Preliminary communication
Neural responses to incongruency in a blocked-trial Stroop fMRI task in major depressive disorder

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Abstract

Background

Patients with major depressive disorder (MDD) perform poorly on the Stroop task, which is a measure of the executive control of attention, with impaired interference resolution. The neural correlates of this deficit are not well described. To examine how this deficit relates to pathophysiological abnormalities in MDD, we conducted an fMRI Stroop study comparing MDD subjects to controls.

Methods

Forty-two unmedicated patients with current MDD and 17 control subjects underwent fMRI scanning with a color-word Stroop task. Subjects assessed font color during alternating color identification (e.g., ‘XXXX’ in blue) and incongruent color/word blocks (e.g., the word ‘red’ in blue). We examined neural activation that was greater in incongruent than color identification blocks (Z>2.3 and corrected p<0.05), controlling for trial-by-trial reaction time.

Results

Compared to controls, MDD subjects exhibited lower activation during incongruent blocks across multiple brain regions, including middle frontal gyrus, paracingulate and posterior cingulate, precuneus, occipital regions, and brain stem. No brain regions were identified in which MDD subjects were more active than controls during incongruent blocks.

Limitations

Not all MDD subjects were antidepressant-naïve.

Conclusions

Brain regions related to executive function, visual processing, and semantic processing are less active during processing of incongruent stimuli in MDD subjects as compared to controls. Deficits of attention in MDD may be the product of a failure to maintain activity across a distributed network in a sustained manner, as is required over the sequential trials in this block design. Further studies may clarify whether the abnormalities represent a trait or state deficit.

Introduction

Studies of neuropsychological function in major depressive disorder (MDD) have identified an array of cognitive disturbances associated with this illness, including impairments of attention, working memory and executive function (Murrough et al., 2011, Veiel, 1997, Zakzanis et al., 1998). The Stroop task (MacLeod, 1991, MacLeod and Sheehan, 2003) is a measure of the executive control of attention that is among those tests commonly affected by depression. In an early meta-analysis (Zakzanis et al., 1998), they found an effect size of approximately 0.63 for poorer interference resolution on this task in MDD; comparable effect sizes were found in our own more recent work (Keilp et al., 2008). Interference resolution during the Stroop task is likely to affect adaptive cognitive performance in everyday life; is possibly related to the risk for suicidal behavior (Keilp et al., 2008, Keilp et al., 2001, Legris et al., 2012); and is predictive of poor antidepressant treatment outcome in depressed elderly (Sneed et al., 2007).

The Stroop task is one of the most extensively studied cognitive paradigms in functional imaging studies (Leung et al., 2000, Mead et al., 2002, Nee et al., 2007, Peterson et al., 1999, Roberts and Hall, 2008, Roelofs and Hagoort, 2002). These studies have identified brain activity during Stroop task performance across multiple brain regions, especially anterior cingulate cortex, lateral prefrontal cortex, lingual gyrus, extrastriate cortex, and perisylvian language areas. Use of the Stroop task in functional imaging studies of individuals with depression may shed light on alterations in the attention network that are related to major depression.

There have been few studies to date comparing brain activity during Stroop task performance between MDD subjects and controls. One study examining adults with MDD showed higher activity relative to controls in rostral anterior cingulate gyrus and left dorsolateral prefrontal cortex during interference trials of a Stroop task using an event-related, mixed trial design (Wagner et al., 2006). The Stroop task in that study was atypical in that response options were presented in a multiple-choice format, with two possible response options on the left and right of the screen, below the target stimulus, in an effort to reduce the need to memorize key presses using a manual response. A second study of adolescents found severity of depression correlated positively with activity in left dorsolateral prefrontal cortex and anterior cingulate gyrus – consistent with findings in MDD patients in the Wagner et al. study – and negatively with activity in right dorsolateral prefrontal cortex during Stroop task performance (Killgore et al., 2007). Stroop stimuli in that study were presented in a blocked fashion, in separate runs, with a verbal response.

Our own behavioral work suggests that in a blocked format, individuals with MDD will perform relatively more slowly in interference blocks compared to non-interference blocks (Keilp et al., 2008). It is unknown if activity in task-relevant brain regions such as anterior cingulate gyrus or dorsolateral prefrontal cortex will remain elevated throughout the block, as was found for individual trials in event related designs such as that employed by Wagner and colleagues (Wagner et al., 2006), or whether activation will differ in other ways. In the study reported here, we examined brain function during a blocked task that was a translation of the computerized behavioral task that we had previously administered. Based on the classical Stroop paradigm (MacLeod, 1991), this task compared blocks of colored X's to blocks of incongruently-colored color names. While this type of design does not allow direct comparison of congruent vs. incongruent stimuli, it is comparable to the version of the task that we have used in our clinical studies. More importantly, it avoids the tendency of subjects to exploit the blocking of stimuli. Since stimuli are blocked, subjects are aware that a set number of stimuli will be similar. The use in other task designs of congruently colored words in a block allows subjects to switch from identifying the color of these items (a harder task) to simply reading the word (an easier task). This defeats the goal of the procedure to compare color identification in conditions where there is no interference, and where there is interference. The use of colored X's in the non-interference block of the current task ensures that subjects will adhere to the instructions to identify the color of the stimulus, because it removes any potential “short-cuts” to easier responding.

In addition to the use of a blocked design, it was suggested that activations during the interference conditions of Stroop tasks, particularly those in dorsal medial frontal cortex, are commonly ascribed to processing of conflict, but may be a product of simple attention to and time on task (Grinband et al., 2011). Given that basic reaction time differences between MDD patients and healthy volunteers might alter the relative strength of regional activations underlying attention performance, this study also attempted to adjust for differences in reaction time on task related to illness (global slowing) by adjusting for response times in our image analyses.

In this manner, we conducted an fMRI study with a blocked-trial Stroop task controlling reaction time on task to evaluate neural responses to incongruency in subjects with major depressive disorder compared to healthy volunteers.

Section snippets

Sample

Around 57 subjects with current MDD diagnosed using the Structured Clinical Interview for DSM-IV, Axis I (SCID-I) (Spitzer et al., 1990) and II (SCID-II) (First et al., 1997) and 23 healthy controls (SCID-I, Non-Patient edition) (First et al., 1996) enrolled in this study. Inclusion criteria for MDD subjects included: (1) age 18–65 years; (2) capacity to provide informed consent; (3) no significant active physical illness; (4) 17-item Hamilton Depression Rating Scale (HDRS) score greater than

Clinical features and behavioral data

Demographic variables including age, sex and handedness did not differ between MDD and controls (Table 1). Similarly, behavioral performance on the Stroop task did not differ between MDD subjects and controls included in imaging analysis, as assessed by reaction time, error rate, and interference rate.

Within-group analyses

In healthy controls, brain regions activating more during incongruent than congruent blocks included paracingulate gyrus, inferior frontal gyrus, precentral gyrus, middle frontal gyrus, precuneus

Discussion

This is the largest study to date examining the neural correlates of Stroop performance in MDD. Despite comparable task performance to controls on the task used in this study, MDD subjects demonstrated less activity across a broadly-distributed network of brain regions during the interference condition. Regions less active during interference in MDD included: middle frontal gyrus, associated with executive control/movement planning (Clark et al., 2010); middle temporal gyrus, which plays a role

Conclusions

In conclusion, our study provides support for specific neural abnormalities in MDD during cognitive processing. Further studies may clarify whether the abnormalities identified in this study represent a trait or state deficit. Additionally, the discrepancy between event-related and blocked-trial interference processing in MDD subjects during the Stroop Task suggests that less activity may be a function of demand inherent in the current task of maintaining arousal over time. Deficits in MDD in

Role of funding source

We received financial support from NARSAD (Dr. Keilp, Principal Investigator), NIMH 5P50 MH62185 (Dr. Mann, Principal Investigator), NIMH 2R01 MH040695 (Dr. Mann, Principal Investigator) and NIMH R01 MH074813 (Dr. Parsey, Principal Investigator).

Conflict of interest

Dr. Kikuchi has received manuscript fees or speaker's honoraria from Astellas Pharma, Dainippon Sumitomo Pharma, GlaxoSmithKline, Jansen Pharmaceutical, Kyowa Hakko Kirin, Otsuka Pharmaceutical, Pfizer, Shionogi and Yoshitomiyakuhin within the past 5 years. All are unrelated to this article. Dr. Miller has received financial compensation for psychiatric evaluations of subjects enrolled in medication studies sponsored by Pfizer and Orexigen Therapeutics unrelated to this article. Dr. Oquendo

Acknowledgments

We thank the following collaborators at the New York State Psychiatric Institute for their contribution: Arno Klein, Binod Thapa-Chhetry, Chrissy DeLorenzo, Elsa Scheie, Frank Gonzalez, Natalie Hesselgrave and Tito Dal Canton.

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