The neurophysiological basis of prolonged negative BOLD signals

Lead Research Organisation: University of Sheffield
Department Name: Psychology

Abstract

A technique called blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) can determine levels of different activity in parts of the living human brain and how malfunctions can occur in disease. However, this technique relies on changes in local blood oxygenation rather than measuring the electrical activity in the brain directly. How increases in brain activity results in blood changes has started to be understood, but how and if decreases in activity affect brain blood oxygen is not at all characterised making neuroimaging data very difficult to interpret in terms of decreases in brain activity. Despite this uncertainty, scientists are stating to use FMRI to infer decreases in brain activity and if this inference is correct their studies suggest that the majority of psychiatric (e.g. schizophrenia, major depressive disorder), neuro-developmental (e.g. Autism) neurological (e.g. Alzheimer?s) brain diseases are characterised an inability to ?turn-off? rather ?turn-on? specific brain regions during mental tasks. By directly measuring reductions brain activity, neuroimaging signals and blood oxygen content at the same time we hope to understand the relationships between them and allow this vital aspect of neuroimaging to further our understanding of brain function and its malfunction in disease states.

Technical Summary

The changes in cerebral blood flow, volume and oxygenation that accompany increases in neural activity form the basis of non-invasive neuroimaging techniques such as blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) which allow human brain mapping. Understanding the relationship between cerebral hemodynamics and the underlying evoked neural activity is therefore vital for the interpretation of neuroimaging data. With a unique combination of optical, electrophysiological and MR techniques in a rodent model we have previously explored the quantitative relationships between increases in activity and the accompanying hemodynamics and positive fMRI signals. However, increasingly deactivations are inferred from prolonged negative BOLD signal changes with little evidence that negative neuroimaging signals ubiquitously reflect reductions in electrical activity. If correct, studies using negative signals to infer reductions in activity suggest that an inability to deactivate specific brain regions appears to be the hallmark of all major neurological and psychiatric conditions. Our recently established dedicated 7T rodent MRI has afforded the signal to noise ratio required to detect prolonged negative BOLD signals following presentation of somatosensory stimuli. Thus the current proposal seeks to use combinations of our established techniques to characterise negative BOLD responses. Concurrent optical imaging spectroscopy and fMRI will allow examination of spatio-temporal concordance between negative BOLD signals and the underlying hemodynamics and further parameterisation of models linking the magnitude of hemodynamics to actual fMRI signal changes. Combinations of optical imaging and laser Doppler techniques will provide multi-modal data with which to explore relationships between decreases in blood flow, volume and oxygen consumption. Quantitative ?negative? neurovascular coupling will be compared from cortical regions signals immediately adjacent to those exhibiting positive BOLD and with negative BOLD responses in the opposite cortex. This will reveal whether re-distribution of local vascular resources is in part responsible for negative BOLD responses in cortical areas that share a common local vasculature. Ex-vivo histological and anatomical tracing techniques will inform the underlying cortical connectivity required for stimulus evoked decreases in activity. We will also perform a series of experiments in the awake animal preparation to assess the effects of anaesthesia on the evoked responses. Finally concurrent measure of ?negative? hemodynamics response and reductions in electrical activity will be used to make dynamic models to predict the entire time series of the CBF response from the underlying neural activity.

Publications

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Boorman L (2015) Long-latency reductions in gamma power predict hemodynamic changes that underlie the negative BOLD signal. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Harris S (2013) The effects of focal epileptic activity on regional sensory-evoked neurovascular coupling and postictal modulation of bilateral sensory processing. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

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Kennerley AJ (2012) Early and late stimulus-evoked cortical hemodynamic responses provide insight into the neurogenic nature of neurovascular coupling. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

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Martin CJ (2013) Functional MRI in conscious rats using a chronically implanted surface coil. in Journal of magnetic resonance imaging : JMRI

 
Description Alzheimers Research UK Interdisciplinary grant scheme
Amount £237,000 (GBP)
Funding ID ARUK-IRG2014-10 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2014 
End 10/2016
 
Description BBSRC Project Grant
Amount £774,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2013 
End 05/2016
 
Description Wellcome Trust Project Grant
Amount £547,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2011 
End 02/2014
 
Title Multi-modal mouse imaging platform 
Description We have spent 8 years refining and improving our anesthetized mouse preparation to increase the quality and reliability of brain neurovascular measurements. These methods were published in a 2015 paper (already attributed to ARUK funding) 
Type Of Material Model of mechanisms or symptoms - non-mammalian in vivo 
Year Produced 2015 
Provided To Others? Yes  
Impact Non as yet but the method will increase the accuracy and reliability of mouse neurovascular research for both health and disease and we expect it to have a strong impact on the field 
 
Description University of Reading 
Organisation University of Reading
Department School of Systems Engineering
Country United Kingdom 
Sector Academic/University 
PI Contribution I am a Co-Investigator with a recently awarded BBSRC grant to investigate the relationships of neural excitation and inhibition and how these effect neurovascular coupling. I provide the biological training to the two post docs on this grant
Collaborator Contribution Reading houses the PI of the grant and their experitise is on the signal processing and computer modelling side of the research
Impact This is system neuroscience and signal processing research
Start Year 2013
 
Description Article in University of Sheffield Discover Magazine 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Our neurovascular imaging research group were part of a focused Neuroscince edition of the Universities Discover magazine. Our Epilepsy funding is an important aspect of this work and the ERUK grant is mentioned in the article.
Year(s) Of Engagement Activity 2016
URL https://www.sheffield.ac.uk/research/impact/stories/neurological-imaging-brain-diseases-1.573959
 
Description Stall at Researchers Night at the University of Sheffield 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Our stall was open for 3 hours and we never had a quiet moment. The younger children loved the magnetic puzzles and especially liked the guess the fruit competition.

No visit organised but my PhD students will be doing some talks in schools later this year on a similar theme
Year(s) Of Engagement Activity 2012