Nearly 800,000 people experience a new or recurrent stroke each year in the US (1). Popular therapies, such as constraint-induced movement therapy (CIMT), utilize intense task-specific practice of the affected limb to improve arm/hand function in acute and chronic stroke with mild impairments (2, 3). Neuroimaging results partially attribute the effectiveness of these arm/hand interventions to cortical reorganization in the ipsilesional hemisphere following training in acute and mild chronic stroke (4). Unfortunately, CIMT requires certain remaining functionality in the paretic hand to execute the tasks, and only about 10% of screened patients are eligible (5), thus disqualifying a large population of individuals with moderate to severe impairments. Recently, studies using device-assisted task-specific interventions specifically targeted toward moderate to severe chronic stroke reported positive clinical results (6–8). However, these studies primarily focus on clinical measures, but it is widely accepted that neural plasticity is a key factor for determining outcome (9–11). Consequently, it remains unclear whether moderate to severe chronic stroke [upper extremity Fugl-Meyer Assessment (UEFMA) < 30] maintains the ability to demonstrate neural changes following an arm/hand intervention.
Neural changes induced by task-specific training have been investigated widely using animal models (12). For instance, monkeys or rodents trained on a skilled reach-to-grasp task express enlarged representation of the digits of the hand or forelimb in primary motor cortex (M1) following training as measured by intracortical microstimulation (13, 14). Additionally, rapid local structural changes in the form of dendritic growth, axonal sprouting, myelination, and synaptogenesis occur (15–18). Importantly, both cortical and structural reorganization corresponds to motor recovery following rehabilitative training in these animals (19, 20).
The functional neural mechanisms underlying effective task-specific arm/hand interventions in acute and chronic stroke subjects with mild impairments support those seen in the animal literature described above. Several variations of task-specific combined arm/hand interventions, including CIMT, bilateral task-specific training, and hand-specific robot-assisted practice, have shown cortical reorganization such as increased sensorimotor activity and enlarged motor maps in the ipsilesional hemisphere related to the paretic arm/hand (21–24). These results suggest increased recruitment of residual resources from the ipsilesional hemisphere and/or decreased recruitment of contralesional resources following training. Although the evidence for a pattern of intervention-driven structural changes remains unclear in humans, several groups have shown increases in gray matter (GM) density in sensorimotor cortices (25), along with increases in fractional anisotropy in ipsilesional corticospinal tract (CST) (26) following task-specific training in acute and chronic stroke individuals with mild impairments.
The extensive nature of neural damage in moderate to severe chronic stroke may result in compensatory mechanisms, such as contralesional or secondary motor area recruitment (27). These individuals show increased contralesional activity when moving their paretic arm, which correlates with impairment (28, 29) and may be related to the extent of damage to the ipsilesional CST (30). This suggests that more impaired individuals may increasingly rely on contralesional corticobulbar tracts such as the corticoreticulospinal tract to activate the paretic limb (29). These tracts lack comparable resolution and innervation to the distal parts of the limb, thus sacrificing functionality at the paretic arm/hand (31). Since this population is largely ignored in current arm/hand interventions, it is unknown whether an arm/hand intervention for these more severely impaired post-stroke individuals will increase recruitment of residual ipsilesional corticospinal resources. These ipsilesional CSTs maintain the primary control of hand and finger extensor muscles (32) and are thus crucial for improved hand function. Task-specific training assisted by a device may reengage and strengthen residual ipsilesional corticospinal resources by training distal hand opening together with overall arm use.
The current study seeks to determine whether individuals with moderate to severe chronic stroke maintain the ability to show cortical reorganization and/or structural changes alongside behavioral improvement following a task-specific intervention. We hypothesize that following a device-assisted task-specific intervention, moderate to severe chronic stroke individuals will show similar functional and structural changes as observed in mildly impaired individuals, demonstrated by (i) a shift in cortical activity related to paretic hand opening from the contralesional hemisphere toward the ipsilesional hemisphere and (ii) an increase in GM density in sensorimotor cortices in the ipsilesional hemisphere.[…]