Sonja E. Findlater

Background and Objectives It is difficult to predict poststroke outcome for individuals with severe motor impairment because both clinical tests and corticospinal tract (CST) microstructure may not reliably indicate severe motor impairment. Here, we test whether imaging biomarkers beyond the CST relate to severe upper limb (UL) impairment poststroke by evaluating white matter microstructure in the corpus callosum (CC). In an international, multisite hypothesis-generating observational study, we determined if (1) CST asymmetry index (CST-AI) can differentiate between individuals with mild-moderate and severe UL impairment and (2) CC biomarkers relate to UL impairment within individuals with severe impairment poststroke. We hypothesized that CST-AI would differentiate between mild-moderate and severe impairment, but CC microstructure would relate to motor outcome for individuals with severe UL impairment. Methods Seven cohorts with individual diffusion imaging and motor impairment (Fugl-Meyer Upper Limb) data were pooled. Hand-drawn regions-of-interest were used to seed probabilistic tractography for CST (ipsilesional/contralesional) and CC (prefrontal/premotor/motor/sensory/posterior) tracts. Our main imaging measure was mean fractional anisotropy. Linear mixed-effects regression explored relationships between candidate biomarkers and motor impairment, controlling for observations nested within cohorts, as well as age, sex, time poststroke, and lesion volume. Results Data from 110 individuals (30 with mild-moderate and 80 with severe motor impairment) were included. In the full sample, greater CST-AI (i.e., lower fractional anisotropy in the ipsilesional hemisphere, p < 0.001) and larger lesion volume (p = 0.139) were negatively related to impairment. In the severe subgroup, CST-AI was not reliably associated with impairment across models. Instead, lesion volume and CC microstructure explained impairment in the severe group beyond CST-AI (p9s < 0.010). Discussion Within a large cohort of individuals with severe UL impairment, CC microstructure related to motor outcome poststroke. Our findings demonstrate that CST microstructure does relate to UL outcome across the full range of motor impairment but was not reliably associated within the severe subgroup. Therefore, CC microstructure may provide a promising biomarker for severe UL outcome poststroke, which may advance our ability to predict recovery in individuals with severe motor impairment after stroke.

Background. Corticospinal tract (CST) damage is considered a biomarker for stroke recovery. Several methods have been used to define CST damage and examine its relationship to motor performance, but which method is most useful remains unclear. Proprioceptive impairment also affects stroke recovery and may be related to CST damage. Methods. Robotic assessment quantified upper-limb motor and proprioceptive performance at 2 weeks and 6 months poststroke (n = 149). Three previously-established CST lesion metrics were calculated using clinical neuroimaging. Diffusion magnetic resonance imaging quantified CST microstructure in a subset of participants (n = 21). Statistical region of interest (sROI) analysis identified lesion locations associated with motor and proprioceptive deficits. Results. CST lesion metrics were moderately correlated with motor scores at 2 weeks and 6 months poststroke. CST fractional anisotropy (FA) was correlated with motor scores at 1 month poststroke, but not at 6 months. The FA ratio of the posterior limb of the internal capsule was not correlated with motor performance. CST lesion metrics were moderately correlated with proprioceptive scores at 2 weeks and 6 months poststroke. sROI analysis confirmed that CST damage was associated with motor and proprioceptive deficits and additionally found that putamen, internal capsule, and corticopontocerebellar tract lesions were associated with poor motor performance. Conclusions. Across all methods used to quantify CST damage, correlations with motor or proprioceptive performance were moderate at best. Future research is needed to identify complementary or alternative biomarkers to address the complexity and heterogeneity of stroke recovery.

Proprioceptive and motor impairments commonly occur after stroke. Relationships between corticospinal tract (CST) fractional anisotropy (FA) and motor recovery have been identified. However, the relationship between sensory tract microstructure and proprioceptive recovery remains unexplored. Using probabilistic tractography, we examined the relationship between diffusion metrics in three tracts known to contain proprioceptive information (a) dorsal‐column medial‐lemniscal (DCML), (b) postcentral gyrus to supramarginal gyrus (POCG‐SMG), (c) postcentral gyrus to Heschl's gyrus (POCG‐HG) and proprioception at 1 (n= 26) and 6 months (n= 19) poststroke. Proprioception was assessed using two robotic tasks. Motor performance was also assessed robotically and compared to CST diffusion metrics. At 1‐month poststroke, a nonsignificant relationship (r= −0.43,p= 0.05) was observed between DCML‐FA and proprioceptive impairment. A moderate relationship was identified between POCG‐SMG FA and POCG‐HG FA and proprioceptive impairment (r= −0.47,p= 0.001 andr= −0.51,p= 0.008, respectively). No relationships were significant at 6 months poststroke. Similar to previous studies, lower CST‐FA correlated with motor impairment at 1 month poststroke (r= −0.58,p= 0.002). While CST‐FA is considered a predictor of motor impairment, our findings suggest that the relationship between FA and tracts containing proprioceptive information is not as straightforward and highlights the importance of sensory association areas in proprioception.

Background . Poststroke impairments of the ipsilesional arm are often discussed, but rarely receive focused rehabilitation. Ipsilesional deficits may affect daily function and although many studies have investigated them in chronic stroke, few characterizations have been made in the subacute phase. Furthermore, most studies have quantified ipsilesional deficits using clinical measures that can fail to detect subtle, but important deficits in motor function. Objective . We aimed to quantify reaching deficits of the contra- and ipsilesional limbs in the subacute phase poststroke. Methods . A total of 227 subjects with first-time, unilateral stroke completed a unilateral assessment of motor function (visually guided reaching) using a KINARM robot. Subjects completed the task with both the ipsi- and contralesional arms. Subjects were assessed on a variety of traditional clinical measures (Functional Independence Measure, Chedoke-McMaster Stroke Assessment, Purdue Pegboard, Behavioral Inattention Test) to compare with robotic measures of motor function. Results . Ipsilesional deficits were common and occurred in 37% (n = 84) of subjects. Impairments of the ipsilesional and contralesional arm were weakly to moderately correlated on robotic measures. Magnitude of impairment of the contralesional arm was similar for subjects with and without ipsilesional deficits. Furthermore, we found that a higher percentage of subjects with right-hemisphere stroke had ipsilesional deficits and more subjects with left-hemisphere subcortical strokes did not have ipsilesional deficits. Conclusions . Magnitude of contralesional impairment and lesion location may be poor predictors of individuals with ipsilesional impairments after stroke. Careful characterization of ipsilesional deficits could identify individuals who may benefit from rehabilitation of the less affected arm.

Kinesthesia is our sense of limb motion, and allows us to gauge the speed, direction, and amplitude of our movements. Over half of stroke survivors have significant impairments in kinesthesia, which leads to greatly reduced recovery and function in everyday activities. Despite the high reported incidence of kinesthetic deficits after stroke, very little is known about how damage beyond just primary somatosensory areas affects kinesthesia. Stroke provides an ideal model to examine structure-function relationships specific to kinesthetic processing, by comparing lesion location with behavioral impairment. To examine this relationship, we performed voxel-based lesion-symptom mapping and statistical region of interest analyses on a large sample of sub-acute stroke subjects (N=142) and compared kinesthetic performance with stroke lesion location. Subjects with first unilateral, ischemic stroke underwent neuroimaging and a comprehensive robotic kinesthetic assessment (~9 days post-stroke). The robotic exoskeleton measured subjects’ ability to perform a kinesthetic mirror-matching task of the upper limbs without vision. The robot moved the stroke-affected arm and subjects’ mirror-matched the movement with the unaffected arm. We found that lesions both within and outside primary somatosensory cortex were associated with significant kinesthetic impairments. Further, sub-components of kinesthesia were associated with different lesion locations. Impairments in speed perception were primarily associated with lesions to the right post-central and supramarginal gyri whereas impairments in amplitude of movement perception were primarily associated with lesions in the right pre-central gyrus, anterior insula, and superior temporal gyrus. Impairments in perception of movement direction were associated with lesions to bilateral post-central and supramarginal gyri, right superior temporal gyrus and parietal operculum. All measures of impairment shared a common association with damage to the right supramarginal gyrus. These results suggest that processing of kinesthetic information occurs beyond traditional sensorimotor areas. Additionally, this dissociation between kinesthetic sub-components may indicate specialized processing in these brain areas that form a larger distributed network.

Proprioception is an important aspect of function that is often impaired in the upper extremity following stroke. Unfortunately, neurorehabilitation has few evidence based treatment options for those with proprioceptive deficits. The authors consider potential reasons for this disparity. In doing so, typical assessments and proprioceptive intervention studies are discussed. Relevant evidence from the field of neuroscience is examined. Such evidence may be used to guide the development of targeted interventions for upper extremity proprioceptive deficits after stroke. As researchers become more aware of the impact of proprioceptive deficits on upper extremity motor performance after stroke, it is imperative to find successful rehabilitation interventions to target these deficits and ultimately improve daily function.

Visuospatial neglect is a disorder that can often result from stroke and is characterized by an inability to attend to contralesional stimuli. Two common subtypes include allocentric (object-centered) neglect and egocentric (viewer-centered) neglect. In allocentric neglect, spatial inattention is localized to the contralesional side of an object regardless of its relative position to the observer. In egocentric neglect, spatial inattention is localized to the contralesional side of the individual's midline. The neuroanatomical correlates of each subtype are unknown. However, recent work has suggested that damage to temporal, inferior parietal, and occipital areas may result in allocentric neglect and that damage to frontoparietal areas may result in egocentric neglect. We used voxel-based lesion-symptom mapping (VLSM) to compare lesion location to behavioral performance on the conventional six subtests of the Behavioral Inattention Test (BIT) in 62 subjects with acute right hemisphere ischemic stroke. Results identified an anatomical dissociation in lesion location between subjects with neglect based on poor performance on allocentric tests (line bisection, copying, and drawing tasks) and on egocentric tests (star, letter, and line cancellation). VLSM analyses revealed that poor performance on the allocentric tests was associated with lesions to the superior and inferior parietal cortices, and the superior and middle temporal gyri. In contrast, poor performance on the egocentric tests was associated with lesions in the precentral gyrus, middle frontal gyrus, insula, and putamen. Interestingly, the letter cancellation test and average performance on egocentric tests were associated with frontal and parietal lesions. Some of these parietal lesion locations overlapped with lesion locations associated with allocentric neglect. These findings are consistent with suggestions that damage to temporal and parietal areas is more associated with allocentric neglect and damage to frontal lobe areas is more associated with egocentric neglect.