Resting state corticolimbic connectivity abnormalities in unmedicated bipolar disorder and unipolar depression☆
Introduction
Converging findings from animal and human studies point to the anterior cingulate–pallidostriatal–thalamic–amygdala circuit as a putative corticolimbic mood-regulating circuit (MRC) that may be dysfunctional in mood disorders (Drevets, 1998, Anand and Charney, 2000, Mayberg, 2003). Brain-imaging techniques such as functional magnetic resonance imaging (fMRI) and positron emission tomography have shown increased activation in major depressive disorder (MDD) of mood-generating limbic areas such as the amygdala (AMYG) (Ketter et al., 2001, Sheline et al., 2001, Drevets et al., 2002, Siegle et al., 2002, Anand et al., 2005a), ventral striatum (VST), and dorsomedial thalamus (DMTHAL) (Drevets, 1998, Taber et al., 2004). Other areas of the brain that are also implicated are the insula, hippocampus and parahippocampal areas (Mayberg et al., 1999, Phillips et al., 2003, Anand et al., 2005a). Conversely, decreased activation of certain cortical areas have been reported in MDD — in particular, the pregenual and ventral subdivisions of the anterior cingulate cortex (pgACC and vACC) (Drevets et al., 1997, Mayberg et al., 1999), the anteromedial prefrontal cortex, the orbitofrontal cortex (OFC), and the dorsolateral prefrontal cortex (DLPFC) (Mayberg et al., 1999, Ketter et al., 2001).
Compared with the literature on MDD, considerably fewer studies have investigated regional brain activation in bipolar disorder (BD). In studies in which phase of illness has been characterized, most have been conducted in BD depression (BDD), which has also has been reported to be associated with increased limbic activation and decreased activation of cortical regions such as the DLPFC and ACC (Buchsbaum et al., 1986, Baxter et al., 1989, Drevets et al., 1997, Yurgelun-Todd et al., 2000, Ketter et al., 2001, Blumberg et al., 2003, Phillips et al., 2003, Chang et al., 2004). In mania (BDM), increased metabolism of the ventral and dorsal ACC, the striatum (Drevets et al., 1997, Blumberg et al., 2000), and the amygdala (Altshuler et al., 2005) [another study reported decreased amygdala activation (Lennox et al., 2004)], and decreased activity of the OFC (Blumberg et al., 1999), have been reported. Strakowski et al. (2004) have reported an abnormality in the anterior limbic network in BD in response to cognitive stimuli. Compared with healthy subjects, unmedicated euthymic BP patients showed increased activation in the limbic and paralimbic areas (parahippocampus, amygdala and insula) as well as ventral prefrontal regions when performing attentional tasks (Strakowski et al., 2004). Therefore, in BD, abnormalities within the prefrontal cortex, subcortical structures such as the striatum and thalamus, and medial temporal structures such as the amygdala and the parahippocampus, are likely to be present (Strakowski et al., 2005, Adler et al., 2006).
Methodological issues such as medication status and inadequate identification of the phase of illness may have contributed to discrepant results in some of the above studies. Unmedicated BD subjects are difficult to recruit for studies. Furthermore, the discrepant findings of changes in local activation also suggest that the abnormality may lie at a circuit level in terms of the corticolimbic connectivity rather than in localized brain regions.
Recently, there has been considerable interest generated from the discovery of spontaneous low frequency (< 0.08 Hz) blood oxygen level-dependent (BOLD) fluctuations (LFBF) in resting state in echoplanar imaging (EPI) data (Raichle et al., 2001). It has been recognized that these LFBFs are not caused by instrumentation or physiological effects (such as cardiac and respiratory cycles) originating outside the brain (Biswal et al., 1995). It has also been shown that these resting state signal changes reflect alterations in blood flow and oxygenation that may be coupled to neuronal activity and that LFBFs correlate between brain areas of plausible functional connectivity (Biswal et al., 1995, Lowe et al., 2000, Cordes et al., 2001, Peltier and Noll, 2002, Hampson et al., 2002, Salvador et al., 2005). Published studies of connectivity abnormalities using the LFBF correlation method have been reported in neuropsychiatric conditions such as attention deficit hyperactivity disorder (ADHD) (Castellanos et al., 2008), schizophrenia (Liang et al., 2006, Garrity et al., 2007, Zhou et al., 2007), Alzheimer's disease (Greicius et al., 2004), substance abuse (Li et al., 2000), multiple sclerosis (Lowe et al., 2002), and autism (Cherkassky et al., 2006).
We have previously reported the results of our study in which corticolimbic connectivity was measured using the resting state LFBF correlation method in unmedicated MDD patients and healthy subjects (Anand et al., 2005a). The results of this study indicated that resting state functional connectivity between the pgACC and the limbic regions – amygdala (AMYG), pallidostriatum (PST) and dorsomedial thalamus (DMTHAL) – is decreased in MDD (Anand et al., 2005a, Anand et al., 2005b). In this study, we report, for the first time, corticolimbic connectivity abnormalities in unmedicated BD patients in both the manic and depressed phase of the illness and a comparison with corticolimbic connectivity abnormalities previously reported in MDD patients and healthy controls. Our unitary hypothesis was that mood dyregulation arises from decreased corticolimbic connectivity, and hence in BD (whether in the manic or the depressed phase) decreased connectivity will be seen similar to that seen in MDD.
Section snippets
Subjects
Medication-free unipolar depressed (MDD), bipolar depressed (BDD) and bipolar manic (BDM) outpatients were recruited from the outpatient clinic at University Hospital, Indiana University School of Medicine, and by advertisement, from the community. Closely matched healthy subjects were recruited through advertisements. All subjects took part in the study after signing an informed consent form approved by the Investigational Review Board (IRB) at Indiana University School of Medicine. Both
Results
Twelve unmedicated bipolar subjects in either the manic (BDM) or the depressed (BDD) phase completed the study. One BDD subject's imaging data were discarded because of technical difficulties during the acquisition of the scan. The results of the remaining 11 BD subjects (6 BDM, 5 BDD) were then compared with those of 15 unipolar depressed (MDD) subjects and 15 healthy subjects who we had previously studied using the same paradigm (Anand et al., 2005a). One BDM patient, after inclusion in the
Discussion
The findings of this study indicated decreased corticolimbic connectivity in BD patients compared with healthy subjects, similar to results previously reported for MDD; however, the abnormalities seemed to be more severe in the BD group. This is not a surprising finding as BD is a more severe illness of mood regulation than MDD. The BD subgroup also had a longer duration of illness and had had more mood episodes than the MDD group, and it was slightly older than the MDD and healthy control
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The results of this study have been previously presented at the Society of Biological Psychiatry meeting in San Diego (2007).