Disrupted Limbic-Prefrontal Effective Connectivity in Response to Fearful Faces in Lifetime Depression

Aleks Stolicyn; Mathew A. Harris; Laura de Nooij; Xueyi Shen; Jennifer A. Macfarlane; Archie Campbell; Christopher J. McNeil; Anca-Larisa Sandu; Alison D. Murray; Gordon D. Waiter; Stephen M. Lawrie; Douglas J. Steele; Andrew M. McIntosh; Liana Romaniuk; Heather C. Whalley

doi:10.1101/2023.07.18.23292846

Disrupted Limbic-Prefrontal Effective Connectivity in Response to Fearful Faces in Lifetime Depression

Aleks Stolicyn^* (Corresponding Author), Mathew A. Harris, Laura de Nooij, Xueyi Shen, Jennifer A. Macfarlane, Archie Campbell, Christopher J. McNeil, Anca-Larisa Sandu, Alison D. Murray, Gordon D. Waiter, Stephen M. Lawrie, Douglas J. Steele, Andrew M. McIntosh, Liana Romaniuk, Heather C. Whalley

^*Corresponding author for this work

Royal Edinburgh Hospital

Research output: Contribution to journal › Article › peer-review

Abstract

Background
Multiple brain imaging studies of negative emotional bias in major depressive disorder (MDD) have used images of fearful facial expressions and focused on the amygdala and the prefrontal cortex. The results have, however, been inconsistent, potentially due to small sample sizes (typically
). It remains unclear if any alterations are a characteristic of current depression or of past experience of depression, and whether there are MDD-related changes in effective connectivity between the two brain regions.

Methods
Activations and effective connectivity between the amygdala and dorsolateral prefrontal cortex (DLPFC) in response to fearful face stimuli were studied in a large population-based sample from Generation Scotland. Participants either had no history of MDD (
in activation analyses,
in connectivity analyses) or had a diagnosis of MDD during their lifetime (LMDD,
in activation analyses,
in connectivity analyses). The within-scanner task involved implicit facial emotion processing of neutral and fearful faces.

Results
Compared to controls, LMDD was associated with increased activations in left amygdala (
) and left DLPFC (
), increased mean bilateral amygdala activation (
), and increased inhibition from left amygdala to left DLPFC, all in response to fearful faces contrasted to baseline. Results did not appear to be attributable to depressive illness severity or antidepressant medication status at scan time.

Limitations
Most studied participants had past rather than current depression, average severity of ongoing depression symptoms was low, and a substantial proportion of participants were receiving medication. The study was not longitudinal and the participants were only assessed a single time.

Conclusions
LMDD is associated with hyperactivity of the amygdala and DLPFC, and with stronger amygdala to DLPFC inhibitory connectivity, all in response to fearful faces, unrelated to depression severity at scan time. These results help reduce inconsistency in past literature and suggest disruption of ‘bottom-up’ limbic-prefrontal effective connectivity in depression.

Original language	English
Journal	Journal of Affective Disorders
Early online date	12 Jan 2024
DOIs	https://doi.org/10.1101/2023.07.18.23292846
Publication status	E-pub ahead of print - 12 Jan 2024

Bibliographical note

This study was supported and funded by the Wellcome Trust Strategic Award "Stratifying Resilience and Depression Longitudinally" (STRADL) (Reference 104036/Z/14/Z), and the Medical Research Council Mental Health Pathfinder Award "Leveraging routinely collected and linked research data to study the causes and consequences of common mental disorders" (Reference MRC-MC_PC_17209). The work was also supported through the Lister Institute of Preventive Medicine award with reference 173096 and the Wellcome-University of Edinburgh Institutional Strategic Support Fund (Reference 204804/Z/16/Z). Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (Reference CZD/16/6) and the Scottish Funding Council (Reference HR03006), and is currently supported by the Wellcome Trust (Reference 216767/Z/19/Z).
Acknowledgements
For further details regarding the NimStim dataset of facial expressions please see https://danlab.psychology.columbia.edu/content/nimstim-set-facial-expressions. Development of the MacBrain Face Stimulus Set was overseen by Nim Tottenham and supported by the John D. and Catherine T. MacArthur Foundation Research Network on Early Experience and Brain Development. Please contact Nim Tottenham at nlt7@columbia.edu for more information concerning the stimulus set. The current work has made use of the resources provided by the Edinburgh Compute and Data Facility (ECDF) (http://www.ecdf.ed.ac.uk/). We would like to thank all Generation Scotland research volunteers who took part in the current study for contributing their time and effort. We would also like to thank all research assistants, clinicians and technicians for their valuable contributions to collection of the data.

Data Availability Statement

Data from the Generation Scotland dataset are available through application to the Generation Scotland Access Committee (access@generationscotland.org) and Edinburgh DataVault (https://doi.org/10.7488/8f68f1ae-0329-4b73-b189-c7288ea844d7).

https://doi.org/10.7488/8f68f1ae-0329-4b73-b189-c7288ea844d7

Keywords

Major depressive disorder
Amygdala
Prefrontal cortex
fearful faces
functional MRI
effective connectivity

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Cite this

Stolicyn, A., Harris, M. A., Nooij, L. D., Shen, X., Macfarlane, J. A., Campbell, A., McNeil, C. J., Sandu, A.-L., Murray, A. D., Waiter, G. D., Lawrie, S. M., Steele, D. J., McIntosh, A. M., Romaniuk, L., & Whalley, H. C. (2024). Disrupted Limbic-Prefrontal Effective Connectivity in Response to Fearful Faces in Lifetime Depression. Journal of Affective Disorders. Advance online publication. https://doi.org/10.1101/2023.07.18.23292846

Stolicyn, A, Harris, MA, Nooij, LD, Shen, X, Macfarlane, JA, Campbell, A, McNeil, CJ , Sandu, A-L, Murray, AD, Waiter, GD, Lawrie, SM, Steele, DJ, McIntosh, AM, Romaniuk, L & Whalley, HC 2024, 'Disrupted Limbic-Prefrontal Effective Connectivity in Response to Fearful Faces in Lifetime Depression', Journal of Affective Disorders. https://doi.org/10.1101/2023.07.18.23292846

@article{5525cf49be2e463e9ce01fcc6ab4baf7,

title = "Disrupted Limbic-Prefrontal Effective Connectivity in Response to Fearful Faces in Lifetime Depression",

abstract = "BackgroundMultiple brain imaging studies of negative emotional bias in major depressive disorder (MDD) have used images of fearful facial expressions and focused on the amygdala and the prefrontal cortex. The results have, however, been inconsistent, potentially due to small sample sizes (typically ). It remains unclear if any alterations are a characteristic of current depression or of past experience of depression, and whether there are MDD-related changes in effective connectivity between the two brain regions.MethodsActivations and effective connectivity between the amygdala and dorsolateral prefrontal cortex (DLPFC) in response to fearful face stimuli were studied in a large population-based sample from Generation Scotland. Participants either had no history of MDD ( in activation analyses, in connectivity analyses) or had a diagnosis of MDD during their lifetime (LMDD, in activation analyses, in connectivity analyses). The within-scanner task involved implicit facial emotion processing of neutral and fearful faces.ResultsCompared to controls, LMDD was associated with increased activations in left amygdala () and left DLPFC (), increased mean bilateral amygdala activation (), and increased inhibition from left amygdala to left DLPFC, all in response to fearful faces contrasted to baseline. Results did not appear to be attributable to depressive illness severity or antidepressant medication status at scan time.LimitationsMost studied participants had past rather than current depression, average severity of ongoing depression symptoms was low, and a substantial proportion of participants were receiving medication. The study was not longitudinal and the participants were only assessed a single time.ConclusionsLMDD is associated with hyperactivity of the amygdala and DLPFC, and with stronger amygdala to DLPFC inhibitory connectivity, all in response to fearful faces, unrelated to depression severity at scan time. These results help reduce inconsistency in past literature and suggest disruption of {\textquoteleft}bottom-up{\textquoteright} limbic-prefrontal effective connectivity in depression.",

keywords = "Major depressive disorder, Amygdala, Prefrontal cortex, fearful faces, functional MRI, effective connectivity",

author = "Aleks Stolicyn and Harris, {Mathew A.} and Nooij, {Laura de} and Xueyi Shen and Macfarlane, {Jennifer A.} and Archie Campbell and McNeil, {Christopher J.} and Anca-Larisa Sandu and Murray, {Alison D.} and Waiter, {Gordon D.} and Lawrie, {Stephen M.} and Steele, {Douglas J.} and McIntosh, {Andrew M.} and Liana Romaniuk and Whalley, {Heather C.}",

note = "This study was supported and funded by the Wellcome Trust Strategic Award {"}Stratifying Resilience and Depression Longitudinally{"} (STRADL) (Reference 104036/Z/14/Z), and the Medical Research Council Mental Health Pathfinder Award {"}Leveraging routinely collected and linked research data to study the causes and consequences of common mental disorders{"} (Reference MRC-MC_PC_17209). The work was also supported through the Lister Institute of Preventive Medicine award with reference 173096 and the Wellcome-University of Edinburgh Institutional Strategic Support Fund (Reference 204804/Z/16/Z). Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (Reference CZD/16/6) and the Scottish Funding Council (Reference HR03006), and is currently supported by the Wellcome Trust (Reference 216767/Z/19/Z). Acknowledgements For further details regarding the NimStim dataset of facial expressions please see https://danlab.psychology.columbia.edu/content/nimstim-set-facial-expressions. Development of the MacBrain Face Stimulus Set was overseen by Nim Tottenham and supported by the John D. and Catherine T. MacArthur Foundation Research Network on Early Experience and Brain Development. Please contact Nim Tottenham at nlt7@columbia.edu for more information concerning the stimulus set. The current work has made use of the resources provided by the Edinburgh Compute and Data Facility (ECDF) (http://www.ecdf.ed.ac.uk/). We would like to thank all Generation Scotland research volunteers who took part in the current study for contributing their time and effort. We would also like to thank all research assistants, clinicians and technicians for their valuable contributions to collection of the data.",

year = "2024",

month = jan,

day = "12",

doi = "10.1101/2023.07.18.23292846",

language = "English",

journal = "Journal of Affective Disorders",

issn = "0165-0327",

publisher = "Elsevier",

}

TY - JOUR

T1 - Disrupted Limbic-Prefrontal Effective Connectivity in Response to Fearful Faces in Lifetime Depression

AU - Stolicyn, Aleks

AU - Harris, Mathew A.

AU - Nooij, Laura de

AU - Shen, Xueyi

AU - Macfarlane, Jennifer A.

AU - Campbell, Archie

AU - McNeil, Christopher J.

AU - Sandu, Anca-Larisa

AU - Murray, Alison D.

AU - Waiter, Gordon D.

AU - Lawrie, Stephen M.

AU - Steele, Douglas J.

AU - McIntosh, Andrew M.

AU - Romaniuk, Liana

AU - Whalley, Heather C.

N1 - This study was supported and funded by the Wellcome Trust Strategic Award "Stratifying Resilience and Depression Longitudinally" (STRADL) (Reference 104036/Z/14/Z), and the Medical Research Council Mental Health Pathfinder Award "Leveraging routinely collected and linked research data to study the causes and consequences of common mental disorders" (Reference MRC-MC_PC_17209). The work was also supported through the Lister Institute of Preventive Medicine award with reference 173096 and the Wellcome-University of Edinburgh Institutional Strategic Support Fund (Reference 204804/Z/16/Z). Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (Reference CZD/16/6) and the Scottish Funding Council (Reference HR03006), and is currently supported by the Wellcome Trust (Reference 216767/Z/19/Z). Acknowledgements For further details regarding the NimStim dataset of facial expressions please see https://danlab.psychology.columbia.edu/content/nimstim-set-facial-expressions. Development of the MacBrain Face Stimulus Set was overseen by Nim Tottenham and supported by the John D. and Catherine T. MacArthur Foundation Research Network on Early Experience and Brain Development. Please contact Nim Tottenham at nlt7@columbia.edu for more information concerning the stimulus set. The current work has made use of the resources provided by the Edinburgh Compute and Data Facility (ECDF) (http://www.ecdf.ed.ac.uk/). We would like to thank all Generation Scotland research volunteers who took part in the current study for contributing their time and effort. We would also like to thank all research assistants, clinicians and technicians for their valuable contributions to collection of the data.

PY - 2024/1/12

Y1 - 2024/1/12

N2 - BackgroundMultiple brain imaging studies of negative emotional bias in major depressive disorder (MDD) have used images of fearful facial expressions and focused on the amygdala and the prefrontal cortex. The results have, however, been inconsistent, potentially due to small sample sizes (typically ). It remains unclear if any alterations are a characteristic of current depression or of past experience of depression, and whether there are MDD-related changes in effective connectivity between the two brain regions.MethodsActivations and effective connectivity between the amygdala and dorsolateral prefrontal cortex (DLPFC) in response to fearful face stimuli were studied in a large population-based sample from Generation Scotland. Participants either had no history of MDD ( in activation analyses, in connectivity analyses) or had a diagnosis of MDD during their lifetime (LMDD, in activation analyses, in connectivity analyses). The within-scanner task involved implicit facial emotion processing of neutral and fearful faces.ResultsCompared to controls, LMDD was associated with increased activations in left amygdala () and left DLPFC (), increased mean bilateral amygdala activation (), and increased inhibition from left amygdala to left DLPFC, all in response to fearful faces contrasted to baseline. Results did not appear to be attributable to depressive illness severity or antidepressant medication status at scan time.LimitationsMost studied participants had past rather than current depression, average severity of ongoing depression symptoms was low, and a substantial proportion of participants were receiving medication. The study was not longitudinal and the participants were only assessed a single time.ConclusionsLMDD is associated with hyperactivity of the amygdala and DLPFC, and with stronger amygdala to DLPFC inhibitory connectivity, all in response to fearful faces, unrelated to depression severity at scan time. These results help reduce inconsistency in past literature and suggest disruption of ‘bottom-up’ limbic-prefrontal effective connectivity in depression.

AB - BackgroundMultiple brain imaging studies of negative emotional bias in major depressive disorder (MDD) have used images of fearful facial expressions and focused on the amygdala and the prefrontal cortex. The results have, however, been inconsistent, potentially due to small sample sizes (typically ). It remains unclear if any alterations are a characteristic of current depression or of past experience of depression, and whether there are MDD-related changes in effective connectivity between the two brain regions.MethodsActivations and effective connectivity between the amygdala and dorsolateral prefrontal cortex (DLPFC) in response to fearful face stimuli were studied in a large population-based sample from Generation Scotland. Participants either had no history of MDD ( in activation analyses, in connectivity analyses) or had a diagnosis of MDD during their lifetime (LMDD, in activation analyses, in connectivity analyses). The within-scanner task involved implicit facial emotion processing of neutral and fearful faces.ResultsCompared to controls, LMDD was associated with increased activations in left amygdala () and left DLPFC (), increased mean bilateral amygdala activation (), and increased inhibition from left amygdala to left DLPFC, all in response to fearful faces contrasted to baseline. Results did not appear to be attributable to depressive illness severity or antidepressant medication status at scan time.LimitationsMost studied participants had past rather than current depression, average severity of ongoing depression symptoms was low, and a substantial proportion of participants were receiving medication. The study was not longitudinal and the participants were only assessed a single time.ConclusionsLMDD is associated with hyperactivity of the amygdala and DLPFC, and with stronger amygdala to DLPFC inhibitory connectivity, all in response to fearful faces, unrelated to depression severity at scan time. These results help reduce inconsistency in past literature and suggest disruption of ‘bottom-up’ limbic-prefrontal effective connectivity in depression.

KW - Major depressive disorder

KW - Amygdala

KW - Prefrontal cortex

KW - fearful faces

KW - functional MRI

KW - effective connectivity

U2 - 10.1101/2023.07.18.23292846

DO - 10.1101/2023.07.18.23292846

M3 - Article

C2 - 38220104

SN - 0165-0327

JO - Journal of Affective Disorders

JF - Journal of Affective Disorders

ER -

Disrupted Limbic-Prefrontal Effective Connectivity in Response to Fearful Faces in Lifetime Depression

Abstract

Bibliographical note

Data Availability Statement

Keywords

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