Highlights
- •What is the primary question addressed by this study?The primary question addressed was whether adding a pro-cognitive medication (vortioxetine) to cognitive training would alter the association of aging with changes in resting state brain networks across a 6-month trial period.
- •What is the main finding of this study?Vortioxetine added to computerized cognitive training produced significantly greater changes in older adult brain network organization than cognitive training alone over 6 months. Discrete intervention group effects were most evident in the interactions of aging with longitudinal changes in whole brain network segregation and with cingulo-opercular network strength.
- •What is the meaning of the finding?For older adults experiencing age-related cognitive decline, adding vortioxetine to intensive cognitive training has a potentially beneficial effect on the correspondence between aging and functional brain network organization.
Abstract
Objective
Age-related cognitive decline is common and potentially modifiable with cognitive
training. Combining cognitive training with pro-cognitive medication offers an opportunity
to modify brain networks to mitigate age-related cognitive decline. We tested the
hypothesis that the efficacy of cognitive training could be amplified by combining
it with vortioxetine, a pro-cognitive and pro-neuroplastic multimodal antidepressant.
Methods
We evaluated the effects of 6 months of computerized cognitive training plus vortioxetine
(versus placebo) on resting state functional connectivity in older adults (age 65+)
with age-related cognitive decline. We first evaluated the association of functional
connectivity with age and cognitive performance (N = 66). Then we compared the effects
of vortioxetine plus cognitive training versus placebo plus cognitive training on
connectivity changes over the training period (n = 20).
Results
At baseline, greater age was significantly associated with lower within-network strength
and network segregation, and poorer cognitive function. Cognitive training plus vortioxetine
over 6 months positively impacted the relationship between age to mean network segregation.
These effects were not observed in the placebo group. In contrast, vortioxetine did
not modify the relationship of age to change in mean within-network strength. Exploratory
analyses identified the cingulo-opercular network as the network most affected by
cognitive training plus vortioxetine.
Conclusion
This preliminary study provides evidence that combining cognitive training with pro-cognitive
medication may modulate the effects of aging on functional brain networks. Results
indicate that for older adults experiencing age-related cognitive decline, vortioxetine
has a potentially beneficial effect on the correspondence between aging and functional
brain network segregation. These results await replication in a larger sample.
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References
- Models of visuospatial and verbal memory across the adult life span.Psychol Aging. 2002; 17: 299-320https://doi.org/10.1037//0882-7974.17.2.299
- Much of late life cognitive decline is not due to common neurodegenerative pathologies.Ann Neurol. 2013; 74: 478-489https://doi.org/10.1002/ana.23964
- Whitepaper: defining and investigating cognitive reserve, brain reserve, and brain maintenance.Alzheimer's & Dementia. 2020; 16: 1305-1311https://doi.org/10.1016/j.jalz.2018.07.219
- Aging, training, and the brain: a review and future directions.Neuropsychol Rev. 2009; 19: 504-522https://doi.org/10.1007/s11065-009-9119-9
- Computerized cognitive training in cognitively healthy older adults: a systematic review and meta-analysis of effect modifiers.PLoS Med. 2014; 11e1001756https://doi.org/10.1371/journal.pmed.1001756
- Augmenting computerized cognitive training with vortioxetine for age-related cognitive decline: a randomized controlled trial.Am J Psychiatry. 2020; 177: 548-555https://doi.org/10.1176/appi.ajp.2019.19050561
- Vortioxetine in major depressive disorder: from mechanisms of action to clinical studies. An updated review.Expert Opin Drug Saf. 2022; 21: 673-690https://doi.org/10.1080/14740338.2022.2019705
- A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder.Int Clin Psychopharmacol. 2012; 27: 215-223https://doi.org/10.1097/YIC.0b013e3283542457
- A randomized, placebo-controlled, active-reference, double-blind, flexible-dose study of the efficacy of vortioxetine on cognitive function in major depressive disorder.Neuropsychopharmacology. 2015; 40: 2025-2037https://doi.org/10.1038/npp.2015.52
- Efficacy of vortioxetine on cognitive functioning in working patients with major depressive disorder.J Clin Psychiatry. 2017; 78: 115-121https://doi.org/10.4088/JCP.16m10744
- Vortioxetine disinhibits pyramidal cell function and enhances synaptic plasticity in the rat hippocampus.J Psychopharmacol. 2014; 28: 891-902https://doi.org/10.1177/0269881114543719
- Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data.Pharmacol Ther. 2015; 145: 43-57https://doi.org/10.1016/j.pharmthera.2014.07.001
- Vortioxetine promotes early changes in dendritic morphology compared to fluoxetine in rat hippocampus.Eur Neuropsychopharmacol. 2016; 26: 234-245https://doi.org/10.1016/j.euroneuro.2015.12.018
- Resting-state functional connectivity in normal brain aging.Neurosci Biobehav Rev. 2013; 37: 384-400https://doi.org/10.1016/j.neubiorev.2013.01.017
- The human brain is intrinsically organized into dynamic, anticorrelated functional networks.Proc Natl Acad Sci USA. 2005; 102: 9673-9678https://doi.org/10.1073/pnas.0504136102
- Resting state network estimation in individual subjects.Neuroimage. 2013; 82: 616-633https://doi.org/10.1016/j.neuroimage.2013.05.108
- Functional network organization of the human brain.Neuron. 2011; 72: 665-678https://doi.org/10.1016/j.neuron.2011.09.006
- A set of functionally-defined brain regions with improved representation of the subcortex and cerebellum.NeuroImage. 2020; 206116290https://doi.org/10.1016/j.neuroimage.2019.116290
- Decreased segregation of brain systems across the healthy adult lifespan.Proc Natl Acad Sci USA. 2014; 111: E4997-E5006https://doi.org/10.1073/pnas.1415122111
- The segregation and integration of distinct brain networks and their relationship to cognition.J Neurosci. 2016; 36: 12083-12094https://doi.org/10.1523/JNEUROSCI.2965-15.2016
- Segregation of functional networks is associated with cognitive resilience in Alzheimer's disease.Brain. 2021; 144: 2176-2185https://doi.org/10.1093/brain/awab112
- Loss of intranetwork and internetwork resting state functional connections with Alzheimer's disease progression.J Neurosci. 2012; 32: 8890-8899https://doi.org/10.1523/JNEUROSCI.5698-11.2012
- Effects of aging on functional and structural brain connectivity.NeuroImage. 2017; 160: 32-40https://doi.org/10.1016/j.neuroimage.2017.01.077
- Attenuated anticorrelation between the default and dorsal attention networks with aging: evidence from task and rest.Neurobiol Aging. 2016; 45: 149-160https://doi.org/10.1016/j.neurobiolaging.2016.05.020
- Vortioxetine reduces BOLD signal during performance of the N-back working memory task: a randomised neuroimaging trial in remitted depressed patients and healthy controls.Mol Psychiatry. 2018; 23: 1127-1133https://doi.org/10.1038/mp.2017.104
- Vortioxetine modulates the regional signal in first-episode drug-free major depressive disorder at rest.Front Psychiatry. 2022; 13950885https://doi.org/10.3389/fpsyt.2022.950885
- Reliability and validity of composite scores from the NIH Toolbox Cognition Battery in adults.J Int Neuropsychol Soc. 2014; 20: 588-598https://doi.org/10.1017/S1355617714000241
- Structured Clinical Interview for DSM-5.American Psychiatric Assocation, Washington, DC2015
- The PHQ-9: validity of a brief depression severity measure.J Gen Intern Med. 2001; 16: 606-613https://doi.org/10.1046/j.1525-1497.2001.016009606.x
- Assessing worry in older and younger adults: psychometric properties of an abbreviated Penn State Worry Questionnaire (PSWQ-A).J Anxiety Disord. 2006; 20: 1036-1054https://doi.org/10.1016/J.JANXDIS.2005.11.006
- A practical method for grading the cognitive state of patients for the clinician.J Psychiatr Res. 1975; 12: 189-198
- Combined cognitive remediation and functional skills training for schizophrenia: effects on cognition, functional competence, and real-world behavior.AJP. 2012; 169: 710-718https://doi.org/10.1176/appi.ajp.2012.11091337
- Cognitive remediation for treatment-resistant depression: effects on cognition and functioning and the role of online homework.J Nerv Ment Dis. 2013; 201: 680-685https://doi.org/10.1097/NMD.0b013e31829c5030
- On time delay estimation and sampling error in resting-state fMRI.NeuroImage. 2019; 194: 211-227https://doi.org/10.1016/j.neuroimage.2019.03.020
- Covariance and correlation analysis of resting state functional magnetic resonance imaging data acquired in a clinical trial of mindfulness-based stress reduction and exercise in older individuals.Front Neurosci. 2022; 16825547https://doi.org/10.3389/fnins.2022.825547
- Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion.NeuroImage. 2012; 59: 2142-2154https://doi.org/10.1016/j.neuroimage.2011.10.018
- Methods to detect, characterize, and remove motion artifact in resting state fMRI.NeuroImage. 2014; 84: 320-341https://doi.org/10.1016/j.neuroimage.2013.08.048
- Cerebrospinal fluid Aβ42 moderates the relationship between brain functional network dynamics and cognitive intraindividual variability.Neurobiol Aging. 2021; 98: 116-123https://doi.org/10.1016/j.neurobiolaging.2020.10.027
- Changes in whole-brain functional networks and memory performance in aging.Neurobiol Aging. 2014; 35: 2193-2202https://doi.org/10.1016/j.neurobiolaging.2014.04.007
- Pathways to neurodegeneration: effects of HIV and aging on resting-state functional connectivity.Neurology. 2013; 80: 1186-1193https://doi.org/10.1212/WNL.0b013e318288792b
- The role of resting-state network functional connectivity in cognitive aging.Front Aging Neurosci. 2020; 12: 177https://doi.org/10.3389/fnagi.2020.00177
- Resting state network modularity along the prodromal late onset Alzheimer's disease continuum.NeuroImage: Clinical. 2019; 22101687https://doi.org/10.1016/j.nicl.2019.101687
- The effect of scan length on the reliability of resting-state fMRI connectivity estimates.NeuroImage. 2013; 83: 550-558https://doi.org/10.1016/j.neuroimage.2013.05.099
Article info
Publication history
Published online: January 13, 2023
Accepted:
January 7,
2023
Received in revised form:
January 3,
2023
Received:
October 27,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
ClinicalTrials.gov identifier: NCT03272711
Identification
Copyright
© 2023 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.
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- Augmentation of cognitive training with vortioxetine opens new avenues for targeting age-related changes in brain connectivityThe American Journal of Geriatric Psychiatry
- PreviewWith a rapidly aging population, there has been great interest in using cognitive training to enhance cognitive function in older adults and age-related diseases. Studies evaluating cognitive enhancing interventions demonstrate mixed findings on efficacy. Effect sizes are heterogenous across studies and there is inconsistent evidence of transfer to improvements in everyday cognitive tasks. To develop more effective treatments, clinical researchers have increasingly turned to interventions that combine approaches (e.g., computerized cognitive training, exercise, neuromodulation) and that attempt to target circuit-specific mechanisms of cognitive dysfunction [1].
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