Research reportAltered prefrontal cortex activity during working memory task in Bipolar Disorder: A functional Magnetic Resonance Imaging study in euthymic bipolar I and II patients
Introduction
Bipolar Disorder (BD) is a highly disabling condition with a complex gene-environment etiology (Craddock and Sklar, 2013). Phenotypic expression of the disorder includes the presence of cognitive deficits, that recently emerged as a core feature of BD (Bora et al., 2009). In addition, there is a substantial body of evidence showing the persistence of cognitive impairment after the resolution of the acute episode (Kurtz and Gerraty, 2009).
Cognitive deficits have been implicated among major factors contributing to patients' impaired quality of life (Arts et al., 2008, Mackala et al., 2014) and adverse outcome (Andreou and Bozikas, 2013).It has been proposed that altered brain activity associated with cognitive deficits may represent a heritable, susceptibility-related phenotype, likely intermediate from a pathophysiological point of view between genes that increase susceptibility to BD and its symptoms (Daban et al., 2012).
Deficits in working memory (WM) are among the most frequently impaired cognitive domains in patients with BD (Gruber et al., 2010, Latalova et al., 2011, Thompson et al., 2007). WM is the cognitive function responsible for temporarily storing and managing the information required to carry out complex cognitive tasks such as learning, reasoning and comprehension: it is, therefore, a fundamental component of higher-level functions (Goldman-Rakic, 1996).
WM deficits in bipolar patients seem to be relatively stable across time (Bourne et al., 2013), largely independent of mood-state (Bourne et al., 2013), severity of symptoms (Pavuluri et al., 2006), comorbidity, and medication regimen (Bearden et al., 2007). According to a recent meta-analysis, a different expression of cognitive dysfunction, including WM deficits, has been reported also in first-episode patients with BD (Lee et al., 2014) and in unaffected siblings of youth with BD, providing more direct support for their potential heritability (Doyle et al., 2009).
The prefrontal cortex (PFC) has been identified as a key neocortical region supporting WM processing (Wang et al., 2006). Previous functional imaging studies in humans have demonstrated the role of PFC activity while generating and testing neuroimaging intermediate phenotypes for complex genetic brain disorders (Blokland et al., 2011). Of note, converging data from post mortem and structural imaging studies have indicated that BD is associated with abnormalities of PFC biology (Manji and Duman, 2001). More specifically, post mortem morphometric brain studies have revealed abnormal size and density of pyramidal and non pyramidal neurons in dorsolateral prefrontal cortex (DLPFC) of patients with BD, as well as unexpected reductions in glia cell number and density (Ongür et al., 1998, Rajkowska et al., 2001, Savitz and Drevets, 2011, Konopaske et al., 2014). Moreover, in vivo studies with structural Magnetic Resonance Imaging (MRI) have demonstrated reduced volume of DLPFC in patients with BD (Selvaraj et al., 2012, Soares, 2003, Soares et al., 2005).
In two recent voxelwise meta-analyses focused on grey matter abnormalities in BD, reductions in anterior cingulate and insular cortex were identified as the most consistent alterations in bipolar patients, potentially related to functional deficits (Bora et al., 2010, Ellison-Wright and Bullmore, 2010).
Consistently with post mortem and structural imaging studies, functional imaging studies have reported both increased and decreased activation in PFC during cognitive and/or emotional tasks in euthymic bipolar patients (Chen et al., 2011). However, clinical and biological correlates of the aforementioned alterations are still under investigation. For instance, Favre and colleagues, using resting state fMRI, have recently demonstrated the lack of anti-correlated-decoupling-activity between the medial PFC and right DLPFC in bipolar euthymic patients compared to healthy subjects, as well as hyperconnectivity between medial PFC and amygdala (Favre et al., 2014).
In a diffusion MRI tractography study, Emsell and coworkers showed abnormal diffusivity in the corpus callosum, cingulum bundle and fornix in euthymic BDI patients vs. controls (Emsell et al., 2013). Similarly, Canales-Rodriguez and colleagues reported an altered microstructural organization at the level of perigenual areas of the frontomedial, anterior cingulate and anterior insular cortex of euthymic bipolar patients; these results, along with abnormalities in prefrontal white matter that connect the anterior cingulate to other structures, may account for some cognitive deficits observed during euthymic phases of BD (Canales-Rodriguez et al., 2014).
Taken as a whole, the aforementioned findings provide further support to the existence of a dysfunctional interaction between the prefrontal-subcortical and limbic network in BD (Strakowski et al., 2005), as reported by recent meta-analyses, combining functional and structural neuroimaging studies (Houenou et al., 2011).
A common experimental task to assess WM is represented by the N-back task (Karlsgodt et al., 2011). To date, fMRI investigation assessing WM through N-back task in euthymic bipolar patients has given mixed results, including hypo- and hyper-activation of PFC relative to controls (Cremaschi et al., 2013, Dell’Osso et al., 2014, Fusar-Poli et al., 2012). Heterogeneity in the results may depend on multiple factors, primarily including the limited sample size and the effects of concomitant pharmacological treatments and other clinical variables (Cremaschi et al., 2013). Interestingly, the only two studies performed in individuals at high genetic risk for BD have shown exaggerated prefrontal activity during WM, suggesting that prefrontal dysfunction may be associated with genetic liability for the disorder (Drapier et al., 2008, Thermenos et al., 2010).
Finally, studied samples of bipolar patients mostly consisted of BDI subjects; therefore, whether patients with BDI and II differ in terms of WM-related brain activity remains to be clarified.
In the present study, we investigated PFC activity, assessed with 3T blood oxygenation level-dependent (BOLD) fMRI, in euthymic patients with BDI and II and healthy subjects during N-back task. Based on the aforementioned studies (Drapier et al., 2008, Savitz et al., 2014, Thermenos et al., 2010), we hypothesized that PFC activity during WM processing may be abnormal in BD patients compared to healthy controls, and that the degree of such dysfunction may help to differentiate BDI vs. BDII.
Section snippets
Participants
Twenty-eight bipolar patients, 15 with BDI (53% male; mean age 34.3±10.3 years), 13 with BDII (54% male; mean age 37.3±8 years), and 27 healthy subjects (55.5% male; mean age 29.4±10.6 years) participated to the study out of an original sample size of 30 bipolar individuals (2 subjects were excluded from the analyses due to excessive head motion during the task). All participants were white Caucasians, who provided written informed consent, after receiving a complete description of the study,
Socio-demographic data
There were no significant differences among the three diagnostic groups (BDI, BDII and HCs) in terms of gender, handedness and years of education, except for age (F(2,52)=3.06, p=0.05) that was included as covariate in the imaging analyses. Socio-demographic data of the sample are provided in Table 1.
Clinical data: BDI vs. BDII patients
With respect to clinical features, no statistically significant differences between diagnostic subgroups were found. Diagnostic subgroups were matched in terms of gender, mean age, family history
Discussion
To authors' knowledge, the present study represents the first evidence specifically showing that abnormal PFC activity during WM may be a potential imaging phenotype associated with diagnosis of BD. In particular, we have found that euthymic patients showed abnormal PFC engagement during WM (fMRI), compared with healthy subjects. More interestingly, BDII patients activated the target area in an intermediate level between BDI and HCs.
At the neurobiological level, previous imaging studies have
Contributors
The authors declare they have participated in the study and article preparation. The final article has been approved by all of them.
Disclosures
The authors do not have any affiliation or financial interest in any organization that might pose a conflict of interest with the content of the present article.
Role of the funding source
The study was partially supported by a research Grant (scientific productivity fund), annually provided by the Fondazione IRCCS Ca' Granda.
Conflict of interest
No conflict declared.
Acknowledgments
The authors would like to thank all the technician support of the Neuroradiology Unit and Dr. Alessandro Sillani for organizing all the scan procedures. Authors would thank also Dr. Beatrice Penzo, involved in the elaboration of data.
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