Cognitive control and brain resources in major depression: An fMRI study using the n-back task
Introduction
Many neuroimaging studies on depression have reported functional abnormalities in the prefrontal cortex (PFC). For instance, resting state studies using PET frequently identify increased metabolism in regions such as medial and orbital PFC (MPFC; OPFC) (Drevets, 2000). Moreover, abnormalities in dorsal and lateral parts of the PFC have also been observed at rest, with hypometabolism in dorsolateral prefrontal cortex (DLPFC) (Baxter et al., 1989, Sackeim et al., 1990) and anterior cingulate cortex (ACC) (Galynker et al., 1998). In addition to resting state studies, some imaging experiments have been conducted with depressed patients performing various cognitive tasks. However, findings obtained from these experiments are still inconsistent. Two independent studies using two different cognitive tasks (n-back Task and Wisconsin Card Sorting Test) did not find any difference in frontal activity between depressed patients and control subjects (Barch et al., 2003, Berman et al., 1993), while three other studies showed decreased activity in the DLPFC using the Tower of London and verbal fluency tasks (Elliott et al., 1997, Okada et al., 2003) and in the ACC using a standard Stroop task (George et al., 1997). A recent functional MRI (fMRI) study using an arithmetic task even found hyperfrontality in the DLPFC in depressed patients compared to normal subjects (Hugdahl et al., 2004).
A confound within the cognitive activation studies that found hypoactivity in depression was the impaired behavioral performance of depressed patients compared to normal subjects. One could argue that the impaired performance is a cause of the cerebral discrepancies between groups instead of being a consequence. This problem has been underlined in schizophrenia by two studies showing that hypofrontality is not present during performance of a cognitive task when patients' performance is balanced with that of controls (Fletcher et al., 1996, Frith et al., 1995). Similar to these studies on schizophrenia, we proposed to compare the cerebral activity between depressed patients and healthy subjects while controlling for the level of performance. The purpose of this study was to assess with fMRI the cerebral activity of depressed patients who perform a cognitive task at normal levels.
Since depressed patients have problems with tasks requiring effort and executive control (Hartlage et al., 1993), we believe that the identification of a cerebral abnormality in depression must be achieved by using an effortful task. Thus, our challenges were, on the one hand, to focus on a cognitive function that would involve effortful processing for depressed patients and, on the other, to recruit depressed patients that could allocate enough resources in order to reach the level of performance of normal subjects.
We used a verbal variant of the n-back task that allows us to parametrically manipulate the workload/complexity within working memory (WM). An increasing amount of evidence suggests that depressed patients are impaired on tasks involving WM (Harvey et al., 2004, Porter et al., 2003). A recent fMRI study on schizophrenia used the n-back task to demonstrate that hyperfrontality arises as patient performance approaches that of healthy subjects, while low-performing patients are uniformly hypofrontal (Callicott et al., 2003). Callicott et al. (2003) suggested that schizophrenic patients with a normal performance at the n-back task are less efficient when processing information and this is reflected by an abnormal hyperfrontality. Based on Callicott's findings, we hypothesized that normal behavioral performance in depressed patients performing the n-back task would be also associated with hyperactivity in the dorsal and lateral regions of the PFC compared to control subjects.
Section snippets
Materials and methods
The study was approved by the Ethics Committee for Biomedical Research of the Pitié-Salpêtrière Hospital.
Demographic and clinical measures
The two groups did not differ in terms of age (t = 1.26, df = 18, P = 0.22), verbal IQ (t = 0.65, df = 18, P = 0.56), years of education (t = 0.1, df = 18, P = 0.92) and sex ratio (×2 = 0.79, df = 1, P = 0.37) (Table 1). Clinical data suggest that patients were moderately to severely depressed with a history of recurring depressive unipolar disorder.
n-back performances
Compared to control subjects, depressed patients were not significantly different at the 0-back task for both response accuracy (t = 0.24, df = 18,
Discussion
The main goal of this study was to examine the brain activity associated with the normal execution of a WM task in depressed patients and healthy subjects. Consistent with our hypothesis, depressed patients exhibited hyperactivity within the WMN while performing the n-back task. To our knowledge, this is the first study that demonstrates hyperactivity in depressed patients who perform an effortful cognitive task at normal levels.
Acknowledgments
This study was supported by NARSAD and by scholarships to POH from Fondation pour la Recherche Médicale. Thanks to Matthew Menear and Hazel M. Sutton for useful comments.
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