investigating the role of gamma-aminobutyric acid (gaba) in sedation

279 Pages·2017·17.32 MB·English

by  Neeraj Saxena

_____________________________________________________________________
INVESTIGATING THE ROLE OF
GAMMA-AMINOBUTYRIC ACID (GABA)
IN SEDATION: A COMBINED
ELECTROPHYSIOLOGICAL, HAEMODYNAMIC
AND SPECTROSCOPIC STUDY IN HUMANS
_____________________________________________________________________

Dr. Neeraj Saxena

Thesis submitted in partial fulfilment of the requirement
for the Degree of
Doctor of Philosophy
at
Cardiff University
2017
School of Medicine
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ACKNOWLEDGEMENTS

I would start off by thanking my supervisors Professors Judith Hall and Richard Wise.
This work would not have been possible without the inspiration, guidance, support and
mentoring provided by them over this long journey. They kept the faith, despite the
slow progress at times, and always managed to find solutions for seemingly
insurmountable problems. Also, thanks to Professor Krish Singh for his invaluable
advice during various stages of this work.

Thanks to CUBRIC and all the scientists based in CUBRIC who provided an immensely
stimulating and supportive environment to carry out this research. Special thanks to
Suresh Muthukumaraswamy, John Evans, Ana Diukova and Tommaso Gili who helped
me understand and learn the basics of neuroimaging techniques and help run the rather
complex studies, surprisingly, smoothly. Also, thanks to Kevin Murphy, Ian Driver and
Gavin Perry for their expertise and advice, especially at crucial moments. Thanks to
other CUBRIC members including Peter Hobden, Spiro Stathakis, Cyril Charron,
Martin Stuart and Angela who went out of their way to help me with the scanning, IT
and other organisational issues. I also thank my anaesthetic colleagues, Danielle Huckle
and Sarah Bell who provided anaesthetic support during these studies.

I also thank my employers (Cardiff University and Cwm Taf University Health Board)
for providing support, for me to be able to spend time towards my thesis while carrying
out my other clinical and academic responsibilities. I also thank National Institute for
Social Care and Health Research (now Health Care Research Wales) for funding some
of my research time.

Last, but by no way the least, I thank all the volunteers who participated in these
research studies and gave up their time to contribute towards the progress of science.

KEY WORDS
Mechanisms: Anaesthesia, Sedation; GABA; Neuroimaging: Magnetoencephalography,
Magnetic Resonance Spectroscopy, Functional MRI, BOLD, Arterial Spin Labeling

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In loving memory of my father who inspired me to never
stop learning.
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SUMMARY

A better understanding of the mechanisms of anaesthesia and sedation are expected not
only to improve the understanding of the neural correlates of consciousness but also to
help improve safety from the complications of anaesthesia/ sedation and develop safer
drugs and objective brain function monitoring systems. Neuroimaging modalities such
as functional MRI, magnetoencephalography and MR spectroscopy provide
complimentary information about brain functions and can help interrogate brain activity
in a living human brain. Most anaesthetic drugs act by enhancing the inhibitory actions
of GABA in the brain. Most neuroimaging research has focused on anaesthetic-induced
unconsciousness, with only few investigating the earliest levels of sedation-induced
altered consciousness.

The work in this thesis used a range of advanced neuroimaging modalities to investigate
the role of GABA (through a GABA-ergic drug, propofol), during mild sedation, in
humans. This was performed as a series of experiments within two, sequential, scanning
sessions, MEG followed by fMRI, in the same participants.

Propofol resulted in a dissociation of the visual gamma band response (decreased
evoked, increased induced power). This was related to a reduced BOLD fMRI response
but there were no changes in MRS detectable GABA concentration. Response to
multisensory stimulation also revealed interesting changes with MEG and fMRI.
Functional connectivity analyses showed changes in connectivities of the posterior
cingulate cortex (key hub of default-mode network) and thalamus with each other and
other key brain regions. Resting state networks were identified with MEG too, which
revealed interesting increases in connectivity in certain band- limited networks while
motor networks showed no change. Perfusion fMRI using arterial spin labelling
revealed a global and regional reduction in perfusion, highlighting some of the key
regions (frontal cortex, precuenus, PCC and thalamus) involved in sedation.

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DECLARATION

This work has not been submitted in substance for any other degree or award at this or any
other university or place of learning, nor is being submitted concurrently in candidature for any
degree or other award.

Signed …… … (candidate) Neeraj Saxena
Date …20.09.2017……………….…………….………

STATEMENT 1

This thesis is being submitted in partial fulfillment of the requirements for the degree of …PhD

Signed …… … (candidate) Neeraj Saxena
Date …20.09.2017……………….…………….………

STATEMENT 2

This thesis is the result of my own independent work/investigation, except where otherwise
stated, and the thesis has not been edited by a third party beyond what is permitted by Cardiff
University’s Policy on the Use of Third Party Editors by Research Degree Students. Other
sources are acknowledged by explicit references. The views expressed are my own.
Signed …… … (candidate) Neeraj Saxena
Date …20.09.2017……………….…………….………

STATEMENT 3

I hereby give consent for my thesis, if accepted, to be available online in the University’s Open
Access repository and for inter-library loan, and for the title and summary to be made available
to outside organisations.
Signed …… … (candidate) Neeraj Saxena
Date …20.09.2017……………….…………….………

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Dissemination of Findings

Published – peer reviewed papers
1. Gili, T., Saxena, N., Diukova, A., Murphy, K., Hall, J. E. & Wise, R. G. 2013.
The thalamus and brainstem act as key hubs in alterations of human brain
network connectivity induced by mild propofol sedation. J Neurosci, 33, 4024-
31.

2. Saxena, N., Muthukumaraswamy, S. D., Diukova, A., Singh, K., Hall, J. &
Wise, R. 2013. Enhanced Stimulus-Induced Gamma Activity in Humans during
Propofol-Induced Sedation. PLoS One, 8, e57685.

Conference Abstracts
1. Saxena, N., Diukova, A., Venzi, M., Gili, T., Huckle, D., Bell, S., Wise, R. G. &
Hall, J. E. 2012. Endogenous brain oscillations during sedation: Initial results of
a magnetoencephalography and functional magnetic resonance imaging study.
Anaesthetic Research Society Meeting 2011 London. British Journal of
Anaesthesia, 721.
2. Gili, T., Saxena, N., Diukova, A., Murphy, K., Hall, J. & Wise, R. 2012a.
Mapping alterations in cortical and subcortical functional connectivity induced
by light sedation. . OHBM Proceedings.
3. Gili, T., Saxena, N., Diukova, A., Murphy, K., Hall, J. & Wise, R. 2012b. Mild
sedation alters eigenvector centrality of BOLD FMRI in the thalamus and
brainstem OHBM Proceedings.
4. Gili, T., Saxena, N., Diukova, A., Murphy, K., Hall, J. & Wise, R. 2012c.
Physiological noise correction may help to detect changes in brain activity
during mild sedation. . OHBM Proceedings.
5. Saxena, N., Diukova, A., Venzi, M., Gili, T., Huckle, D., Bell, S., Wise, R. G. &
Hall, J. E. 2012. Endogenous brain oscillations during sedation: initial results of
a magnetoencephalography and functional magnetic resonance imaging study.
British Journal of Anaesthesia, 108, 721P.
6. Saxena, N., Gili, T., Huckle, D., Bell, S., Hall, J. & Wise, R. Mild propofol
sedation reduces frontal lobe and thalamic cerebral blood flow: an arterial spin
labelling study. BJA Research forum, 2016 London. British Journal of
Anaesthesia, e841.

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Papers to be submitted
1. Mild propofol sedation reduces frontal lobe and thalamic cerebral blood flow: an
arterial spin labeling study.

Invited presentations
1. Society of Intravenous Anaesthesia- Annual Scientific Meeting-2014:
Neurobiology of sedation: what can we learn from functional neuroimaging?

2. Royal College of Anaesthetists – Jubilee Current Concepts Symposium 2013:
Rising stars in anaesthesia, pain and critical care, London- Depth of sedation and
anaesthesia: What does neuroimaging tell us?

3. Anaesthesia Post fellowship study day, Cardiff, 2013- Anaesthesia and
consciousness: Insights from neuroimaging.
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