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Cognitive Control in Late-Life Depression: Response Inhibition Deficits and Dysfunction of the Anterior Cingulate Cortex

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Objectives

Geriatric depression is associated with frontolimbic functional deficits, and this frontal dysfunction may underlie the marked executive control deficits often seen in this population. The authors' goal was to assess the integrity of frontal cortical functioning in geriatric depression, while these individuals performed a standard cognitive control task. The N2 component of the event-related potential (ERP), an evoked response generated within the anterior cingulate cortex (ACC), is significantly enhanced when nondepressed individuals successfully inhibit a response, providing an excellent metric of frontal inhibitory function.

Design

The authors used a variant of a demanding Go/NoGo task-switching paradigm that required participants to inhibit response execution during NoGo trials by overcoming a potent response tendency established by frequent Go trials.

Participants

The authors compared a cohort of depressed geriatric outpatients (N = 11) with a similarly aged group of nondepressed participants (N = 11).

Measurements

Reaction times, accuracy, and high-density event-related potential recordings from a 64-channel electrode montage were obtained.

Results

A significantly enhanced N2 to NoGo trials was observed in nondepressed elderly participants, with generators localized to the ACC. In contrast, this enhancement was strongly reduced in the depressed sample. Source analysis and topographic mapping pointed to a displacement of N2 generators toward more posterior areas of the middle frontal gyrus in depressed subjects.

Conclusions

Findings confirm previous reports of an inhibitory control deficit in depressed elderly who show significantly increased rates of commission errors (i.e., failures to inhibit responses on NoGo trials). Electrophysiologic data suggest underlying dysfunction in ACC as the basis for this deficit.

Section snippets

Participants

Eleven nondemented, depressed patients (six males) with nonpsychotic major depression (by Structured Clinical Interview for DSM-III-R, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; and a 24-item baseline Hamilton Depression Rating Scale [score of 17 or higher]) participated in this study. Of the 11 patients diagnosed with major depressive disorder, 4 were taking selective serotonin reuptake inhibitors. Mean age of the patient group was 73.4 years. Eleven nondepressed

RESULTS

Table 1 shows reaction time (RT) and accuracy (hits and false alarms) data for both groups. Mean RT for depressed (766 milliseconds) and nondepressed participants (789 milliseconds) in Go trials did not differ from each other (t20 = 0.82, p = 0.96). However, the depressed participants showed a significantly reduced hit rate (t20 = 9.7, p <0.0001) and increased false alarm rate (t20 = −3.1, p <0.01) when compared with the nondepressed subjects.

Figure 1 displays the ERP in Go and NoGo trials for

DISCUSSION

The principal finding of this study is that patients suffering from geriatric depression displayed a much-attenuated N2 effect when compared with nondepressed elders. Source analysis and topographic mapping pointed to a predominantly midline frontal generator of this N2 effect, which was localized to the ACC in the nondepressed group. In contrast, there was an apparent displacement of N2 generators toward more posterior areas of the middle frontal gyrus in the depressed group. There is

CONCLUSIONS

Although structural neuroimaging studies have consistently pointed to dysfunction in the ACC as an important neural substrate in geriatric depression, electrophysiologic studies of ACC function have been considerably less consistent in their findings. In this study, using a well-characterized and highly challenging task-switching design, we assessed response inhibition mechanisms in the ACC as reflected by the N2 ERP component and the N2 effect. Our data suggest clear differences between

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This work was supported by training grant T32 MH019132 from the National Institute of Mental Health (to RK, GSA), the National Institute on Aging AG22696 (to JJF), and the National Institute of Mental Health MH65350 (to JJF). Additional support was derived from the following sources: R01 MH097414 (GSA), K23 MH067702 (CFM), and P30 MH68638 (GSA).

Richard Katz and Pierfilippo De Sanctis contributed equally to this work.

All of the authors attest that there are no conflicts of interest, financial, or otherwise, pertaining to the work presented in this manuscript. Prof. Foxe takes full responsibility for the integrity of the data and attests that all authors had full access to the data in this study. Dr. Alexopoulos has received research grants from Forest Pharmaceuticals, Inc. and participated in scientific advisory board meetings of Forest Pharmaceuticals. He has given lectures supported from Forest, Cephalon, Bristol Meyers, Janssen, Pfizer, and Lilly and has received support by Comprehensive Neuroscience, Inc. for the development of treatment guidelines in late-life psychiatric disorders.

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