Observational Study of Neuroimaging Biomarkers of Severe Upper Limb Impairment After Stroke.

BACKGROUND AND OBJECTIVES: It is difficult to predict post-stroke outcome for people with severe motor impairment, as 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 impairment post-stroke by evaluating white matter microstructure in the corpus callosum (CC). In an international, multisite hypothesis-generating observational study we determined if: a) CST asymmetry index can differentiate between individuals with mild-moderate and severe upper limb impairment; and b) CC biomarkers relate to upper limb impairment within individuals with severe impairment post-stroke. We hypothesised that CST asymmetry index would differentiate between mild-moderate and severe impairment, but CC microstructure would relate to motor outcome for individuals with severe upper limb 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-effect regression explored relationships between candidate biomarkers and motor impairment, controlling for observations nested within cohorts, as well as age, sex, time post-stroke and lesion volume. RESULTS: Data from 110 individuals (30 mild-moderate, 80 with severe motor impairment) were included. In the full sample, greater CST asymmetry index (i.e., lower fractional anisotropy in the ipsilesional hemisphere, p<.001) and larger lesion volume (p=.139) were negatively related to impairment. In the severe subgroup, CST asymmetry index was not reliably associated with impairment across models. Instead, lesion volume and CC microstructure explained impairment in the severe group beyond CST asymmetry index (p's<.010). CONCLUSIONS: Within a large cohort of individuals with severe upper limb impairment, CC microstructure related to motor outcome post-stroke. Our findings demonstrate that CST microstructure does relate to upper limb 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 upper limb outcome post-stroke, which may advance our ability to predict recovery in people with severe motor impairment after stroke.

Comparing CST Lesion Metrics as Biomarkers for Recovery of Motor and Proprioceptive Impairments 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.

Errors in proprioceptive matching post-stroke are associated with impaired recruitment of parietal, supplementary motor, and temporal cortices.

Deficits in proprioception, the ability to discriminate the relative position and movement of our limbs, affect ~50% of stroke patients and reduce functional outcomes. Our lack of knowledge of the anatomical correlates of proprioceptive processing limits our understanding of the impact that such deficits have on recovery. This research investigated the relationship between functional impairment in brain activity and proprioception post-stroke. We developed a novel device and task for arm position matching during functional MRI (fMRI), and investigated 16 subjects with recent stroke and nine healthy age-matched controls. The stroke-affected arm was moved by an experimenter (passive arm), and subjects were required to match the position of this limb with the opposite arm (active arm). Brain activity during passive and active arm movements was determined, as well as activity in association with performance error. Passive arm movement in healthy controls was associated with activity in contralateral primary somatosensory (SI) and motor cortices (MI), bilateral parietal cortex, supplementary (SMA) and premotor cortices, secondary somatosensory cortices (SII), and putamen. Active arm matching was associated with activity in contralateral SI, MI, bilateral SMA, premotor cortex, putamen, and ipsilateral cerebellum. In subjects with stroke, similar patterns of activity were observed. However, in stroke subjects, greater proprioceptive error was associated with less activity in ipsilesional supramarginal and superior temporal gyri, and lateral thalamus. During active arm movement, greater proprioceptive error was associated with less activity in bilateral SMA and ipsilesional premotor cortex. Our results enhance our understanding of the correlates of proprioception within the temporal parietal cortex and supplementary/premotor cortices. These findings also offer potential targets for therapeutic intervention to improve proprioception in recovering stroke patients and thus improve functional outcome.

Proprioception and motor performance after stroke: An examination of diffusion properties in sensory and motor pathways.

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 and r = -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.

Lesion locations associated with persistent proprioceptive impairment in the upper limbs after stroke.

Proprioceptive deficits are common after stroke and have been associated with poorer recovery. Relatively little is known about the brain regions beyond primary somatosensory cortex that contribute to the percept of proprioception in humans. We examined a large sample (n = 153) of stroke survivors longitudinally to determine which brain regions were associated with persistent post-stroke proprioceptive deficits. A robotic exoskeleton quantified two components of proprioception, position sense and kinesthesia (movement sense), at 2 weeks and again at 6 months post-stroke. A statistical region of interest (sROI) analysis compared the lesion-behaviour relationships of those subjects with cortical and subcortical stroke (n = 136). The impact of damage to brainstem and cerebellum (n = 17) was examined separately. Results indicate that damage to the supramarginal gyrus, the arcuate fasciculus, and Heschl's gyrus are associated with deficits in position sense and kinesthesia at 6 months post-stroke. These results suggest that regions beyond the primary somatosensory cortex contribute to our sense of limb position and movement. This information extends our understanding of proprioceptive processing and may inform personalized interventions such as non-invasive brain stimulation where specific brain regions can be targeted to potentially improve stroke recovery.

Differential Impact of Acute Lesions Versus White Matter Hyperintensities on Stroke Recovery.

Background Understanding how the size of acute lesions and white matter hyperintensities ( WMH ) impact stroke recovery can improve our ability to predict outcomes and tailor treatments. The aim of this exploratory study was to investigate the role of acute lesion volume and WMH volume on longitudinal recovery of specific sensory, motor, and cognitive impairments after stroke using robotic and clinical measures. Methods and Results Eighty-two individuals were assessed at 1, 6, 12, and 26 weeks poststroke with robotic tasks and commonly used clinical measures. The volumes of acute lesions and WMH were measured on fluid-attenuated inversion recovery images. Linear mixed models were used to investigate the role of acute lesions and WMH on parameters derived from the robotic tasks and clinical measures. Regression analysis determined the added value of acute lesion and WMH volumes along with measures of initial performance to predict outcomes at 6 months. Acute lesion volume has widespread effects on sensory, motor, and overall functional recovery poststroke. The impact of WMH was specific to cognitive impairments. Apart from the robotic position sense task, neither lesion volume nor WMH measure had significant ability to predict outcomes at 6 months over using initial impairment as measured by robotic assessments alone. Conclusions While acute lesion volume and WMH may impact different impairments poststroke, their clinical utility in predicting outcomes at 6 months poststroke is limited.

Robotic Characterization of Ipsilesional Motor Function in Subacute Stroke.

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.

Upper Extremity Proprioception After Stroke: Bridging the Gap Between Neuroscience and Rehabilitation.

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.

Localization of Impaired Kinesthetic Processing Post-stroke.

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.

Central perception of position sense involves a distributed neural network - Evidence from lesion-behavior analyses.

It is well established that proprioceptive inputs from the periphery are important for the constant update of arm position for perception and guiding motor action. The degree to which we are consciously aware of the position of our limb depends on the task. Our understanding of the central processing of position sense is rather limited, largely based on findings in animals and individual human case studies. The present study used statistical lesion-behavior analysis and an arm position matching task to investigate position sense in a large sample of subjects after acute stroke. We excluded subjects who performed abnormally on clinical testing or a robotic visually guided reaching task with their matching arm in order to minimize the potential confound of ipsilesional impairment. Our findings revealed that a number of regions are important for processing position sense and include the posterior parietal cortex, the transverse temporal gyrus, and the arcuate fasciculus. Further, our results revealed that position sense has dissociable components - spatial variability, perceived workspace area, and perceived workspace location. Each component is associated with unique neuroanatomical correlates. These findings extend the current understanding of the neural processing of position sense and identify some brain areas that are not classically associated with proprioception.

Lesion Sites Associated with Allocentric and Egocentric Visuospatial Neglect in Acute Stroke.

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.

Anatomical correlates of proprioceptive impairments following acute stroke: a case series.

BACKGROUND: Proprioception is the sensation of position and movement of our limbs and body in space. This sense is important for performing smooth coordinated movements and is impaired in approximately 50% of stroke survivors. In the present case series we wanted to determine how discrete stroke lesions to areas of the brain thought to be critical for somatosensation (thalamus, posterior limb of internal capsule, primary somatosensory cortex and posterior parietal cortex) would affect position sense and kinesthesia in the acute stages post-stroke. Given the known issues with standard clinical measures of proprioception (i.e. poor sensitivity and reliability) we used more modern quantitative robotic assessments to measure proprioception. METHODS: Neuroimaging (MRI, n=10 or CT, n=2) was performed on 12 subjects 2-10 days post-stroke. Proprioception was assessed using a KINARM robot within the same time frame. Visually guided reaching was also assessed to allow us to compare and contrast proprioception with visuomotor performance. RESULTS AND CONCLUSIONS: Proprioceptive impairments were observed in 7 of 12 subjects. Thalamic lesions (n=4) were associated with position sense (n=1) or position sense and kinesthesia (n=1) impairments. Posterior limb of the internal capsule lesions (n=4) were associated with primarily position sense (n=1) or kinesthesia (n=2) impairments. Lesions affecting primary somatosensory cortex and posterior parietal cortex (n=2) were associated with significant position sense and kinesthesia impairments. All subjects with damage to hypothesized structures displayed impairments with performance on the visually guided reaching task. Across the proprioceptive tasks, we saw that position sense and kinesthesia were impaired to differing degrees, suggesting a potential dissociation between these two components of proprioception.