Changes in brain perfusion with training-related visuomotor improvement in MS

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. A better understanding of the mechanisms supporting brain plasticity in MS would help to develop targeted interventions to promote recovery. A total of 29 MS patients and 19 healthy volunteers underwent clinical assessment and multi-modal MRI acquisition [fMRI during serial reaction time task (SRT), DWI, T1w structural scans and ASL of resting perfusion] at baseline and after 4-weeks of SRT training. Reduction of functional hyperactivation was observed in MS patients following the training, shown by the stronger reduction of the BOLD response during task execution compared to healthy volunteers. The functional reorganization was accompanied by a positive correlation between improvements in task accuracy and the change in resting perfusion after 4 weeks' training in right angular and supramarginal gyri in MS patients. No longitudinal changes in WM and GM measures and no correlation between task performance improvements and brain structure were observed in MS patients. Our results highlight a potential role for CBF as an early marker of plasticity, in terms of functional (cortical reorganization) and behavioral (performance improvement) changes in MS patients that may help to guide future interventions that exploit preserved plasticity mechanisms.

Keywords: MRI; multiple sclerosis; perfusion; plasticity; recovery; training.

FIGURE 1

Serial reaction time (SRT) task. (A) Example of SRT task presented during the scan. Participants were asked to respond as quickly as possible to the location of visual stimuli presented on a computer screen by pressing the corresponding key on a keypad with one of four fingers (index to little finger) of their right hand. (B) Block design of the task. A total of 12 task blocks (8 Sequence and 4 Random blocks) were interleaved with rest blocks.

FIGURE 2

Behavioral performance during SRT task. (A) Performance recorded during the scan session 1 (before the home training) and 2 (following the home training). Patients (red) and controls (blue) showed increased accuracy (left) and decreased reaction time (right) after the training. Higher accuracy was observed in HC compared to MS in both sessions. The center of the plot represents median. The bars represent the range from lower and upper quartile. Whiskers indicate variability outside the upper and lower quartiles (maximum and minimum values). Asterisks indicate statistically significant differences between groups (top—MS patients report lower than controls) or sessions (bottom—performance improving after the training). (B) Performance recorded during the home training and reported as mean ± sem. Patients (red) and controls (blue) showed increase of accuracy and decrease of reaction times with the home training.

FIGURE 3

Functional BOLD activation and changes after 4 weeks of training. At baseline (A) MS patients show higher task related BOLD activation compared to controls in 4 clusters: right hemisphere, mainly corresponding to the pre-cuneal cortex, left cingulate gyrus and bilaterally in the medial portion of pre and post-central gyri. After 4 weeks of SRT training (B) a significant group × time interaction was observed in MS patients in the right pre-central gyrus and the right inferior temporal lobe. (C) BOLD response extracted from green ROI, showing a larger reduction in task induced BOLD response after training (session 2) in MS group (red) compared to controls (blue). Values are reported as BOLD% change, error bars represent SEM. *Indicate a significant statistical difference between groups.

FIGURE 4

Changes in brain perfusion with training in MS patients. (A) Bar graph representing CBF values (ml/100 g/min) extracted in Gray Matter only for MS patients (red) and healthy controls (blue). Values are reported as Mean ± SEM. (B) Plot showing the trend of the correlation observed with the voxel-wise analysis. CBF values (percentage change after training compared to before) were extracted only in significant area [red area in (C)] and plotted against the increase of performance, calculated by the slope of improvement in accuracy, in MS patients. (C) Patients’ mean BOLD response to task at baseline (gray), and voxel-wise correlation between behavioral SRT (accuracy) improvement over home-training and increase in resting perfusion in patients after 4 weeks of training (red). *Indicate a significant statistical difference between groups.

FIGURE 5

Between-group differences in brain structure. (A) Patients showed lower WM fractional anisotropy (FA) at baseline compared to controls. Green defines the WM skeleton, in which the group-based statistical contrast was carried out; yellow-red indicates regions where patients show lower FA than controls (corpus callosum, left and right corticospinal tract, and left and right optic radiation). Differences were considered significant at p < 0.05. (B) Patients showed lower GM volume at baseline in yellow/red regions, including left/right fusiform gyrus, left/right intra-calcarine gyrus, left/right cingulate gyrus, left/right inferior temporal gyrus, right parahippocampal gyrus, left/right thalamus, left/right caudate, right putamen and cerebellum. Patients showed higher GM volume in brain stem, left frontal gyrus and left motor cortex. Differences were considered significant at p < 0.05.