Functional connectivity in the cognitive control network and the default mode network in late-life depression
Open accessAbstract
Background Abnormalities have been identified in the Cognitive Control Network (CCN) and the Default Mode Network (DMN) during episodes of late-life depression. This study examined whether functional connectivity at rest (FC) within these networks characterizes late-life depression and predicts antidepressant response.Methods 26 non-demented, non-MCI older adults were studied. Of these, 16 had major depression and 10 had no psychopathology. Depressed patients were treated with escitalopram (target dose 20 mg) for 12 weeks after a 2-week placebo phase. Resting state time series was determined prior to treatment. FC within the CCN was determined by placing seeds in the dACC and the DLPFC bilaterally. FC within the DMN was assessed from a seed placed in the posterior cingulate.Results Low resting FC within the CCN and high resting FC within the DMN distinguished depressed from normal elderly subjects. Beyond this "double dissociation", low resting FC within the CCN predicted low remission rate and persistence of depressive symptoms and signs, apathy, and dysexecutive behavior after treatment with escitalopram. In contrast, resting FC within the DMN was correlated with pessimism but did not predict treatment response.Conclusions If confirmed, these findings may serve as a signature of the brain's functional topography characterizing late-life depression and sustaining its symptoms. By identifying the network abnormalities underlying biologically meaningful characteristics (apathy, dysexecutive behavior, pessimism) and sustaining late-life depression, these findings can provide a novel target on which new somatic and psychosocial treatments can be tested.
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Patients with LLD exhibit decreased resting-state fMRI connectivity within the CCN, which is linked to dysexecutive behavior and resistance to antidepressant treatment.
“Prior research has demonstrated that patients with LLD exhibited decreased resting-state functional magnetic resonance imaging (fMRI) connectivity within the CCN, which was linked to dysexecutive behavior and resistance to antidepressant treatment.9”
From Can Intermittent Theta-Burst Stimulation of Dorsolateral Prefrontal Cortex Relieve Executive Dysfunction in Patients With Late-Life Depression? (2024) · cites this paper as [9]
In older adults, executive functioning and neuroticism are separate factors that both raise risk for and maintain mood problems and cognitive decline.
“Converging neuropsychological and neuroimaging evidence indicates the cognitive process of executive functioning and the personality trait of neuroticism each individually and independently predispose and perpetuate mood disturbance and cognitive decline in older adults9–12.”
From State of the Science of Neural Systems in Late‐Life Depression: Impact on Clinical Presentation and Treatment Outcome (2018) · cites this paper as [11]
Research has identified three main functional networks-cognitive control, default mode, and salience-in older depressed patients and in other psychiatric conditions.
“Converging evidence has identified three prominent functional networks in geriatric depression and other psychiatric illnesses11, 20, 21.”
From State of the Science of Neural Systems in Late‐Life Depression: Impact on Clinical Presentation and Treatment Outcome (2018) · cites this paper as [11]
Key symptoms of late-life depression track with lower cognitive control network activity and overactivity in salience and default mode networks.
“prominent symptoms of LLD are associated with decreased activity in the CCN (executive dysfunction) and hyperactivity in the SN and DMN (emotional arousal, rumination, apathy, negativity bias)11, 21.”
From State of the Science of Neural Systems in Late‐Life Depression: Impact on Clinical Presentation and Treatment Outcome (2018) · cites this paper as [11]
Lower baseline cognitive control network connectivity was associated with executive test performance and separated older depressed patients who remitted after 12 weeks of antidepressants from those who did not.
“Decreased CCN connectivity at baseline also correlated with behavioral measures of executive functioning and distinguished older depressed adults who remitted following 12 weeks of antidepressant treatment from those who did not.”
From State of the Science of Neural Systems in Late‐Life Depression: Impact on Clinical Presentation and Treatment Outcome (2018) · cites this paper as [11]
A study of 16 older adults with non-psychotic unipolar depression found lower connectivity between left dorsolateral prefrontal cortex and dorsal anterior cingulate, and between left dorsolateral prefrontal cortex and bilateral inferior parietal cortex, than in healthy older controls.
“Alexopoulos et al. 11 found that 16 older adults with non-psychotic unipolar depression exhibited decreased functional connectivity between the left DLPFC and dorsal anterior cingulate and the left DLPFC and bilateral inferior parietal cortices when compared to non-depressed healthy older adults.”
From State of the Science of Neural Systems in Late‐Life Depression: Impact on Clinical Presentation and Treatment Outcome (2018) · cites this paper as [11]
Scores on these tests are linked to structural and functional abnormalities in cognitive control areas including dorsolateral prefrontal cortex, dorsal and rostral anterior cingulate, and parietal association cortex.
“Performance on these tests correlates with structural and functional abnormalities in cognitive control regions, namely the dorsolateral prefrontal cortex (DLPFC), the dorsal and rostral regions of the anterior cingulate, and parietal association regions10, 11.”
From State of the Science of Neural Systems in Late‐Life Depression: Impact on Clinical Presentation and Treatment Outcome (2018) · cites this paper as [11]
Non-remitters had lower baseline connectivity among bilateral dorsolateral prefrontal cortex, dorsal anterior cingulate, and inferior parietal cortex than remitters.
“compared to remitters, non-remitters demonstrated decreased functional connectivity at baseline between the bilateral DLPFC, dorsal anterior cingulate, and inferior parietal cortices11.”
From State of the Science of Neural Systems in Late‐Life Depression: Impact on Clinical Presentation and Treatment Outcome (2018) · cites this paper as [11]
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- Authors
- Alexopoulos, G. S., Hoptman, M. J., Kanellopoulos, D., Murphy, C. F., Lim, K. O., & Gunning, F. M.
- Affiliations
- Cornell University (US)
- Nathan Kline Institute for Psychiatric Research (US)
- University of Minnesota (US)
- Corresponding author
- Alexopoulos, George S.
- ORCID
- Venue
- Journal of Affective Disorders
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 139
- Issue
- 1
- Pages
- 56-65
- ISSN
- 0165-0327 (ISSN-L)
- PMC
- PMC3340472
- OpenAlex
- W2020259042
- Cited by
- 437
- References
- 96
- Citations by year
- 2026: 13 · 2025: 28 · 2024: 33 · 2023: 30 · 2022: 41 · 2021: 67 · 2020: 29 · 2019: 34 · 2018: 32 · 2017: 32 · 2016: 25 · 2015: 31 · 2014: 25 · 2013: 14 · 2012: 1
- FWCI
- 11.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Affective Disorders (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH079414, P30MH085943, P030 MH085943, R01 MH65653, K23 MH74818, R01MH065653, T32MH019132, K23MH074818)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Mental Health Research Topics
- Keywords
- geriatric depression, cognitive control network, default mode network, resting-state functional connectivity, escitalopram, antidepressant response prediction, apathy, pessimism, older adults, anterior cingulate cortex, dorsolateral prefrontal cortex, posterior cingulate cortex
- MeSH terms
- Age Factors, Aged, Brain, Cognition, Depressive Disorder, Major, Major Depressive Disorder, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Nerve Net, Rest, Citalopram, Single-Blind Method, Selective Serotonin Reuptake Inhibitors
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