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Identification of BDNF sensitive electrophysiological markers of synaptic activity and their structural correlates in healthy subjects using a genetic approach utilizing the functional BDNF Val66Met polymorphism

Identification of BDNF sensitive electrophysiological markers of synaptic activity and their structural correlates in healthy subjects using a genetic approach utilizing the functional BDNF Val66Met polymorphism
Identification of BDNF sensitive electrophysiological markers of synaptic activity and their structural correlates in healthy subjects using a genetic approach utilizing the functional BDNF Val66Met polymorphism
Increasing evidence suggests that synaptic dysfunction is a core pathophysiological hallmark of neurodegenerative disorders. Brain-derived neurotropic factor (BDNF) is key synaptogenic molecule and targeting synaptic repair through modulation of BDNF signalling has been suggested as a potential drug discovery strategy. The development of such “synaptogenic” therapies depend on the availability of BDNF sensitive markers of synaptic function that could be utilized as biomarkers for examining target engagement or drug efficacy in humans. Here we have utilized the BDNF Val66Met genetic polymorphism to examine the effect of the polymorphism and genetic load (i.e. Met allele load) on electrophysiological (EEG) markers of synaptic activity and their structural (MRI) correlates. Sixty healthy adults were prospectively recruited into the three genetic groups (Val/Val, Val/Met, Met/Met). Subjects also underwent fMRI, tDCS/TMS, and cognitive assessments as part of a larger study. Overall, some of the EEG markers of synaptic activity and brain structure measured with MRI were the most sensitive markers of the polymorphism. Met carriers showed decreased oscillatory activity and synchrony in the neural network subserving error-processing, as measured during a flanker task (ERN); and showed increased slow-wave activity during resting. There was no evidence for a Met load effect on the EEG measures and the polymorphism had no effects on MMN and P300. Met carriers also showed reduced grey matter volume in the anterior cingulate and in the (left) prefrontal cortex. Furthermore, anterior cingulate grey matter volume, and oscillatory EEG power during the flanker task predicted subsequent behavioural adaptation, indicating a BDNF dependent link between brain structure, function and behaviour associated with error processing and monitoring. These findings suggest that EEG markers such as ERN and resting EEG could be used as BDNF sensitive functional markers in early clinical development to examine target engagement or drug related efficacy of synaptic repair therapies in humans.
1932-6203
1-16
Fox, Michael A.
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Soltész, Fruzsina
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Suckling, John
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Lawrence, Phil
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Tait, Roger
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Ooi, Cinly
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Bentley, Graham
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Dodds, Chris M.
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Miller, Sam R.
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Wille, David R.
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Byrne, Misha
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McHugh, Simon M.
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Bellgrove, Mark A.
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Croft, Rodney J.
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Lu, Bai
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Bullmore, Edward T.
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Nathan, Pradeep J.
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Fox, Michael A.
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Soltész, Fruzsina
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Suckling, John
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Lawrence, Phil
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Tait, Roger
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Ooi, Cinly
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Bentley, Graham
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Dodds, Chris M.
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Miller, Sam R.
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Wille, David R.
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Byrne, Misha
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McHugh, Simon M.
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Bellgrove, Mark A.
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Croft, Rodney J.
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Lu, Bai
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Bullmore, Edward T.
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Nathan, Pradeep J.
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Fox, Michael A., Soltész, Fruzsina, Suckling, John, Lawrence, Phil, Tait, Roger, Ooi, Cinly, Bentley, Graham, Dodds, Chris M., Miller, Sam R., Wille, David R., Byrne, Misha, McHugh, Simon M., Bellgrove, Mark A., Croft, Rodney J., Lu, Bai, Bullmore, Edward T. and Nathan, Pradeep J. (2014) Identification of BDNF sensitive electrophysiological markers of synaptic activity and their structural correlates in healthy subjects using a genetic approach utilizing the functional BDNF Val66Met polymorphism. PLoS ONE, 9 (4), 1-16. (doi:10.1371/journal.pone.0095558). (PMID:24760076)

Record type: Article

Abstract

Increasing evidence suggests that synaptic dysfunction is a core pathophysiological hallmark of neurodegenerative disorders. Brain-derived neurotropic factor (BDNF) is key synaptogenic molecule and targeting synaptic repair through modulation of BDNF signalling has been suggested as a potential drug discovery strategy. The development of such “synaptogenic” therapies depend on the availability of BDNF sensitive markers of synaptic function that could be utilized as biomarkers for examining target engagement or drug efficacy in humans. Here we have utilized the BDNF Val66Met genetic polymorphism to examine the effect of the polymorphism and genetic load (i.e. Met allele load) on electrophysiological (EEG) markers of synaptic activity and their structural (MRI) correlates. Sixty healthy adults were prospectively recruited into the three genetic groups (Val/Val, Val/Met, Met/Met). Subjects also underwent fMRI, tDCS/TMS, and cognitive assessments as part of a larger study. Overall, some of the EEG markers of synaptic activity and brain structure measured with MRI were the most sensitive markers of the polymorphism. Met carriers showed decreased oscillatory activity and synchrony in the neural network subserving error-processing, as measured during a flanker task (ERN); and showed increased slow-wave activity during resting. There was no evidence for a Met load effect on the EEG measures and the polymorphism had no effects on MMN and P300. Met carriers also showed reduced grey matter volume in the anterior cingulate and in the (left) prefrontal cortex. Furthermore, anterior cingulate grey matter volume, and oscillatory EEG power during the flanker task predicted subsequent behavioural adaptation, indicating a BDNF dependent link between brain structure, function and behaviour associated with error processing and monitoring. These findings suggest that EEG markers such as ERN and resting EEG could be used as BDNF sensitive functional markers in early clinical development to examine target engagement or drug related efficacy of synaptic repair therapies in humans.

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Accepted/In Press date: 28 March 2014
Published date: 23 April 2014
Organisations: Psychology

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Local EPrints ID: 375326
URI: https://eprints.soton.ac.uk/id/eprint/375326
ISSN: 1932-6203
PURE UUID: 4b167bab-bf1b-4c83-a19b-e265d86e54c7

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Date deposited: 20 Mar 2015 15:16
Last modified: 17 Jul 2017 21:18

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Contributors

Author: Michael A. Fox
Author: Fruzsina Soltész
Author: John Suckling
Author: Phil Lawrence
Author: Roger Tait
Author: Cinly Ooi
Author: Graham Bentley
Author: Chris M. Dodds
Author: Sam R. Miller
Author: David R. Wille
Author: Misha Byrne
Author: Simon M. McHugh
Author: Mark A. Bellgrove
Author: Rodney J. Croft
Author: Bai Lu
Author: Edward T. Bullmore
Author: Pradeep J. Nathan

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