Approximately 85% of stroke survivors experience significant motor impairment in the contralesional (CL) arm (1), which can include a loss of independent joint control (2, 3), weakness (4), and spasticity (5). After stroke, precise, individuated control of single joints is often replaced by highly stereotyped patterns of multi-joint movement caused by abnormal muscle co-activation patterns (6). The most prevalent of these patterns is the flexion synergy, which is characterized by an abnormal coupling of shoulder abduction and elbow, wrist, and finger flexion (7, 8). This impairment has a negative impact on reaching ability (9) and hand function (3, 10), both critical components of functional use of the arm during activities of daily living. Despite the debilitating nature of this motor impairment, the underlying neuropathophysiology is not fully understood.
One hypothesis for why the flexion synergy emerges is that following a reduction of corticofugal input from the lesioned hemisphere, there is an increased dependence on CL motor cortex and bulbospinal pathways, such as reticulospinal (RetST) and rubrospinal (RubST) tracts. Therefore, in the present study, we quantify microstructural properties in white matter of both the brain and the brainstem, focusing primarily on corticoreticulospinal and corticorubrospinal systems. We evaluate whether these microstructural properties increase in integrity in relation to arm synergy and hand impairment severity, which could be indicative of increased use.
Although the RetST was previously believed to be predominantly involved in gross movements, such as locomotion (11, 12) and posture (13, 14), recent work in primates suggests the RetST also influences the motor neurons that control forearm and intrinsic hand muscles (15). In the non-human primate, stimulation of the RetST produces ipsilateral wrist flexor, elbow flexor, and shoulder abductor activation (16), mirroring the flexion synergy pattern observed in humans poststroke. Furthermore, stimulating the RetST after a corticospinal tract (CST) lesion elicits increased excitatory post-synaptic potentials in motoneurons innervating the forearm flexor and intrinsic hand muscles (17). This evidence makes the contralesional corticoreticulospinal system a compelling candidate for underlying abnormal joint coupling in humans with hemiparetic stroke.
In the non-human primate, the RubST also contributes to reaching and grasping movements (18) and has been shown to be important in recovery of hand function after CST damage (19, 20). One study showed that increased white matter integrity in bilateral red nucleus (RN) correlated with worse clinical outcomes in humans with chronic stroke (21); however, the RubST has been reported as relatively insignificant in humans (22, 23). The evidence for whether the RetST and the RubST contribute to abnormal joint coupling and hand impairment in humans poststroke still remains indirect and inconclusive.
We used high-resolution diffusion tensor imaging (DTI) (24) tract-based spatial statistics (TBSS) (25) to perform a voxel-wise comparison of white matter microstructure between stroke and control individuals. We analyzed fractional anisotropy (FA), a measurement typically associated with tract integrity, as well as axial diffusivity (AD) and radial diffusivity (RD), which represent diffusion parallel and perpendicular to the principle direction of diffusion, respectively. Because previous studies have reported altered diffusion properties in lesioned tissue (26–28), we excluded potential lesion-compromised voxels from our TBSS analysis to assess changes in normal-appearing white matter. We used the TBSS-derived white matter skeleton to investigate whether microstructural tissue properties within specific regions of the brainstem (CST, RetST, RubST) and subcortical white matter within CL motor areas [primary motor area (M1), premotor area (PM), supplementary motor area (SMA), body of the corpus callosum] are sensitive to upper extremity (UE) motor impairment in chronic stroke individuals.
We evaluated UE motor impairment using the Fugl-Meyer Assessment (FMA), a stroke-specific, performance-based motor impairment index, which measures impairments, such as loss of independent joint function, stretch reflex hyper-excitability, and altered sensation (29). It is one of the most widely used clinical scales of motor impairment poststroke (30). While previous studies have looked at diffusion MRI metrics in relation to the entire FMA score (31, 32), we used only the UE measurements of arm synergies and hand function to determine whether microstructural properties in specific white matter regions of interest (ROIs) were correlated.
In the present study, we hypothesized that microstructural integrity in specific regions of the extrapyramidal brainstem would be increased in chronic stroke in a manner sensitive to synergy and hand-related impairment severity. We demonstrate a significant decrease in FA in bilateral corona radiata and body of the corpus callosum in chronic stroke when compared to controls; however, within stroke subjects, specific brainstem regions show the highest FA in individuals with the most synergy-driven arm and hand impairment. More precisely, we describe the relation between CL RetST integrity and both expression of synergy and hand impairment and between ipsilesional (IL) RubST integrity and hand impairment in chronic hemiparetic stroke individuals.[…]