5-HT4 Receptor Agonist Effects on Functional Connectivity in the Human Brain: Implications for Procognitive Action

Marieke A.G. Martens; Lucy C. Wright; Daisy Gibson; Gershon Spitz; Cassandra D. Gould van Praag; Sana Suri; Philip J. Cowen; Susannah E. Murphy; Catherine J. Harmer; Angharad de Cates

doi:10.1016/j.bpsc.2023.03.014

5-HT₄ Receptor Agonist Effects on Functional Connectivity in the Human Brain: Implications for Procognitive Action

Marieke A.G. Martens, Lucy C. Wright, Daisy Gibson, Gershon Spitz, Cassandra D. Gould van Praag, Sana Suri, Philip J. Cowen, Susannah E. Murphy, Catherine J. Harmer, Angharad de Cates^*

^*Corresponding author for this work

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Abstract

Background: Cognitive deficits are often comorbid with mood disorders and can cause significant functional impairment even after resolution of the primary mood symptoms. We do not currently have pharmacological treatments that adequately address these deficits. 5-HT4 receptor agonists show promise as potential procognitive agents in animal and early human translational studies. Optimal cognitive performance in humans is directly associated with appropriate functional connectivity between specific resting-state neural networks. However, so far the effect of 5-HT₄ receptor agonism on resting-state functional connectivity (rsFC) in the brain in humans is unknown.

Methods: We collected resting-state functional magnetic resonance imaging scans from 50 healthy volunteers, of whom 25 received 6 days × 1 mg prucalopride (a highly selective 5-HT₄ receptor agonist) and 25 received placebo in a randomized double-blind design.

Results: Network analyses identified that participants in the prucalopride group had enhanced rsFC between the central executive network and the posterior/anterior cingulate cortex. Seed analyses also showed greater rsFC between the left and right rostral anterior cingulate cortex and the left lateral occipital cortex, and reduced rsFC between the hippocampus and other default mode network regions.

Conclusions: Similar to other potentially procognitive medications, low-dose prucalopride in healthy volunteers appeared to enhance rsFC between regions involved in cognitive networks and reduce rsFC within the default mode network. This suggests a mechanism for the behavioral cognitive enhancement previously seen with 5-HT₄ receptor agonists in humans and supports the potential for 5-HT₄ receptor agonists to be used in clinical psychiatric populations.

Original language	English
Pages (from-to)	1124-1134
Number of pages	11
Journal	Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
Volume	8
Issue number	11
Early online date	23 Apr 2023
DOIs	https://doi.org/10.1016/j.bpsc.2023.03.014
Publication status	Published - Nov 2023

Bibliographical note

Acknowledgments and Disclosures:
This work was supported by the NIHR Oxford Health Biomedical Research Centre, NIHR Oxford Cognitive Health Clinical Research Facility, and Wellcome Centre for Integrative Neuroscience (Grant No. 203139/Z/16/Z). ANdC was funded by a Wellcome Trust Clinical Doctoral Research Fellowship (Grant No. 216430/Z/19/Z) and received a travel grant from the Royal College of Psychiatrists/Gatsby Foundation. MAGM and SEM were funded by the NIHR Oxford Health Biomedical Research Centre. SS was supported by a UK Alzheimer’s Society Research Fellowship (Grant No. 441) and Academy of Medical Sciences/Wellcome Trust/Government Department of Business, Energy and Industrial Strategy/British Heart Foundation Springboard Grant No. SBF006/1078. The views expressed are those of the authors and not necessarily those of the Wellcome Trust, NHS, NIHR, or Department of Health. None of these bodies had a significant role in the design, collection and analysis of data, or decision to publish this article. This research was funded in whole, or in part, by the Wellcome Trust. For the purpose of open access, the author has applied a CC BY public copyright license to any author accepted manuscript version arising from this submission.

The preregistration of the study on clinicaltrials.gov can be found at https://clinicaltrials.gov/ct2/show/NCT03572790. The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) are the following. Code used for functional magnetic resonance imaging preprocessing and analysis is available at Gitlab (https://git.fmrib.ox.ac.uk/acates/7dp_code) (78). Unthresholded functional magnetic resonance imaging group-level statistical maps will be made available on NeuroVault. De-identified participant-level functional magnetic resonance imaging data will be made available on the Wellcome Centre for Integrative Neuroscience Open Data server. This is currently in development. Register to find out when materials are available for download at https://web.maillist.ox.ac.uk/ox/subscribe/win-open-data. Further inquiries can be directed to the corresponding author.

CJH has received consultancy fees from P1vital Ltd., Janssen Pharmaceuticals, Sage Therapeutics, Pfizer, Zogenix, Compass Pathways, and Lundbeck. SEM has received consultancy fees from Zogenix, Sumitomo Dainippon Pharma, P1vital Ltd., UCB, and Janssen Pharmaceuticals. CJH and SEM hold grant income from Zogenix and Janssen Pharmaceuticals. CJH, SEM, and PJC hold grant income from a collaborative research project with Pfizer. All other authors report no biomedical financial interests or potential conflicts of interest.

ClinicalTrials.gov: Effects of Seven Day Prucalopride Administration in Healthy Volunteers; https://clinicaltrials.gov/ct2/show/NCT03572790; NCT03572790.

Keywords

Cognition
fMRI
Procognitive
Prucalopride
Serotonin
5-HT4

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Martens, M. A. G., Wright, L. C., Gibson, D., Spitz, G., van Praag, C. D. G., Suri, S., Cowen, P. J., Murphy, S. E., Harmer, C. J., & de Cates, A. (2023). 5-HT₄ Receptor Agonist Effects on Functional Connectivity in the Human Brain: Implications for Procognitive Action. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 8(11), 1124-1134. https://doi.org/10.1016/j.bpsc.2023.03.014

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title = "5-HT4 Receptor Agonist Effects on Functional Connectivity in the Human Brain: Implications for Procognitive Action",

abstract = "Background: Cognitive deficits are often comorbid with mood disorders and can cause significant functional impairment even after resolution of the primary mood symptoms. We do not currently have pharmacological treatments that adequately address these deficits. 5-HT4 receptor agonists show promise as potential procognitive agents in animal and early human translational studies. Optimal cognitive performance in humans is directly associated with appropriate functional connectivity between specific resting-state neural networks. However, so far the effect of 5-HT4 receptor agonism on resting-state functional connectivity (rsFC) in the brain in humans is unknown.Methods: We collected resting-state functional magnetic resonance imaging scans from 50 healthy volunteers, of whom 25 received 6 days × 1 mg prucalopride (a highly selective 5-HT4 receptor agonist) and 25 received placebo in a randomized double-blind design.Results: Network analyses identified that participants in the prucalopride group had enhanced rsFC between the central executive network and the posterior/anterior cingulate cortex. Seed analyses also showed greater rsFC between the left and right rostral anterior cingulate cortex and the left lateral occipital cortex, and reduced rsFC between the hippocampus and other default mode network regions.Conclusions: Similar to other potentially procognitive medications, low-dose prucalopride in healthy volunteers appeared to enhance rsFC between regions involved in cognitive networks and reduce rsFC within the default mode network. This suggests a mechanism for the behavioral cognitive enhancement previously seen with 5-HT4 receptor agonists in humans and supports the potential for 5-HT4 receptor agonists to be used in clinical psychiatric populations.",

keywords = "Cognition, fMRI, Procognitive, Prucalopride, Serotonin, 5-HT4",

author = "Martens, {Marieke A.G.} and Wright, {Lucy C.} and Daisy Gibson and Gershon Spitz and {van Praag}, {Cassandra D. Gould} and Sana Suri and Cowen, {Philip J.} and Murphy, {Susannah E.} and Harmer, {Catherine J.} and {de Cates}, Angharad",

note = "Acknowledgments and Disclosures: This work was supported by the NIHR Oxford Health Biomedical Research Centre, NIHR Oxford Cognitive Health Clinical Research Facility, and Wellcome Centre for Integrative Neuroscience (Grant No. 203139/Z/16/Z). ANdC was funded by a Wellcome Trust Clinical Doctoral Research Fellowship (Grant No. 216430/Z/19/Z) and received a travel grant from the Royal College of Psychiatrists/Gatsby Foundation. MAGM and SEM were funded by the NIHR Oxford Health Biomedical Research Centre. SS was supported by a UK Alzheimer{\textquoteright}s Society Research Fellowship (Grant No. 441) and Academy of Medical Sciences/Wellcome Trust/Government Department of Business, Energy and Industrial Strategy/British Heart Foundation Springboard Grant No. SBF006/1078. The views expressed are those of the authors and not necessarily those of the Wellcome Trust, NHS, NIHR, or Department of Health. None of these bodies had a significant role in the design, collection and analysis of data, or decision to publish this article. This research was funded in whole, or in part, by the Wellcome Trust. For the purpose of open access, the author has applied a CC BY public copyright license to any author accepted manuscript version arising from this submission. The preregistration of the study on clinicaltrials.gov can be found at https://clinicaltrials.gov/ct2/show/NCT03572790. The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) are the following. Code used for functional magnetic resonance imaging preprocessing and analysis is available at Gitlab (https://git.fmrib.ox.ac.uk/acates/7dp_code) (78). Unthresholded functional magnetic resonance imaging group-level statistical maps will be made available on NeuroVault. De-identified participant-level functional magnetic resonance imaging data will be made available on the Wellcome Centre for Integrative Neuroscience Open Data server. This is currently in development. Register to find out when materials are available for download at https://web.maillist.ox.ac.uk/ox/subscribe/win-open-data. Further inquiries can be directed to the corresponding author. CJH has received consultancy fees from P1vital Ltd., Janssen Pharmaceuticals, Sage Therapeutics, Pfizer, Zogenix, Compass Pathways, and Lundbeck. SEM has received consultancy fees from Zogenix, Sumitomo Dainippon Pharma, P1vital Ltd., UCB, and Janssen Pharmaceuticals. CJH and SEM hold grant income from Zogenix and Janssen Pharmaceuticals. CJH, SEM, and PJC hold grant income from a collaborative research project with Pfizer. All other authors report no biomedical financial interests or potential conflicts of interest. ClinicalTrials.gov: Effects of Seven Day Prucalopride Administration in Healthy Volunteers; https://clinicaltrials.gov/ct2/show/NCT03572790; NCT03572790.",

year = "2023",

month = nov,

doi = "10.1016/j.bpsc.2023.03.014",

language = "English",

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Martens, MAG, Wright, LC, Gibson, D, Spitz, G, van Praag, CDG, Suri, S, Cowen, PJ, Murphy, SE, Harmer, CJ & de Cates, A 2023, '5-HT₄ Receptor Agonist Effects on Functional Connectivity in the Human Brain: Implications for Procognitive Action', Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, vol. 8, no. 11, pp. 1124-1134. https://doi.org/10.1016/j.bpsc.2023.03.014

TY - JOUR

T1 - 5-HT4 Receptor Agonist Effects on Functional Connectivity in the Human Brain

T2 - Implications for Procognitive Action

AU - Martens, Marieke A.G.

AU - Wright, Lucy C.

AU - Gibson, Daisy

AU - Spitz, Gershon

AU - van Praag, Cassandra D. Gould

AU - Suri, Sana

AU - Cowen, Philip J.

AU - Murphy, Susannah E.

AU - Harmer, Catherine J.

AU - de Cates, Angharad

N1 - Acknowledgments and Disclosures: This work was supported by the NIHR Oxford Health Biomedical Research Centre, NIHR Oxford Cognitive Health Clinical Research Facility, and Wellcome Centre for Integrative Neuroscience (Grant No. 203139/Z/16/Z). ANdC was funded by a Wellcome Trust Clinical Doctoral Research Fellowship (Grant No. 216430/Z/19/Z) and received a travel grant from the Royal College of Psychiatrists/Gatsby Foundation. MAGM and SEM were funded by the NIHR Oxford Health Biomedical Research Centre. SS was supported by a UK Alzheimer’s Society Research Fellowship (Grant No. 441) and Academy of Medical Sciences/Wellcome Trust/Government Department of Business, Energy and Industrial Strategy/British Heart Foundation Springboard Grant No. SBF006/1078. The views expressed are those of the authors and not necessarily those of the Wellcome Trust, NHS, NIHR, or Department of Health. None of these bodies had a significant role in the design, collection and analysis of data, or decision to publish this article. This research was funded in whole, or in part, by the Wellcome Trust. For the purpose of open access, the author has applied a CC BY public copyright license to any author accepted manuscript version arising from this submission. The preregistration of the study on clinicaltrials.gov can be found at https://clinicaltrials.gov/ct2/show/NCT03572790. The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) are the following. Code used for functional magnetic resonance imaging preprocessing and analysis is available at Gitlab (https://git.fmrib.ox.ac.uk/acates/7dp_code) (78). Unthresholded functional magnetic resonance imaging group-level statistical maps will be made available on NeuroVault. De-identified participant-level functional magnetic resonance imaging data will be made available on the Wellcome Centre for Integrative Neuroscience Open Data server. This is currently in development. Register to find out when materials are available for download at https://web.maillist.ox.ac.uk/ox/subscribe/win-open-data. Further inquiries can be directed to the corresponding author. CJH has received consultancy fees from P1vital Ltd., Janssen Pharmaceuticals, Sage Therapeutics, Pfizer, Zogenix, Compass Pathways, and Lundbeck. SEM has received consultancy fees from Zogenix, Sumitomo Dainippon Pharma, P1vital Ltd., UCB, and Janssen Pharmaceuticals. CJH and SEM hold grant income from Zogenix and Janssen Pharmaceuticals. CJH, SEM, and PJC hold grant income from a collaborative research project with Pfizer. All other authors report no biomedical financial interests or potential conflicts of interest. ClinicalTrials.gov: Effects of Seven Day Prucalopride Administration in Healthy Volunteers; https://clinicaltrials.gov/ct2/show/NCT03572790; NCT03572790.

PY - 2023/11

Y1 - 2023/11

N2 - Background: Cognitive deficits are often comorbid with mood disorders and can cause significant functional impairment even after resolution of the primary mood symptoms. We do not currently have pharmacological treatments that adequately address these deficits. 5-HT4 receptor agonists show promise as potential procognitive agents in animal and early human translational studies. Optimal cognitive performance in humans is directly associated with appropriate functional connectivity between specific resting-state neural networks. However, so far the effect of 5-HT4 receptor agonism on resting-state functional connectivity (rsFC) in the brain in humans is unknown.Methods: We collected resting-state functional magnetic resonance imaging scans from 50 healthy volunteers, of whom 25 received 6 days × 1 mg prucalopride (a highly selective 5-HT4 receptor agonist) and 25 received placebo in a randomized double-blind design.Results: Network analyses identified that participants in the prucalopride group had enhanced rsFC between the central executive network and the posterior/anterior cingulate cortex. Seed analyses also showed greater rsFC between the left and right rostral anterior cingulate cortex and the left lateral occipital cortex, and reduced rsFC between the hippocampus and other default mode network regions.Conclusions: Similar to other potentially procognitive medications, low-dose prucalopride in healthy volunteers appeared to enhance rsFC between regions involved in cognitive networks and reduce rsFC within the default mode network. This suggests a mechanism for the behavioral cognitive enhancement previously seen with 5-HT4 receptor agonists in humans and supports the potential for 5-HT4 receptor agonists to be used in clinical psychiatric populations.

AB - Background: Cognitive deficits are often comorbid with mood disorders and can cause significant functional impairment even after resolution of the primary mood symptoms. We do not currently have pharmacological treatments that adequately address these deficits. 5-HT4 receptor agonists show promise as potential procognitive agents in animal and early human translational studies. Optimal cognitive performance in humans is directly associated with appropriate functional connectivity between specific resting-state neural networks. However, so far the effect of 5-HT4 receptor agonism on resting-state functional connectivity (rsFC) in the brain in humans is unknown.Methods: We collected resting-state functional magnetic resonance imaging scans from 50 healthy volunteers, of whom 25 received 6 days × 1 mg prucalopride (a highly selective 5-HT4 receptor agonist) and 25 received placebo in a randomized double-blind design.Results: Network analyses identified that participants in the prucalopride group had enhanced rsFC between the central executive network and the posterior/anterior cingulate cortex. Seed analyses also showed greater rsFC between the left and right rostral anterior cingulate cortex and the left lateral occipital cortex, and reduced rsFC between the hippocampus and other default mode network regions.Conclusions: Similar to other potentially procognitive medications, low-dose prucalopride in healthy volunteers appeared to enhance rsFC between regions involved in cognitive networks and reduce rsFC within the default mode network. This suggests a mechanism for the behavioral cognitive enhancement previously seen with 5-HT4 receptor agonists in humans and supports the potential for 5-HT4 receptor agonists to be used in clinical psychiatric populations.

KW - Cognition

KW - fMRI

KW - Procognitive

KW - Prucalopride

KW - Serotonin

KW - 5-HT4

U2 - 10.1016/j.bpsc.2023.03.014

DO - 10.1016/j.bpsc.2023.03.014

M3 - Article

SN - 2451-9022

VL - 8

SP - 1124

EP - 1134

JO - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

JF - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

IS - 11

ER -