Cognitive function, inflammation and
neurodegeneration after traumatic brain injury !
Professor David Sharp, NIHR Research Professor,
Computational Clinical and Cognitive Neuroimaging Laboratory, Imperial College
London
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Overview!
•  There is frequently a poor outcome after traumatic brain injury
(TBI).
•  This is often due to cognitive impairments.
•  Treatments are limited for these problems.
•  TBI is heterogenous.
•  Therefore, patient stratification is needed to select the
appropriate treatments.
•  TBI can be thought of as a disorder of network disconnection,
so measuring the connections and functions of brain networks
will be useful.
•  Neuroimaging can be used to identify the underlying causes for
cognitive impairment, and so stratify treatments.
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The hidden costs!
•  TBI is the biggest cause of death and disability in the under 40s.
•  Due mainly to road traffic accidents, assaults, falls…and blast
exposure
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Death rate after TBI!
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TBI is a heterogenous disease!
Job
Loss
Axonal
Injury
Time
Neurotransmitter
Abnormality
Cognitive
Impairment
Eg. attention
Homelessness
Network
Dysfunction
Prison
Neurodegeneration
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Case History!
28yr male
Top cover
Wearing body armour, Helmet and eye protection
50 Kg IED.
Multiple fractures. Superficial lacerations. Left sided pneumothorax.
Initial GCS 12/15
2 weeks of retrograde amnesia
6 weeks of post-traumatic amnesia
On neuropsychological assessment;
•  Impaired executive function, memory and processing speed
Returned to work in a limited capacity but struggled and has now been
signed off as unable to continue soldiering.
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Structural imaging findings!
T2Flair
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Network dysfunction after traumatic brain injury!
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Traumatic (diffuse) axonal injury pathology!
Shear, tensile,
compressive strain
White matter pathology
Rest
Acceleration
Grade 2: lesions in corpus callosum
Deceleration
Grade 3: lesions also in brainstem
Mac Donald et al J Neurosci ‘07
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Diffusion tensor imaging video!
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Diffusion tensor imaging and structural connectivity!
Traumatic axonal injury
Normal White matter
White matter - TBI
Grade 2: lesions in corpus callosum
Grade 3: lesions also in brainstem
Adams et al ‘85
Traumatic axonal injury
Low fractional
anisotropy
Mori et al Neur
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White matter damage after blast and civilian TBI!
Blast TBI > Controls
Civilian TBI > Controls
Z=34
Z=20
Z=4
Z=-5
David Baxter
Z=-35
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Case - DTI Diagnostic Data!
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White matter damage and memory impairment!
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Machine learning for predicting cognitive impairment!
Predicting Executive Function
Predicting Processing
Speed
White matter tracts Contributing to prediction
Hellyer et al Ann Neurol 2013
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Network function after TBI!
Rob Leech
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Information Processing Speed and Attention after TBI!
Choice Reaction Time Task
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image and then insert it again.
Xavier de Boissezon
First third (T1)
Valerie Bonnelle
Reaction Time
Last third (T3)
Increased variability
Vigilance decrement
Time
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Default mode network control and sustained attention!
Impaired sustained attention after TBI
Bonnelle et al J Neurosci ‘11
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Default mode network connectivity and sustained attention!
DMN function predicts sustained attention
Cingulum bundle damage and attention
Posterior cingulate functional connectivity
Bonnelle et al J Neurosci ‘11
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Treating network dysfunction!
Liddle et al. J Child Psychol Psych (2011)
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Treating attention after TBI!
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•
•
•
RCT N=34, split into pilot and replication phases
Moderate or severe TBI and attention complaints
Methylphenidate 0.3mg/kg, 6 week trial with repeated cross-over design
Results
•
•
•
•
Positive effects
(1) Information processing speed, including the CRT (effect size 0.32)
(2) Caregiver ratings of attention (effect size 0.5)
(3) Attentiveness during individual work tasks (effect size 0.62)
•  No effects on sustained attention or dual task performance
•  (despite previous work)
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Treating attention after TBI!
Limited impact of work, particularly in the UK.
Patients are not usually treated with any cognitive enhancers.
This reflects a general nihilism about many aspects of the treatment of these patients
Problems:
1)  How to select patients to treat?
2)  What dose to use for individuals?
3)  How to balance potential side effects and benefits of treatment?
4)  There is no clear clinical/neuropsychological phenotype to provide confidence
in starting treatment
Strategies for selecting patients for treatment
1)  Treat all suitable patients with attentional impairment and see if they respond.
2)  Exclude those patients with other likely causes for attentional impairment
e.g. psychiatric problems such as depression, then treat all patients.
3) Use objective evidence of factors relevant to the functioning of the drug.
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Treating attention after TBI!
Patient stratification is needed:
1)  Methyphenidate is a noradrenergic and dopaminergic reuptake inhibitor
2)  Response is likely to reflect the state of these neurotransmitter systems.
3)  Behavioral effects of dopamine are non-linear...both too much and too little is bad.
Goldman_Rakic et. Al. Brain Res Reviews 2000
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Dopaminergic imaging!
Dopamine imaging
Methylphenidate
Treatment
Imaging
Cognitive response
Hypothesis: Dopamine imaging can be used to identify the subset
of patients likely to have a good response to methylphenidate.
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Acknowledgements!
Imperial College London
Dr Robert Leech
Mr Mark Wilson
Professor Murray Shanahan
Dr Serena Counsell
Dr Tim Ham
Dr Anil Ramlackhansingh
Ms Emer Hughes
Dr Valerie Bonnelle
Professor David Brooks
Dr Tony Goldstone
Dr Maneesh Patel
Dr Gregory Scott
Mr Pete Hellyer
Royal College of Defence Medicine
Surg Capt Mark Midwinter
Dr A K Samra
Defence Science & Technology Lab
Dr Emrys Kirkman (DSTL)
DMRC
Col Etherington
Wng Cmdr A Bennett
Dr Kit Malia
Doreen Rowland
University College London
Dr Richard Greenwood
Dr Alex Leff
Dr Kirsi Kinnunen
Goldsmiths College
Professor Jane Powell
Mr Sagar Jilka
University of Leuven
Dr Christian Beckmann
Kings College London
Dr Federico Turkheimer
The subjects who took part in this research.
Follow us on twitter: @Neurosharp