Predictors and brain connectivity changes associated with arm motor function improvement from intensive practice in chronic stroke

Abstract

Background and Purpose: The brain changes that underlie therapy-induced improvement in motor function after stroke remain obscure. This study sought to demonstrate the feasibility and utility of measuring motor system physiology in a clinical trial of intensive upper extremity rehabilitation in chronic stroke-related hemiparesis. Methods: This was a substudy of two multi-center clinical trials of intensive robotic and intensive conventional therapy arm therapy in chronic, significantly hemiparetic, stroke patients. Transcranial magnetic stimulation was used to measure motor cortical output to the biceps and extensor digitorum communus muscles. Magnetic resonance imaging (MRI) was used to determine the cortical anatomy, as well as to measure fractional anisotropy, and blood oxygenation (BOLD) during an eyes-closed rest state. Region-of-interest time-series correlation analysis was performed on the BOLD signal to determine interregional connectivity. Functional status was measured with the upper extremity Fugl-Meyer and Wolf Motor Function Test. Results: Motor evoked potential (MEP) presence was associated with better functional outcomes, but the effect was not significant when considering baseline impairment. Affected side internal capsule fractional anisotropy was associated with better function at baseline. Affected side primary motor cortex (M1) activity became more correlated with other frontal motor regions after treatment. Resting state connectivity between affected hemisphere M1 and dorsal premotor area (PMAd) predicted recovery. Conclusions: Presence of motor evoked potentials in the affected motor cortex and its functional connectivity with PMAd may be useful in predicting recovery. Functional connectivity in the motor network shows a trends towards increasing after intensive robotic or non-robotic arm therapy. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00372411 \& NCT00333983.

Keywords: Predictors; brain connectivity; motor function; robotic.

Conflict of interest statement

Competing interests: No competing interests were disclosed.

Figures

Figure 1.. Study Design.

The timeline of baseline measures and the therapy interventions are shown graphically. MRI and TMS measurements were performed before or after the intervention.

Figure 2.

Resting state connectivity (correlations.)A: The 11 regions of interest (ROIs) are shown on representative axial slices of an example brain MRI. The top slices show the cerebellar ROI, then the PMAv on the left bottom slice, and PMAd, M1, and superior parietal regions from anterior to posterior. The SMA is represented by a single midline ROI.B. Correlation matrix with correlations at baseline in two resting states scans in the same participant.C. Example correlation in a single slice with a affected side M1 ROI as the seed.

Figure 3.. Clinical Outcomes.

The baseline and change in Fugl-Meyer score are shown for each participant, grouped by whether there was initial motor evoked potential as measured by TMS. Change 1 is across the intervention; Change 2 is between the end of the intervention and the last outcome measurement (12 weeks.) Negative changes are always shown below the baseline. Source data is in Dataset1.

Figure 4.. Recruitment curves on the affected upper extremity.

A. Single participant (#1) recruitment curves in the EDC and the second baseline and two follow-up measurements. Stimulation strength is indicated on the x-axis as a percentage of resting motor threshold. Raw data is in Dataset2-ExampleRecCurve|.B. The slope of the recruitment curve between 100 and 120% of resting motor threshold stimulation strength was extracted from each recruitment curve of each participant that had measurable recruitment curves that could be measured on the affected side EDC. The first two measurements are both baseline periods. Changes in the recruitment curve slope were not significant.C. Recruitment curve slope in biceps (otherwise, as inB.) Data is in Dataset2-RecCurvSlope.

Figure 5.. Ipsilateral Silent Period.

An example of ipsilateral silent period measured at baseline (left) and immediately after the 12 weeks intervention (right) in participant RB5. EMG is measured in mV in the EDC muscle contralateral to the TMS stimulator in the upper trace and ipsilateral in the lower trace, which is offset by 2 mV. Before the intervention there is little activation of the muscle and also no apparent silent period. There is much more activation of the muscle after the intervention and also a visible short ipsilateral silent period.

Figure 6.. Change in connectivity of AM1.

The mean change and S.D. of the Z-transformed correlation coefficient of the affected primary motor cortex (AM1) with each of the other regions is shown. Note that all regions showed an increase in connectivity except the parietal regions. Region names include ‘A’ for affected side hemisphere (the side opposite to the affected hemisphere in the case of the cerebellum, ‘CER’) and ‘U’ for unaffected, with region names as in Figure 2.