Working-Memory fMRI Displays Major Activation Differences Between Recurrent Unmedicated and Euthymic Major Depressive Disorder Patients: A Quick Review


Major depression disorder (MDD) is a psychiatric disorder characterized by a widespread and steady low mood linked to anhedonia, low self-esteem, sadness, and worthlessness. The limbic-thalamic-cortical network is a major mechanism involved in the pathophysiology of MDD. Several neuroimaging and neurocognitive studies have increased the evidence of frontal and limbic dysfunction in MDD individuals in working memory (WM) processing. Many studies recognize an abnormal neural activation on the left prefrontal cortex and the cingulate cortex in MDD patients during WM activities. Nonetheless, these studies are not consistent with each other since some studies suggest more activity, less activity, or no activity at all of the regions under consideration. Other studies using the n-back task and fMRI, in MDD patients, have shown reduced neuronal activity in the bilateral thalamus, right precentral gyrus, and right parietal cortex relative to healthy individuals. The goal of the two studies discussed in this short review is to analyze the WM processing during the n-back task while increasing memory load. Both researchers predicted hyperactivation on the cingulate gyrus and prefrontal areas in MDD patients compared to control subjects 


In the study conducted by Schoning et al (2009), 56 patients (28 MDD individuals and 28 control subjects) were analyzed with fMRI at 3T. MDD patients were treated with antidepressants until achieving a stable euthymic state. They participated in the study before leaving the hospital. Control subjects were matched to MDD patients according to sex, age, and education level. The verbal n-back task was used to analyze WM activity in both groups. WM load was measured in three conditions (0-, 1- and 2-back). In the 0-back condition, subjects pressed a bottom when the target appeared on the screen. In the 1-back condition, participants responded when the letter presented was similar to the previously displayed letter. The 2-back condition was alike, but subjects responded when the letter was similar to the letter in two previous trials. Each subject was displayed the n-back blocks in a previously established order 1-0-2-0-1-2. The behavioral data analysis (accuracy rate and reaction time) was performed for the three levels of memory load using ANOVA analysis. The fMRI data were analyzed using SPM5. In order to obtain activation maps across participants, the contrast images (2vs0-back and 2vs1-back, for example) were analyzed in a second-level random-effects analysis. Sample t-tests were performed to show the contrasts in each group.

Matsuo et al (2007) recruited 15 untreated subjects with high MDD prevalence and 15 control individuals. A numerical n-back task was used to analyze WM activity, as previously described. The performance was again measured in terms of reaction time and accuracy rate. Imaging data were obtained using fMRI while measuring prefrontal cortex activity during n-back task activities. The data was analyzed using FSL-FEAT software. They produced Z-statistics images for the three WM conditions, and the 1vs0, 2vs0, and 2vs1-back contrasts were completed. The brain activation data was obtained with a multi-subject analysis and showed activation patterns within each cohort and between cohorts. The behavioral data analysis was performed using the Mann-Whitney U-test for the WM task accuracy and reaction delay. Friedman’s test was used to make comparisons among the three WM conditions.


The behavioral analysis showed no differences between control subjects and MDD patients in both studies. As expected, the n-back task accuracy rate decreased, and the reaction time response increased as the WM load in patients increased from 0-back to 2-back conditions. In the imaging data, Matsuo et al (2007) reported a significantly increased activation in MDD patients in the dorsolateral prefrontal cortex (specifically in the left middle frontal gyrus, Brodmann Area, and the left superior frontal gyrus) and cingulate gyrus in the 2vs1-back contrast. The other contrasts did not show statistically significant differences in brain activity. In the same way, Schoning et al (2009) reported increased activation in the anterior and posterior cingulate cortex and parahippocampal gyrus in the 2vs0-back contrasts in MDD patients. The 2vs1-back contrast showed similarly increased activation in the anterior and posterior cingulate cortex, parahippocampal gyrus, and hippocampus. Interestingly, other brain regions such as the superior, middle, and inferior frontal gyrus, insula, pre-and postcentral gyrus, cerebellum, temporal, occipital, and parietal lobe, also showed increased neural activity compared to control subjects. Statistical analyses found no significant differences between MDD patients and control subjects in the prefrontal cortex (particularly the dorsolateral and ventrolateral prefrontal cortex).


Unmedicated individuals with a high MDD prevalence showed hyperactivation in the left dorsolateral prefrontal cortex and anterior cingulate gyrus during WM activities compared to control individuals. On the other hand, MDD patients in the euthymic state of the condition showed hyperactivation of the cingulate cortex, while lateral prefrontal activation was absent compared to control subjects. In both studies, behavioral WM performance in the n-back task was alike between MDD and control individuals. These results suggest that untreated recurrent MDD patients exhibit greater dorsolateral prefrontal cortex and anterior cingulate gyrus activity to keep adequate levels of WM performance compared to control subjects. This may explain why we see hyperactivation of the mentioned areas while MDD and control subjects performed equivalently in the reaction time and accuracy rate activities in the n-back tasks. Similarly, it is feasible to conclude from the results that even after recovery from MDD, when the depressed mood is relatively absent, individuals will show hyperactivation of the rostral and caudal cingulate gyrus regions during working memory activities. Again, enhanced activation of the cingulate gyrus may be necessary for euthymic MDD patients to perform similarly in WM tasks relative to healthy individuals.

Combing and extrapolating the results from these studies, it can be concluded that the brain possesses WM compensatory mechanisms to keep equal levels of activity performance in MDD patients. Additionally, it is possible to infer that the dorsolateral prefrontal cortex shows a faster recovery rate in MDD patients compared to the cingulate cortex. For future research, it would be interesting to study how long the cingulate cortex takes to return to normal neural activity in terms of the n-back task, WM performance.


Matsuo K., Glahn DC., Peluso MAM., Hatch JP., Monkul ES., Najt P., Sanches M., Zamarripa F., Li J., Lancaster JL., Fox PT., Gao J-H. & Soares JC. (2007). Prefrontal Hyperactivation During Working Memory Task in Untreated Individuals with Major Depressive Disorder. Molecular Psychiatry 12, 158-166.

Schoning S., Zwitserlood P., Engelien A., Behnken A., Kugel H., Schiffbauer H., Lipina K., Pachur C., Kersting A., Dannlowski U., Baune B., Zwanzger P., Reker T., Heindel W., Arolt V. & Konrad C. (2009) Working-Memory fMRI Reveals Cingulate Hyperactivation in Euthymic Major Depression. Human Brain Mapping 30: 2746-2756.

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