Lee B. Reid

Rehabilitation and neuroplasticity in children with unilateral cerebral palsy

Cerebral palsy is a childhood-onset, lifelong neurological disorder that primarily impairs motor function. Unilateral cerebral palsy (UCP), which impairs use of one hand and perturbs bimanual co-ordination, is the most common form of the condition. The main contemporary upper limb rehabilitation strategies for UCP are constraint-induced movement therapy and bimanual intensive therapy. In this Review, we outline the factors that are crucial to the success of motor rehabilitation in children with UCP, including the dose of training, the relevance of training to daily life, the suitability of training to the age and goals of the child, and the ability of the child to maintain close attention to the tasks. Emerging evidence suggests that the first 2 years of life are a critical period during which interventions for UCP could be more effective than in later life. Abnormal brain organization in UCP, and the effects of development on rehabilitation, must also be understood to develop new effective interventions. Therefore, we also consider neuroimaging methods that can provide insight into the neurobiology of UCP and how the condition responds to existing therapies. We discuss how these methods could shape future rehabilitative strategies based on the neurobiology of UCP and the therapy-induced changes seen in the brain.

Interpreting Intervention Induced Neuroplasticity with fMRI: The Case for Multimodal Imaging Strategies.

Direct measurement of recovery from brain injury is an important goal in neurorehabilitation, and requires reliable, objective, and interpretable measures of changes in brain function, referred to generally as “neuroplasticity.” One popular imaging modality for measuring neuroplasticity is task-based functional magnetic resonance imaging (t-fMRI). In the field of neurorehabilitation, however, assessing neuroplasticity using t-fMRI presents a significant challenge. This commentary reviews t-fMRI changes commonly reported in patients with cerebral palsy or acquired brain injuries, with a focus on studies of motor rehabilitation, and discusses complexities surrounding their interpretations. Specifically, we discuss the difficulties in interpreting t-fMRI changes in terms of their underlying causes, that is, differentiating whether they reflect genuine reorganisation, neurological restoration, compensation, use of preexisting redundancies, changes in strategy, or maladaptive processes. Furthermore, we discuss the impact of heterogeneous disease states and essential t-fMRI processing steps on the interpretability of activation patterns. To better understand therapy-induced neuroplastic changes, we suggest that researchers utilising t-fMRI consider concurrently acquiring information from an additional modality, to quantify, for example, haemodynamic differences or microstructural changes. We outline a variety of such supplementary measures for investigating brain reorganisation and discuss situations in which they may prove beneficial to the interpretation of t-fMRI data.

Motor pathway degeneration in young ataxia telangiectasia patients: A diffusion tractography study.

Background Our understanding of the effect of ataxia–telangiectasia mutated gene mutations on brain structure and function is limited. In this study, white matter motor pathway integrity was investigated in ataxia telangiectasia patients using diffusion MRI and probabilistic tractography. Methods Diffusion MRI were obtained from 12 patients (age range: 7–22 years, mean: 12 years) and 12 typically developing age matched participants (age range 8–23 years, mean: 13 years). White matter fiber tracking and whole tract statistical analyses were used to assess quantitative fractional anisotropy and mean diffusivity differences along the cortico-ponto-cerebellar, cerebellar-thalamo-cortical, somatosensory and lateral corticospinal tract length in patients using a linear mixed effects model. White matter tract streamline number and apparent fiber density in patient and control tracts were also assessed. Results Reduced fractional anisotropy along all analyzed patient tracts were observed (p < 0.001). Mean diffusivity was significantly elevated in anterior tract locations but was reduced within cerebellar peduncle regions of all patient tracts (p < 0.001). Reduced tract streamline number and tract volume in the left and right corticospinal and somatosensory tracts were observed in patients (p < 0.006). In addition, reduced apparent fiber density in the left and right corticospinal and right somatosensory tracts (p < 0.006) occurred in patients. Conclusions Whole tract analysis of the corticomotor, corticospinal and somatosensory pathways in ataxia telangiectasia showed significant white matter degeneration along the entire length of motor circuits, highlighting that ataxia–telangiectasia gene mutation impacts the cerebellum and multiple other motor circuits in young patients.

Surface-Based fMRI-Driven Diffusion Tractography in the Presence of Significant Brain Pathology: A Study Linking Structure and Function in Cerebral Palsy.

Diffusion MRI (dMRI) tractography analyses are difficult to perform in the presence of brain pathology. Automated methods that rely on cortical parcellation for structural connectivity studies often fail, while manually defining regions is extremely time consuming and can introduce human error. Both methods also make assumptions about structure-function relationships that may not hold after cortical reorganisation. Seeding tractography with functional-MRI (fMRI) activation is an emerging method that reduces these confounds, but inherent smoothing of fMRI signal may result in the inclusion of irrelevant pathways. This paper describes a novel fMRI-seeded dMRI-analysis pipeline based on surface-meshes that reduces these issues and utilises machine-learning to generate task specific white matter pathways, minimising the requirement for manually-drawn ROIs. We directly compared this new strategy to a standard voxelwise fMRI-dMRI approach, by investigating correlations between clinical scores and dMRI metrics of thalamocortical and corticomotor tracts in 31 children with unilateral cerebral palsy. The surface-based approach successfully processed more participants (87%) than the voxel-based approach (65%), and provided significantly more-coherent tractography. Significant correlations between dMRI metrics and five clinical scores of function were found for the more superior regions of these tracts. These significant correlations were stronger and more frequently found with the surface-based method (15/20 investigated were significant; R2 = 0.43–0.73) than the voxelwise analysis (2 sig. correlations; 0.38 & 0.49). More restricted fMRI signal, better-constrained tractography, and the novel track-classification method all appeared to contribute toward these differences.

Brain changes following four weeks of unimanual motor training: Evidence from behavior, neural stimulation, cortical thickness, and functional MRI

Although different aspects of neuroplasticity can be quantified with behavioral probes, brain stimulation, and brain imaging assessments, no study to date has combined all these approaches into one comprehensive assessment of brain plasticity. Here, 24 healthy right‐handed participants practiced a sequence of finger‐thumb opposition movements for 10 min each day with their left hand. After 4 weeks, performance for the practiced sequence improved significantly (P < 0.05 FWE) relative to a matched control sequence, with both the left (mean increase: 53.0% practiced, 6.5% control) and right (21.0%; 15.8%) hands. Training also induced significant (cluster p‐FWE < 0.001) reductions in functional MRI activation for execution of the trained sequence, relative to the control sequence. These changes were observed as clusters in the premotor and supplementary motor cortices (right hemisphere, 301 voxel cluster; left hemisphere 700 voxel cluster), and sensorimotor cortices and superior parietal lobules (right hemisphere 864 voxel cluster; left hemisphere, 1947 voxel cluster). Transcranial magnetic stimulation over the right (“trained”) primary motor cortex yielded a 58.6% mean increase in a measure of motor evoked potential amplitude, as recorded at the left abductor pollicis brevis muscle. Cortical thickness analyses based on structural MRI suggested changes in the right precentral gyrus, right post central gyrus, right dorsolateral prefrontal cortex, and potentially the right supplementary motor area. Such findings are consistent with LTP‐like neuroplastic changes in areas that were already responsible for finger sequence execution, rather than improved recruitment of previously nonutilized tissue. Hum Brain Mapp 38:4773–4787, 2017.

White matter integrity in dyskinetic cerebral palsy: Relationship with intelligence quotient and executive function

Background Dyskinetic cerebral palsy (CP) is one of the most disabling motor types of CP and has been classically associated with injury to the basal ganglia and thalamus. Although cognitive dysfunction is common in CP, there is a paucity of published quantitative analyses investigating the relationship between white matter (WM) microstructure and cognition in this CP type. Aims This study aims (1) to compare brain WM microstructure between people with dyskinetic CP and healthy controls, (2) to identify brain regions where WM microstructure is related to intelligence and (3) to identify brain regions where WM microstructure is related to executive function in people with dyskinetic CP and (4) to identify brain regions where the correlations are different between controls and people with CP in IQ and executive functions. Patients and methods Thirty-three participants with dyskinetic CP (mean ± SD age: 24.42 ± 12.61, 15 female) were age and sex matched with 33 controls. Participants underwent a comprehensive neuropsychological battery to assess intelligence quotient (IQ) and four executive function domains (attentional control, cognitive flexibility, goal setting and information processing). Diffusion weighted MRI scans were acquired at 3T. Voxel-based whole brain groupwise analyses were used to compare fractional anisotropy (FA) and of the CP group to the matched controls using a general lineal model. Further general linear models were used to identify regions where white matter FA correlated with IQ and each of the executive function domains. Results White matter FA was significantly reduced in the CP group in all cerebral lobes, predominantly in regions connected with the parietal and to a lesser extent the temporal lobes. There was no significant correlation between IQ or any of the four executive function domains and WM microstructure in the control group. In participants with CP, lower IQ was associated with lower FA in all cerebral lobes, predominantly in locations that also showed reduced FA compared to controls. Attentional control, goal setting and information processing did not correlate with WM microstructure in the CP group. Cognitive flexibility was associated with FA in regions known to contain connections with the frontal lobe (such as the superior longitudinal fasciculus and cingulum) as well as regions not known to contain tracts directly connected with the frontal lobe (such as the posterior corona radiata, posterior thalamic radiation, retrolenticular part of internal capsule, tapetum, body and splenium of corpus callosum). Conclusion The widespread loss in the integrity of WM tissue is mainly located in the parietal lobe and related to IQ in dyskinetic CP. Unexpectedly, executive functions are only related with WM microstructure in regions containing fronto-cortical and posterior cortico-subcortical pathways, and not being specifically related to the state of fronto-striatal pathways which might be due to brain reorganization. Further studies of this nature may improve our understanding of the neurobiological bases of cognitive impairments after early brain insult.

Measuring neuroplasticity associated with cerebral palsy rehabilitation: an MRI based power analysis

Researchers in the field of child neurology are increasingly looking to supplement clinical trials of motor rehabilitation with neuroimaging in order to better understand the relationship between behavioural training, brain changes, and clinical improvements. Randomised controlled trials are typically accompanied by sample size calculations to detect clinical improvements but, despite the large cost of neuroimaging, not equivalent calculations for concurrently acquired imaging neuroimaging measures of changes in response to intervention. To aid in this regard, a power analysis was conducted for two measures of brain changes that may be indexed in a trial of rehabilitative therapy for cerebral palsy: cortical thickness of the impaired primary sensorimotor cortex, and fractional anisotropy of the impaired, delineated corticospinal tract. Power for measuring fractional anisotropy was assessed for both region‐of‐interest‐seeded and fMRI‐seeded diffusion tractography. Taking into account practical limitations, as well as data loss due to behavioural and image‐processing issues, estimated required participant numbers were 101, 128 and 59 for cortical thickness, region‐of‐interest‐based tractography, and fMRI‐seeded tractography, respectively. These numbers are not adjusted for study attrition. Although these participant numbers may be out of reach of many trials, several options are available to improve statistical power, including careful preparation of participants for scanning using mock simulators, careful consideration of image processing options, and enrolment of as homogeneous a cohort as possible. This work suggests that smaller and moderate sized studies give genuine consideration to harmonising scanning protocols between groups to allow the pooling of data.

Brain Changes Following Four Weeks of Unimanual Motor Training: Evidence From fMRI-Guided Diffusion MRI Tractography

We have reported reliable changes in behavior, brain structure, and function in 24 healthy right‐handed adults who practiced a finger‐thumb opposition sequence task with their left hand for 10 min daily, over 4 weeks. Here, we extend these findings by using diffusion MRI to investigate white‐matter changes in the corticospinal tract, basal‐ganglia, and connections of the dorsolateral prefrontal cortex. Twenty‐three participant datasets were available with pre‐training and post‐training scans. Task performance improved in all participants (mean: 52.8%, SD: 20.0%; group P < 0.01 FWE) and widespread microstructural changes were detected across the motor system of the “trained” hemisphere. Specifically, region‐of‐interest‐based analyses of diffusion MRI (n = 22) revealed significantly increased fractional anisotropy (FA) in the right caudate nucleus (4.9%; P < 0.05 FWE), and decreased mean diffusivity in the left nucleus accumbens (−1.3%; P < 0.05 FWE). Diffusion MRI tractography (n = 22), seeded by sensorimotor cortex fMRI activation, also revealed increased FA in the right corticospinal tract (mean 3.28%; P < 0.05 FWE) predominantly reflecting decreased radial diffusivity. These changes were consistent throughout the entire length of the tract. The left corticospinal tract did not show any changes. FA also increased in white matter connections between the right middle frontal gyrus and both right caudate nucleus (17/22 participants; P < 0.05 FWE) and right supplementary motor area (18/22 participants; P < 0.05 FWE). Equivalent changes in FA were not seen in the left (non‐trained) hemisphere. In combination with our functional and structural findings, this study provides detailed, multifocal evidence for widespread neuroplastic changes in the human brain resulting from motor training. Hum Brain Mapp 38:4302–4312, 2017.

Structural and functional brain changes following four weeks of unimanual motor training: evidence from fMRI-guided diffusion MRI tractography

We have reported reliable changes in behaviour, brain structure and function in 24 healthy right-handed adults who practiced a finger-thumb opposition sequence task with their left hand for 10 mins daily, over four weeks. Here we extend these findings by employing diffusion MRI to investigate white-matter changes in the corticospinal tract, basal-ganglia, and connections of the dorsolateral prefrontal cortex. Twenty-three participant datasets were available with pre-training and post-training scans. Task performance improved in all participants (mean: 52.8%, SD: 20.0%; group p<0.01 FWE) and widespread microstructural changes were detected across the motor system of the ‘trained’ hemisphere. Specifically, region-of-interest based analyses of diffusion MRI (n=21) revealed significantly increased fractional anisotropy in the right caudate nucleus (4.9%; p<0.05 FWE), and decreased mean diffusivity in the left nucleus accumbens (-1.3%; p<0.05 FWE). Diffusion MRI tractography (n=22), seeded by sensorimotor cortex fMRI activation, also revealed increased fractional anisotropy in the right corticomotor tract (mean 3.28%; p<0.05 FWE) predominantly reflecting decreased radial diffusivity. These changes were consistent throughout the entire length of the tract. The left corticomotor tract did not show any changes. FA also increased in white matter connections between the right middle frontal gyrus and both right caudate nucleus (17/22 participants; p<0.05 FWE) and right supplementary motor area (18/22 participants; p<0.05 FWE). Equivalent changes in FA were not seen in the left (‘non-trained’) hemisphere. In combination with our functional and structural findings, this study provides detailed, multifocal evidence for widespread neuroplastic changes in the human brain resulting from motor training.

Structural and functional brain changes following four weeks of unimanual motor training: evidence from behaviour, neural stimulation, cortical thickness and functional MRI

Although different aspects of neuroplasticity can be quantified with behavioural probes, brain stimulation, and brain imaging assessments, no study to date has combined all these approaches into one comprehensive assessment of brain plasticity. Here, 24 healthy right-handed participants practised a sequence of finger-thumb opposition movements for 10 minutes each day with their left hand. After four weeks, performance for the practised sequence improved significantly (p < 0.05 FWE) relative to a matched control sequence, with both the left (mean increase: 53.0% practised, 6.5% control) and right (21.0%; 15.8%) hands. Training also induced significant (cluster p-FWE < 0.001) reductions in functional MRI activation for execution of the learned sequence, relative to the control sequence. These changes were observed as clusters in the premotor and supplementary motor cortices (right hemisphere, 301 voxel cluster; left hemisphere 700 voxel cluster), as well as sensorimotor cortices and superior parietal lobules (right hemisphere 864 voxel cluster; left hemisphere, 1947 voxel cluster). Transcranial magnetic stimulation over the right (‘trained’) primary motor cortex yielded a 58.6% mean increase in a measure of motor evoked potential amplitude, as recorded at the left abductor pollicis brevis muscle. Cortical thickness analyses based on structural MRI suggested changes in the right precentral gyrus, right post central gyrus, right dorsolateral prefrontal cortex and potentially the right supplementary motor area. Such findings are consistent with LTP-like neuroplastic changes in areas that were already responsible for finger sequence execution, rather than improved recruitment of previously non-utilised tissue.