Depression in the elderly is common and causes significant distress and disability. Approximately 15% of the elderly have significant depressive symptoms (1
). Depression is the second leading cause of ‘global disease burden’ (2
), the leading predictor of poor outcome from medical illnesses such as heart disease (3
), and the primary diagnosis in most elderly suicides (5
). Moreover, the number of elderly is expected to double by 2030 (6
), further increasing the public health burden of late-life depression (LLD). Unfortunately, current depression treatments, which are borrowed from the treatment of mid-life depression, are only partly effective in the elderly; 40-50% of those with LLD have a delayed or limited response to first-line antidepressant treatment (7
). Much of the limited response may be due to differences in the underlying neurobiology between mid-life depression and LLD. However, the neurobiologic bases of the depressive syndrome and treatment response in LLD are not well understood.
A prominent theory for delayed or brittle response in LLD is that the neuropathology in LLD is distinguished by cerebrovascular and/or neurodegenerative changes, which are associated with dysfunction in frontostriatal cognitive circuits. Convergent evidence from structural MRI, cognitive assessment, and electrophysiologic studies supports the frontostriatal hypothesis of LLD (8
). Conventional structural MRI, Diffusion Tensor Imaging (DTI), and Magnetic Resonance Spectroscopy (MRS) studies (9
) have shown that elderly depressed individuals have higher rates (compared to age-matched non-depressed individuals) of gray and white-matter brain structural changes affecting frontal and subcortical areas, and consistent with small vessel ischemic disease. Cognitive assessment in LLD shows a pattern of impairment in executive tasks and slowed information processing speed, also suggestive of dysfunction of frontal and striatal cognitive circuits (14
). Functional neuroimaging studies in LLD have shown decreased resting cerebral blood flow and glucose metabolism in prefrontal and anterior cingulate regions of the brain (15
). Additionally, we have recently shown altered functioning in the dorsolateral prefrontal cortex (dLPFC) and striatum in LLD during a sequence learning task (16
). Similar findings of decreased dLPFC and dACC activation have also been found in mid-life major depression (17
Among the particular cognitive functions subserved by the frontostriatal circuit are those that are often described as executive or cognitive control. In fact, there seem to be several discrete components of executive-control, which can be mapped to different anatomic regions of the prefrontal cortex. For instance, MacDonald et al (18
) illustrated the different roles of the dLPFC and dACC during a cognitive-control task. In MacDonald's study, comparison subjects performed a Stroop task in which each trial was preceded by an instruction, either ‘read the word’ or ‘name the color’. This was followed by a delay and then the Stroop stimulus. The dLPFC was active during the instruction phase, showing heightened activity with increased preparatory demand (i.e., the color naming instruction), whereas, the dACC was selectively active during the response phase, also showing heightened activity on the color naming trials, which are associated with high response conflict.
The current study was designed to examine the dLPFC - dACC cognitive-control circuit in LLD. To the extent that LLD is associated with frontostriatal dysfunction, we hypothesized that we would detect alterations in activation during a Stroop task. Specifically, following from previous PET and fMRI studies (15
), we expected decreased dLPFC and dACC activation in LLD, and due to the evidence of prefrontal white matter damage in LLD, we also expected decreased functional connectivity (evaluated with dLPFC to dACC time-series correlations) in the depressed subjects compared to non-depressed comparison subjects.
In this study we specifically questioned how the changes in functional activation are affected by treatment and response: Are changes in the circuit's function limited to or specific to the acute depressed episode, or do they persist once patients respond to treatment? If they persist do they reflect the underlying persistent neurobiology, i.e., the biological changes that make someone vulnerable to depression? Since the structural white matter changes are persistent, we predicted that changes in functional connectivity would persist despite treatment and response. However, the decreased regional dLPFC and dACC activation might resolve with treatment response, as has previously been shown for mid-life depression (19