Cognitive function, inflammation and neurodegeneration after traumatic brain injury!

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1 Cognitive function, inflammation and neurodegeneration after traumatic brain injury! Professor David Sharp, NIHR Research Professor, Computational Clinical and Cognitive Neuroimaging Laboratory, Imperial College London

2 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.

3 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

4 Death rate after TBI! C 3 NL

5 TBI is a heterogenous disease! Axonal Injury Job Loss Time Neurotransmitter Abnormality Network Dysfunction Cognitive Impairment Eg. attention Homelessness Prison Neurodegeneration

6 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.

7 Structural imaging findings! T2Flair

8 C3NL Network dysfunction after traumatic brain injury!

9 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

10 Diffusion tensor imaging video! C 3 NL

11 Diffusion tensor imaging and structural connectivity! C 3 NL 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 Mori et al Neur anisotropy

12 C3NL 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

13 Case - DTI Diagnostic Data! C 3 NL

14 White matter damage and memory impairment! C 3 NL

15 C3NL Machine learning for predicting cognitive impairment! Predicting Executive Function Predicting Processing Speed White matter tracts Contributing to prediction Hellyer et al Ann Neurol 2013

16 Network function after TBI! Rob Leech

17 Information Processing Speed and Attention after TBI! Choice Reaction Time Task The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. Restart your computer, and then open the file again. If the red x still appears, you may have to delete the image and then insert it again. Xavier de Boissezon Valerie Bonnelle Reaction Time First third (T1) Last third (T3) Increased variability Vigilance decrement Time

18 Default mode network control and sustained attention! C 3 NL Impaired sustained attention after TBI Bonnelle et al J Neurosci 11

19 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

20 Treating network dysfunction! Liddle et al. J Child Psychol Psych (2011)

21 Treating attention after TBI! 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)

22 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.

23 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

24 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.

25 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 University College London Dr Richard Greenwood Dr Alex Leff Dr Kirsi Kinnunen University of Leuven Dr Christian Beckmann 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 Goldsmiths College Professor Jane Powell Mr Sagar Jilka Kings College London Dr Federico Turkheimer The subjects who took part in this research. Follow us on

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