MRI case studies

Our researchers performed novel re-processing of existing MRI data to investigate anatomical alterations within the brains of Multiple Sclerosis (MS) patients.

The MRC Confidence in Concept (CiC) award for Nottingham had the explicit aim of identifying anatomical targets for treatments that aim to induce beneficial network plasticity.

Our researchers proposed to achieve this by performing novel re-processing of existing MRI data from cognitively-phenotyped MS patients and controls allowing a comprehensive model of anatomical-functional alterations leading to CI in MS.

They had three specific objectives: to identify specific network modules/interconnecting hubs that become altered in cognitively impaired MS patients, to identify anatomical substrates and associated pathology that lead to the modular dysfunction, and to confirm functional connectivity alterations involving these anatomical structures, supporting their candidacy as targets for directed therapies.

The project was successful in addressing the overarching aim and the specific objectives. The team’s analysis included MRI data from 52 people with MS and 36 matched controls including 3T diffusion tensor and resting state functional MRI.

Effective connectivity

They employed a measure of effective connectivity (Granger Causality analysis) to investigate the integrity of a candidate brain network with nodes in the dorsolateral-prefrontal cortex and the caudate nucleus.

This network was chosen because of known roles in cognitive processing in healthy people and disease states. Correlation was sought between effective connectivity metrics and performance in a test of working memory, sustained attention and information processing speed.

Researchers also employed a mediation analysis to test the mediating effect of altered effective connectivity on the relationship between MS-related structural damage within the dorsolateral-prefrontal circuit and cognitive performance.

Their analysis identified reduced effective connectivity in the afferent limb of the dorsolateral-prefrontal circuit in people with MS with cognitive dysfunction, with bilateral effective connectivity reductions resulting in more severe cognitive dysfunction than unilateral reductions alone.

Reduced effective connectivity in the afferent limb of the dorsolateral-prefrontal circuit mediated the relationship between structural alterations in components of the circuit and cognitive status. Specificity of the BRC’s findings was shown by the absence of any relationship between cognition and effective connectivity in the analogous and anatomically proximal motor circuit.

The team demonstrated good stability of effective connectivity measures in people with MS over an eight-month interval. Furthermore, they went on to demonstrate that the key positive and negative results could be replicated in an independent cohort of people with MS.

Therapeutic strategies aimed at improving cognition

The BRC’s finding that altered effective connectivity in the dorsolateral-prefrontal circuit occurs in people with MS and relates to cognitive status provided researchers with a potential target for therapeutic strategies aimed at improving cognition. Based on this work, investigators applied for a University of Nottingham Precision Imaging Beacon Accelerator award to allow them to perform a pilot study of applying a neuromodulatory technique called intermittent theta burst stimulation (iTBS) to enhance cognitive performance in people with MS. 

The pilot study showed that the procedure was well-tolerated, and increases in effective connectivity between the dorsolateral prefrontal cortex and the caudate nucleus were observed in five out of six participants after a single administration of iTBS.

BRC researchers presented the work to the Nottingham MS PPI group who strongly supported them developing a feasibility study of therapeutic iTBS for cognitive problems in MS. Based on a combination of the MRC CiC-funded work showing a potential target for neuromodulation, the UoN Accelerator funded pilot study showing good tolerability of iTBS in people with MS and the strong PPI support, the MRI research team was successful in the award of a project grant from the MS Society for a feasibility trial of connectivity-guided iTBS for cognitive impairment in MS (PI - Professor Rob Dineen, £245,000 over 36 months).