Dorsolateral and dorsomedial prefrontal gray matter density changes associated with bipolar depression

Palo Alto Veterans Affairs Health Care System, Psychiatry Service, Palo Alto, CA, USA. <>
Psychiatry Research (Impact Factor: 2.47). 05/2009; 172(3):200-4. DOI: 10.1016/j.pscychresns.2008.06.007
Source: PubMed


Mood states are associated with alterations in cerebral blood flow and metabolism, yet changes in cerebral structure are typically viewed in the context of enduring traits, genetic predispositions, or the outcome of chronic psychiatric illness. Magnetic resonance imaging (MRI) scans were obtained from two groups of patients with bipolar disorder. In one group, patients met criteria for a current major depressive episode whereas in the other no patient did. No patient in either group met criteria for a current manic, hypomanic, or mixed episode. Groups were matched with respect to age and illness severity. Analyses of gray matter density were performed with Statistical Parametric Mapping software (SPM5). Compared with non-depressed bipolar subjects, depressed bipolar subjects exhibited lower gray matter density in the right dorsolateral and bilateral dorsomedial prefrontal cortices and portions of the left parietal lobe. In addition, gray matter density was greater in the left temporal lobe and right posterior cingulate cortex/parahippocampal gyrus in depressed than in non-depressed subjects. Our findings highlight the importance of mood state in structural studies of the brain-an issue that has received insufficient attention to date. Moreover, our observed differences in gray matter density overlap metabolic areas of change and thus have implications for the conceptualization and treatment of affective disorders.

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Available from: Allyson Rosen, Oct 03, 2015
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    • "We studied 150 consecutively admitted inpatients affected by a major depressive episode, without psychotic features, with a diagnosis of bipolar disorder type I (Structured Clinical Interview for DSM Disorders). We excluded currently euthymic or manic patients because during depressive episodes, patients with BD show reduced GM volumes , which are lower both than those observed in healthy controls and than those observed in euthymia (Brooks et al. 2009), thus raising the possibility that some brain structural markers of BD could be state dependent (Benedetti et al. 2011c). Patients were either drug-free (n=97) or on treatment with lithium (n=53). "
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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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    • "Such variation of reported effects across studies could be partly explained by the heterogeneity of the BD sample being studied (e.g. combining subjects with BDI and BDII or combining subjects in different mood states), (Brooks et al. 2009), or differences in data acquisition methods or processing approaches (Jones and Cercignani 2010). Given these discrepancies in WM findings between BD and healthy subjects, further investigation using DTI is warranted. "
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    ABSTRACT: With the introduction of diffusion tensor imaging (DTI), structural differences in white matter (WM) architecture between psychiatric populations and healthy controls can be systematically observed and measured. In particular, DTI-tractography can be used to assess WM characteristics over the entire extent of WM tracts and aggregated fiber bundles. Using 64-direction DTI scanning in 27 participants with bipolar disorder (BD) and 26 age-and-gender-matched healthy control subjects, we compared relative length, density, and fractional anisotrophy (FA) of WM tracts involved in emotion regulation or theorized to be important neural components in BD neuropathology. We interactively isolated 22 known white matter tracts using region-of-interest placement (TrackVis software program) and then computed relative tract length, density, and integrity. BD subjects demonstrated significantly shorter WM tracts in the genu, body and splenium of the corpus callosum compared to healthy controls. Additionally, bipolar subjects exhibited reduced fiber density in the genu and body of the corpus callosum, and in the inferior longitudinal fasciculus bilaterally. In the left uncinate fasciculus, however, BD subjects exhibited significantly greater fiber density than healthy controls. There were no significant differences between groups in WM tract FA for those tracts that began and ended in the brain. The significance of differences in tract length and fiber density in BD is discussed.
    Brain Imaging and Behavior 10/2012; 7(2). DOI:10.1007/s11682-012-9202-3 · 4.60 Impact Factor
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    • "For example, the medial prefrontal cortex, a region implicated in cognitive perspective taking (Eslinger, 1998; Shamay-Tsoory et al., 2009) and theory of mind (Gallagher and Frith, 2003; Mar, 2011), shows hyperactivity (Biver et al., 1994; Nofzinger et al., 2005) and reduced tissue volume (Lai et al., 2000; Lacerda et al., 2004) in patients with MDD. The dorsolateral prefrontal cortex (DLPFC), shows tissue volume loss (Coffey et al., 1993; Konarski et al., 2008; Brooks et al., 2009) and hypometabolism in patients with MDD (Biver et al., 1994; Dunn et al., 2002; Davidson et al., 2003) and may contribute to reductions in cognitive flexibility and the generation of ideas also thought requisite to empathic responding (Eslinger, 1998; Rankin et al., 2005). Moreover, tissue volume loss (Sheline et al., 1998; Caetano et al., 2004; Hastings et al., 2004) and hypermetabolism (Drevets, 2000; Sheline et al., 2001) has been reported in the amygdala, a region involved in modulating attention to emotionally salient stimuli (thought to be necessary to understand and respond to the feeling states of others). "
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    ABSTRACT: Individuals with major depressive disorder (MDD) demonstrate deficits in multiple social cognitive domains; however, systematic investigations of empathic responding have not been performed. Twenty patients with MDD completed two measures of empathy, the Interpersonal Reactivity Index (IRI: Davis, 1980, 1983) and the Toronto Empathy Questionnaire (TEQ: Spreng et al., 2009). Relative to matched controls, patients with MDD reported significantly reduced levels of empathy measured broadly on the TEQ and specifically in cognitive ('Perspective Taking') and affective ('Empathic Concern') domains captured by the IRI. A higher illness burden (i.e., greater number of past depressive episodes) was associated with greater reductions in perspective taking ability. This study provides early evidence of impaired empathic abilities in patients with MDD that may worsen with illness progression. Alternatively, reductions in perspective taking ability may contribute to a more severe course of illness in this population. Further longitudinal work is needed to characterize the relation between social cognitive performance and social functioning in this population.
    Psychiatry Research 07/2011; 188(2):231-6. DOI:10.1016/j.psychres.2011.04.013 · 2.47 Impact Factor
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