genotype groups, and were proportional to the duration of treatment. Conclusions Lithium and rs334558 influenced GM volumes in areas critical for the generation and control of affect, which have been widely implicated in the process of BD pathophysiology. In the light of the protective effects of lithium on white matter integrity, our results suggest that the clinical effects of lithium associate with a neurotrophic effect on the whole brain, probably mediated by GSK-3β inhibition.
    Psychopharmacology 10/2014; 232(7). DOI:10.1007/s00213-014-3770-4 · 3.88 Impact Factor
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