Robotic Rehabilitation and Transcranial Direct Current Stimulation in Children With Bilateral Cerebral Palsy.

Aim: To identify challenges of combining robotic upper extremity rehabilitation with tDCS in children with upper extremity bilateral cerebral palsy (CP) by assessing feasibility, tolerability and safety. Methods: This was an unblinded, open-label, pilot clinical trial. Participants completed 10 × 1 h sessions of robotic rehabilitation combined with motor cortex anodal tDCS. Feasibility, acceptability and practicality, were assessed including the number of participants completing the protocol, factors limiting participation, time required for sessions, and completion of functional assessments and tolerability scales. To assess safety, standardized clinical and robotic measures of sensorimotor function were performed. The trial was registered at clinicaltrials.gov (NCT04233710). Results: Eight children were recruited (mean age 8y ± 1.8y, range 6-11 years) and 5 completed the intervention. There were no serious adverse events. One child developed focal seizures 6 weeks after the trial that were deemed to be unrelated. Barriers to completion included time and scheduling demands and patient factors, specifically cognitive/behavioral impairments and dyskinesia. No decline in clinical function was appreciated. Conclusions: Robotic upper extremity rehabilitation combined with tDCS may be feasible in children with bilateral CP. Careful participant selection, family engagement, and protocol adaptations are recommended to better understand the feasibility and tolerability of future trials.

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.

Recovery after stroke: the severely impaired are a distinct group.

INTRODUCTION: Stroke causes different levels of impairment and the degree of recovery varies greatly between patients. The majority of recovery studies are biased towards patients with mild-to-moderate impairments, challenging a unified recovery process framework. Our aim was to develop a statistical framework to analyse recovery patterns in patients with severe and non-severe initial impairment and concurrently investigate whether they recovered differently. METHODS: We designed a Bayesian hierarchical model to estimate 3-6 months upper limb Fugl-Meyer (FM) scores after stroke. When focusing on the explanation of recovery patterns, we addressed confounds affecting previous recovery studies and considered patients with FM-initial scores <45 only. We systematically explored different FM-breakpoints between severe/non-severe patients (FM-initial=5-30). In model comparisons, we evaluated whether impairment-level-specific recovery patterns indeed existed. Finally, we estimated the out-of-sample prediction performance for patients across the entire initial impairment range. RESULTS: Recovery data was assembled from eight patient cohorts (n=489). Data were best modelled by incorporating two subgroups (breakpoint: FM-initial=10). Both subgroups recovered a comparable constant amount, but with different proportional components: severely affected patients recovered more the smaller their impairment, while non-severely affected patients recovered more the larger their initial impairment. Prediction of 3-6 months outcomes could be done with an R2=63.5% (95% CI=51.4% to 75.5%). CONCLUSIONS: Our work highlights the benefit of simultaneously modelling recovery of severely-to-non-severely impaired patients and demonstrates both shared and distinct recovery patterns. Our findings provide evidence that the severe/non-severe subdivision in recovery modelling is not an artefact of previous confounds. The presented out-of-sample prediction performance may serve as benchmark to evaluate promising biomarkers of stroke recovery.

Investigating the neuroanatomy underlying proprioception using a stroke model.

Neuroanatomical investigations have associated cortical areas, beyond Primary Somatosensory Cortex (S1), with impaired proprioception. Cortical regions have included temporoparietal (TP) regions (supramarginal gyrus, superior temporal gyrus, Heschl's gyrus) and insula. Previous approaches have struggled to account for concurrent damage across multiple brain regions. Here, we used a targeted lesion analysis approach to examine the impact of specific combinations of cortical and sub-cortical lesions and quantified the prevalence of proprioceptive impairments when different regions are damaged or spared. Seventy-seven individuals with stroke (49 male; 28 female) were identified meeting prespecified lesion criteria based on MRI/CT imaging: 1) TP lesions without S1, 2) TP lesions with S1, 3) isolated S1 lesions, 4) isolated insula lesions, and 5) lesions not impacting these regions (other regions group). Initially, participants meeting these criteria (1-4) were grouped together into right or left lesion groups and compared to each other, and the other regions group (5), on a robotic Arm Position Matching (APM) task and a Kinesthesia (KIN) task. We then examined the behaviour of individuals that met each specific criteria (groups 1-5). Proprioceptive impairments were more prevalent following right hemisphere lesions than left hemisphere lesions. The extent of damage to TP regions correlated with performance on both robotic tasks. Even without concurrent S1 lesions, TP and insular lesions were associated with impairments on the APM and KIN tasks. Finally, lesions not impacting these regions were much less likely to result in impairments. This study highlights the critical importance of TP and insular regions for accurate proprioception. SIGNIFICANCE STATEMENT: This work advances our understanding of the neuroanatomy of human proprioception. We validate the importance of regions, beyond the dorsal column medial lemniscal pathway and S1, for proprioception. Further, we provide additional evidence of the importance of the right hemisphere for human proprioception. Improved knowledge on the neuroanatomy of proprioception is crucial for advancing therapeutic approaches which target individuals with proprioceptive impairments following neurological injury or with neurological disorders.

Inhibitory Control Deficits in Children with Tic Disorders Revealed by Object-Hit-and-Avoid Task.

Background: Tic disorders may reflect impaired inhibitory control. This has been evaluated using different behavioural tasks, yielding mixed results. Our objective was to test inhibitory control in children with tics through simultaneous presentation of multiple, mobile stimuli. Methods: Sixty-four children with tics (mean age 12.4 years; 7.5-18.5) were evaluated using a validated robotic bimanual exoskeleton protocol (Kinarm) in an object-hit-and-avoid task, in which target and distractor objects moved across a screen and participants aimed to hit only the targets while avoiding distractors. Performance was compared to 146 typically developing controls (mean age 13 years; 6.1-19.9). The primary outcome was the percentage of distractors struck. Results: ANCOVA (age as covariate) showed participants struck significantly more distractors (participants without comorbid ADHD, 22.71% [SE 1.47]; participants with comorbid ADHD, 23.56% [1.47]; and controls, 15.59% [0.68]). Participants with comorbid ADHD struck significantly fewer targets (119.74 [2.77]) than controls, but no difference was found between participants without comorbid ADHD (122.66 [2.77]) and controls (127.00 [1.28]). Participants and controls did not differ significantly in movement speed and movement area. Just over 20% of participants with tics fell below the age-predicted norm in striking distractors, whereas fewer than 10% fell outside age-predicted norms in other task parameters. Conclusions: In children with tics (without comorbid ADHD), acting upon both targets and distractors suggests reduced ability to suppress responses to potential triggers for action. This may be related to increased sensorimotor noise or abnormal sensory gating.

Unimanual and bimanual motor performance in children with developmental coordination disorder (DCD) provide evidence for underlying motor control deficits.

Much of our understanding of motor control deficits in children with developmental coordination disorder (DCD) comes from upper limb assessments focusing on the dominant limb. Here, using two robotic behavioural tasks, we investigated motor control in both the dominant and non-dominant limbs of children with DCD. Twenty-six children with diagnosed DCD (20 males; mean age 10.6 years ± 1.3 years) and 155 controls were included in this cross-sectional study. Participants completed a visually guided reaching task with their dominant and non-dominant limbs and a bimanual object hitting task. Motor performance was quantified across nine parameters. We determined the number of children with DCD who fell outside of the typical performance range of the controls on these parameters and compared the DCD and control groups using ANCOVAs, accounting for age. Children with DCD demonstrated impairments in six out of nine parameters; deficits were more commonly noted in the non-dominant limb. Interestingly, when looking at individual performance, several children with DCD performed in the range of controls. These findings indicate that children with DCD display deficits in motor control in both the dominant and non-dominant limb and highlight the importance of including detailed assessments of both limbs when investigating children with DCD. They also demonstrate the variability in motor control performance evidenced by children with DCD.

Statistical Considerations for Drawing Conclusions About Recovery.

BACKGROUND: Numerous studies have found associations when change scores are regressed onto initial impairments in people with stroke (slopes ≈ 0.7). However, there are important statistical considerations that limit the conclusions we can draw about recovery from these studies. OBJECTIVE: To provide an accessible checklist of conceptual and analytical issues on longitudinal measures of stroke recovery. Proportional recovery is an illustrative example, but these considerations apply broadly to studies of change over time. METHODS: Using a pooled data set of n = 373 Fugl-Meyer Assessment upper extremity scores, we ran simulations to illustrate 3 considerations: (1) how change scores can be problematic in this context; (2) how "nil" and nonzero null-hypothesis significance tests can be used; and (3) how scale boundaries can create the illusion of proportionality, whereas other analytical procedures (eg, post hoc classifications) can augment this problem. RESULTS: Our simulations highlight several limitations of common methods for analyzing recovery. We find that uniform recovery leads to similar group-level statistics (regression slopes) and individual-level classifications (into fitters and nonfitters) that have been claimed as evidence for the proportional recovery rule. New analyses, however, also speak to the complexities in variance about the regression slope. CONCLUSIONS: Our results highlight that one cannot identify whether proportional recovery is true or not based on commonly used methods. We illustrate how these techniques, measurement tools, and post hoc classifications (eg, nonfitters) can create spurious results. Going forward, the field needs to carefully consider the influence of these factors on how we measure, analyze, and conceptualize recovery.

Robotic assessment of rapid motor decision making in children with perinatal stroke.

BACKGROUND: Activities of daily living frequently require children to make rapid decisions and execute desired motor actions while inhibiting unwanted actions. Children with hemiparetic cerebral palsy due to perinatal stroke may have deficits in executive functioning in addition to motor impairments. The objective of this study was to use a robotic object hit and avoid task to assess the ability of children with hemiparetic cerebral palsy to make rapid motor decisions. METHODS: Forty-five children with hemiparetic cerebral palsy due to perinatal stroke and 146 typically developing children (both groups ages 6-19 years) completed a robotic object hit and avoid task using the Kinarm Exoskeleton. Objects of different shapes fell from the top of the screen with increasing speed and frequency. Children were instructed to hit two specific target shapes with either hand, while avoiding six distractor shapes. The number of targets and distractors hit were compared between children with hemiparetic cerebral palsy and typically developing children, accounting for age effects. We also compared performance to a simpler object hit task where there were no distractors. RESULTS: We found that children with hemiparetic cerebral palsy hit a greater proportion of total distractors compared to typically developing children, demonstrating impairments in inhibitory control. Performance for all children improved with age. Children with hemiparetic cerebral palsy hit a greater percentage of targets with each arm on the more complex object hit and avoid task compared to the simpler object hit task, which was not found in typically developing children. CONCLUSIONS: Children with hemiparetic cerebral palsy due to perinatal stroke demonstrated impairments in rapid motor decision making including inhibitory control, which can impede their ability to perform real-world tasks. Therapies that address both motor performance and executive functions are necessary to maximize function in children with hemiparetic cerebral palsy.

Assessment of Sex Differences in Recovery of Motor and Sensory Impairments Poststroke.

Background. Understanding potential sex differences in stroke recovery is important for prognosis, ensuring appropriate allocation of health care resources, and for stratification in research studies. Previously, functional measures have shown poorer outcomes for females, however, little is known about sex differences that may exist in specific motor and sensory impairments. Objective. The aim of this study was to utilize robotic assessments of motor and sensory impairments to determine if there are sex differences at the impairment level in stroke recovery over the first 6 months poststroke. Methods. We used robotic and clinical assessments of motor and sensory impairments at 1, 6, 12, and 26 weeks poststroke in 108 males and 52 females. Linear mixed models were used to examine the effect of sex on recovery poststroke, controlling for age and lesion volume. Results. In general, we did not find significant sex differences across a range of assessments. The exception to this was a sex × age interaction for the Purdue Pegboard Assessment, where we found that females had better performance than males at younger ages (<62 years), but males had better performance at older ages. Conclusions. While recruitment biases need to be acknowledged when generalizing our results to stroke recovery at-large, our results suggest that sex differences do not exist at the impairment level poststroke.

Bringing proportional recovery into proportion: Bayesian modelling of post-stroke motor impairment.

Accurate predictions of motor impairment after stroke are of cardinal importance for the patient, clinician, and healthcare system. More than 10 years ago, the proportional recovery rule was introduced by promising that high-fidelity predictions of recovery following stroke were based only on the initially lost motor function, at least for a specific fraction of patients. However, emerging evidence suggests that this recovery rule is subject to various confounds and may apply less universally than previously assumed. Here, we systematically revisited stroke outcome predictions by applying strategies to avoid confounds and fitting hierarchical Bayesian models. We jointly analysed 385 post-stroke trajectories from six separate studies-one of the largest overall datasets of upper limb motor recovery. We addressed confounding ceiling effects by introducing a subset approach and ensured correct model estimation through synthetic data simulations. Subsequently, we used model comparisons to assess the underlying nature of recovery within our empirical recovery data. The first model comparison, relying on the conventional fraction of patients called 'fitters', pointed to a combination of proportional to lost function and constant recovery. 'Proportional to lost' here describes the original notion of proportionality, indicating greater recovery in case of a more severe initial impairment. This combination explained only 32% of the variance in recovery, which is in stark contrast to previous reports of >80%. When instead analysing the complete spectrum of subjects, 'fitters' and 'non-fitters', a combination of proportional to spared function and constant recovery was favoured, implying a more significant improvement in case of more preserved function. Explained variance was at 53%. Therefore, our quantitative findings suggest that motor recovery post-stroke may exhibit some characteristics of proportionality. However, the variance explained was substantially reduced compared to what has previously been reported. This finding motivates future research moving beyond solely behaviour scores to explain stroke recovery and establish robust and discriminating single-subject predictions.

Assessment of bilateral motor skills and visuospatial attention in children with perinatal stroke using a robotic object hitting task.

BACKGROUND: While motor deficits are the hallmark of hemiparetic cerebral palsy, children may also experience impairments in visuospatial attention that interfere with participation in complex activities, including sports or driving. In this study, we used a robotic object hitting task to assess bilateral sensorimotor control and visuospatial skills in children with hemiparesis due to perinatal arterial ischemic stroke (AIS) or periventricular venous infarct (PVI). We hypothesized that performance would be impaired bilaterally and be related to motor behavior and clinical assessment of visuospatial attention. METHODS: Forty-nine children with perinatal stroke and hemiparetic cerebral palsy and 155 typically developing (TD) children participated in the study. Participants performed a bilateral object hitting task using the KINARM Exoskeleton Robot, in which they used virtual paddles at their fingertips to hit balls that fell from the top of the screen with increasing speed and frequency over 2.3 min. We quantified performance across 13 parameters including number of balls hit with each hand, movement speed and area, biases between hands, and spatial biases. We determined normative ranges of performance accounting for age by fitting 95% prediction bands to the TD children. We compared parameters between TD, AIS, and PVI groups using ANCOVAs accounting for age effects. Lastly, we performed regression analysis between robotic and clinical measures. RESULTS: The majority of children with perinatal stroke hit fewer balls with their affected arm compared to their typically developing peers. We also found deficits with the ipsilesional ("unaffected") arm. Children with AIS had greater impairments than PVI. Despite hitting fewer balls, we only identified 18% of children as impaired in hand speed or movement area. Performance on the Behavioral Inattention Test accounted for 21-32% of the variance in number of balls hit with the unaffected hand. CONCLUSIONS: Children with perinatal stroke-induced hemiparetic cerebral palsy may have complex bilateral deficits reflecting a combination of impairments in motor skill and visuospatial attention. Clinical assessments and interventions should address the interplay between motor and visuospatial skills.

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.

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.

Development of a method to quantify inter-limb coupling in individuals with hemiparetic stroke.

A common motor deficit in individuals post-stroke is altered interlimb coupling. Efforts at one extremity can cause involuntary muscle activity and movement at a different extremity. An important step in understanding interlimb coupling and developing effective treatment strategies is to have an accurate quantification of the motor behavior. This paper outlines the development of an approach to measure interlimb coupling between the upper and lower extremity. Isometric and EMG based approaches were explored before determining that the use of a haptic robotic system was ideal to quantify altered interlimb coupling. This is a novel engineering approach that can measure biomechanical parameters while avoiding confounding factors. Preliminary evidence shows that lower extremity efforts cause involuntary movement in the upper extremity in stereotypical flexion and extension patterns.

Assessment of the contralesional corticospinal tract in early-onset pediatric hemiplegia: Preliminary findings.

While pediatric hemiplegia results from a unilateral lesion, the immature state of the brain at the time of injury increases the likelihood of observing changes in the non-lesioned hemisphere as well. The purpose of this preliminary study was to use diffusion tensor imaging to evaluate the contralesional corticospinal tracts in individuals with early-onset pediatric hemiplegia. Twelve individuals with pediatric hemiplegia and ten age-matched controls underwent diffusion tensor imaging (DTI). Corticospinal projections were reconstructed using probabilistic tractography for both the lesioned and contralesional side in pediatric hemiplegia as well as the dominant and non-dominant sides in control subjects. The contralesional tract was found to have decreased white matter integrity relative to control subjects. Compared to controls, the contralesional tract also showed increased tract volume. The increase in volume suggests the presence of ipsilateral corticospinal projections from the contralesional hemisphere that are maintained during development to control the paretic extremities. Decreases in integrity may be explained by diffuse damage or incomplete maturation. The findings of this study support the notion of bilateral motor involvement in pediatric hemiplegia, and the need to address bilateral neural changes as well as motor deficits in this population.

The effect of injury timing on white matter changes in the corpus callosum following unilateral brain injury.

Motor impairments following unilateral brain injuries may be related to changes in the corpus callosum. The purpose of this study was to determine if the corpus callosum is impacted differently in pediatric versus adult hemiplegia. Diffusion tensor imaging was completed on 41 participants (11 pediatric hemiplegia, 10 adult hemiplegia, 10 pediatric control and 10 adult control). Fractional anisotropy values and cross-sectional areas for five regions of the corpus callosum were compared between subject groups. Additionally, the amount of involuntary activity in the paretic elbow was quantified during non-paretic elbow flexion tasks for a subset of pediatric hemiplegia participants. Fractional anisotropy values were reduced in pediatric hemiplegia compared to pediatric control subjects in callosal regions corresponding to premotor and supplementary motor areas, primary sensory cortex, and parietal, temporal, and occipital cortices. Differences in fractional anisotropy between adult stroke and adult controls were only found in the region corresponding to parietal, temporal, and occipital cortices. Cross-sectional area was affected in all regions of the corpus callosum in pediatric hemiplegia, but only in the primary sensory region in adult hemiplegia. Additionally, changes in the cross-sectional areas were correlated with involuntary mirror movements in the pediatric hemiplegia group. In conclusion, the corpus callosum is affected to a greater extent in pediatric compared to adult hemiplegia, which may explain why unsuppressed mirror movements and difficulty with bimanual coordination are greater problems in this population.