The Neurocognitive Sequelae of Chronic Traumatic Brain Injury and the Utility of Treatment with Methylphenidate

Traumatic Brain Injury (TBI) is a serious world-wide public health concern with a pressing need for adequate, effective long-term treatment. Cognitive deficits are a common complaint after TBI and persistent disabilities endure well into the chronic phases of the injury. Few recognised standard treatments exist for treating cognitive deficits associated with TBI. Advances in Magnetic Resonance Imaging (MRI) technology using structural, functional, and diffusion imaging have shown utility in revealing subtle neurobiological abnormalities in patients with TBI which were previously undetectable with routine brain imaging. These have been employed here to study the behavioural, cognitive, and functional consequences of TBI alongside the neurobiological correlates of improved cognition with pharmacological treatment i.e., Methylphenidate (MPh). This work aims to further our understanding of the detrimental functional consequences of TBI and inform targeted neurorehabilitation options. In the first experimental chapter, I use task-based functional MRI data acquired during a Tower of London (TOL) task that gauges working memory, visuospatial planning, and executive function i.e., executive planning. I explore the detrimental effects of TBI and the usefulness of MPh treatment on behavioural performance, activity, regional connectivity, and MPh-driven behavioural-neurofunctional relationships. I found that patients with TBI have deficits in accuracy and reaction time, together with differences in activity and connectivity, and some of these deficits are ameliorated with a single dose of MPh. These were in the insula, striatum, thalamus, parietal, and cerebellar regions. Moreover, differences in connectivity between the cerebellum, thalamus, and parietal cortex indicate MPh-driven behavioural improvements. In the second experimental chapter, I use task-based functional MRI data collected during a Rapid Visual Information Processing (RVIP) task that evaluates attention, and more specifically, one particular domain, namely sustained attention. I found that patients have deficits in accuracy, sensitivity, and response bias. Patients demonstrate hyperactivity in frontal, parietal, and subcortical structures and exhibit connectivity deficits within a network dedicated to sustained attention. A single dose of MPh normalised aspects of regional hyperactivity and resulted in striatal areas connecting to additional frontoparietal regions to support sustained attention. Furthermore, MPh-induced changes in connectivity of the cerebellum and striatal regions related to behavioural improvements with MPh administration. In the third experimental chapter, I investigate the effects of MPh on resting-state functional connectivity to ascertain the relationship between resting-state neurofunctional differences and changes in the in-scanner behavioural results with MPh treatment that demonstrated significance from previous findings and work. I found that resting-state functional connectivity from the right insula, inferior frontal, and opercula regions were impaired whether patients took MPh or not. However, MPh appeared to upregulate the resting-state connectivity of parts of the left insula and IFG to parts of the cerebellum. These functional connectivity changes are linked to changes in performance in multiple cognitive domains including working memory, sustained attention, and executive planning. In the fourth and final experimental chapter, I use diffusion MRI to examine the regional structural deficits following TBI, how residual structural connectivity contributes to enhanced cognitive function in cognitive domains from in-scanner behavioural results that demonstrated significance from previous findings and work, and how structural connectivity and integrity might inform more successful responsiveness to MPh treatment. Patients display reduced white matter integrity in regions relevant for specific cognitive domains, disrupted fibre tractography, and compromised axonal projections. These were in the corona radiata, cingulum, and external capsule which connect frontoparietal and subcortical regions. Nonetheless, patients display some increased structural connectivity which could be attributed to compensatory neuroplasticity following TBI. Furthermore, differences in residual structural integrity between patients are related to improvements in numerous cognitive domains including working memory, executive planning, sustained attention, and response inhibition with MPh treatment. Through these investigations, this thesis aims to further the existing understanding of the neurocognitive consequences of brain injury, to carve out a place for functional and diffusion imaging in understanding these neurocognitive consequences and treating them in patients with chronic TBI, as well as explore the utility of MPh in treating this complex and heterogenous condition.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Peattie, Alexander

Advisors dc:contributor.advisor

• Stamatakis, Emmanuel
• Menon, David

• Traumatic Brain Injury
• Methylphenidate
• Cognitive Function
• Executive Function
• Tower of London
• Sustained Attention
• Rapid Visual Information Processing
• Working Memory
• N-back
• Response Inhibition
• Stop-signal
• Magnetic Resonance Imaging
• MRI
• fMRI
• dMRI
• Diffusion Tensor Imaging
• Dopamine
• Noradrenaline
• Serotonin
• Catecholamines
• Diffuse Axonal Injury
• White Matter Damage
• Chronic Traumatic Brain Injury
• Brain Injury
• TBI
• MPh

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/4947ebe7-5b52-43d4-a454-b6af51159ee1/download
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

eng

Author Identifier

0000-0003-2115-7640

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/368639