Final Report Summary - SEMORE-CP (Identifying structural and functional biomarkers of the brain indicating SensoriMotor Recovery in Cerebral Palsy)
Cerebral palsy (CP) is caused by a non-progressive lesion of the developing fetal or infant brain and is by far the most common physical disability during childhood. Irrespective of the severity of the disability, children with CP experience lifelong impairments of motor and sensory functions that restrict their independence and put a high emotional and financial burden on families, caretakers and society. It is currently believed that early treatment is key to minimize long-term disability and maximize the child’s functional potential. The challenge is to provide treatment tailored to the specific brain damage of the child, which is known to be highly heterogeneous and determines how he or she can recover best. Brain lesions range from relatively localized damage to the motor pathways to severe malformations typically seen when the incident occurs during the first months of pregnancy. At these early stages of development the brain is still highly plastic, which permits alterations from the pre-programmed pathway of brain organization. As a result, the final “wiring” of the sensorimotor system might deviate from that expected, a phenomenon that is unique to unilateral CP (38% of the CP population). If the pattern and extent of “re-wiring” can be identified, it may offer clinical utility.
The overall goal of this project is to identify neural biomarkers predicting sensorimotor dysfunction in children and adolescents with unilateral CP (age 7-25 years), with specific emphasis on developing methods that can be easily acquired and shared across multiple clinical sites. The working hypothesis is that the initial brain damage and concurrent structural reorganization of the sensorimotor system (and most notably the corticospinal tract, CST) form a primary source of variability amongst children with unilateral CP, and that this (re)wiring constrains the maximal functional potential that can theoretically be reached. See here for a video describing the project: http://www.ncm.hest.ethz.ch/the-group/team/ellen-jaspers.html).
The identification of biomarkers of the sensorimotor network was investigated based on structural and functional connectivity analyses. A first biomarker that was explored was the occurrence of mirror movements in children with unilateral CP and the relation with underlying brain lesion type and upper limb functional outcome (Jaspers et al., DMCN, 2015; see here for a video describing the main findings: https://youtu.be/JJH_gAdtwnU). This study clearly showed that mirror movements in the paretic and the non-paretic hand are different phenomena, with mirror movements in the paretic hand being more related to the underlying brain lesion. These results, together with the framework that was presented in the hypothesis and theory article (Jaspers et al., Front Pediatrics, 2016) served as the basis for further studies. The development of a grip force tracking device, the GriFT device, allowed the quantitative assessment of mirror movements (Fig. 1). The characterization, feasibility and validity of the GriFT device was based on data collected from 176 typically developing children (Jaspers et al., IEEE Trans Biomed Eng, under review). Based on these data, a normative database was compiled for mirror movement frequency, strength, and temporal features (synchronization and time lag). To further assess the value of mirror movements with respect to the sensorimotor (CST) wiring pattern, mirror movement data, transcranial magnetic stimulation (TMS) and/or MRI were performed in 56 children and adolescents with unilateral CP (age 7-23 years). This project used both existing clinical databases and prospective data collection in collaboration with the Pediatric Research Group of the Department of Rehabilitation Sciences (KU Leuven, Belgium).
Single pulse TMS over the hand area of the motor cortex in the lesioned and non-lesioned hemisphere is used to elicit a muscle response in the paretic hand of the participant with unilateral CP. With this neurophysiological biomarker, the CST wiring pattern can be categorized based on whether a muscle response in the paretic hand can be elicited from the lesioned hemisphere only (contralateral wiring), from the non-lesioned hemisphere only (pure ipsilateral wiring) or from both hemispheres (bilateral wiring) (Fig. 2). The MRI-protocols included T1/T2-weighted imaging, Diffusion Kurtosis Imaging (DKI), and resting-state functional MRI (rs-fMRI).
The comparison of mirror movements between unilateral CP (n=44, age 7-23 years) and typically developing children showed a clear distinction between “pathological” and “physiological” mirror movements. Mirror movement characteristics were then used to categorize participants with unilateral CP into three groups, based on mirror movement amount and synchronization in the paretic hand. To assess the value of this categorization, its sensitivity and specificity was calculated with respect to the CST wiring pattern as measured with TMS. First results have shown that the mirror movement assessment proved highly discriminative regarding the CST wiring pattern. We hypothesize that knowledge of the structural integrity of the CST might help to further dissociate ipsilateral vs. bilateral CST-wiring patterns.
To assess structural integrity of the CST, we used a novel T1/T2-contrast method (“Myelin Enhanced Contrast” (MEC) method) and diffusion analyses based on DKI. The MEC-method constitutes a sensitive tool for quantifying structural connectivity based on white matter tissue. These calculations were performed in 50 participants with unilateral CP. Current analyses focus on improving the normalization procedure and concurrent segmentation of regions of interest. Diffusion imaging analyses was performed in 40 participants with unilateral CP, with specific focus on diffusion measures such as fractional anisotropy and mean diffusivity at the level of the posterior limb of the internal capsule. This region of interest was manually segmented in both the lesioned and non-lesioned hemisphere and current analyses focuses on its added value as a biomarker to predict the CST wiring pattern.
The investigation of functional connectivity of the sensorimotor maps was based on resting-state fMRI. A new method and analysis pipeline was first developed to create probability maps to reflect the general organization principles of the brain, while taking into account inter-subject variability, which is known to be especially heterogeneous in CP. This analysis pipeline was tested using resting state data of 200 healthy controls and the resulting probability maps of the corticostriatal fingerprint have been published (Jaspers et al., HBM, 2016). The connectivity probability maps will also be calculated using resting state data of 400 typically developing children to identify age-related changes in the probability maps. Next, results will be compared to resting state data in children and adolescents with unilateral CP to identify alterations in the sensorimotor resting-state network in CP and how these alterations are related to sensorimotor function (data collection ongoing).
With this project, I have taken the first crucial steps in the identification of clinically relevant neural biomarkers that go beyond the traditional clinical assessments and that allow categorizing children based on their corticospinal tract wiring pattern. Such categorization will pave the road for larger multicenter clinical trials necessary to determine how sensorimotor rehabilitation can be tailored to the needs of the individual with CP (the science story of this project can be found here: https://youtu.be/1pmPwQfvqs0).
The overall goal of this project is to identify neural biomarkers predicting sensorimotor dysfunction in children and adolescents with unilateral CP (age 7-25 years), with specific emphasis on developing methods that can be easily acquired and shared across multiple clinical sites. The working hypothesis is that the initial brain damage and concurrent structural reorganization of the sensorimotor system (and most notably the corticospinal tract, CST) form a primary source of variability amongst children with unilateral CP, and that this (re)wiring constrains the maximal functional potential that can theoretically be reached. See here for a video describing the project: http://www.ncm.hest.ethz.ch/the-group/team/ellen-jaspers.html).
The identification of biomarkers of the sensorimotor network was investigated based on structural and functional connectivity analyses. A first biomarker that was explored was the occurrence of mirror movements in children with unilateral CP and the relation with underlying brain lesion type and upper limb functional outcome (Jaspers et al., DMCN, 2015; see here for a video describing the main findings: https://youtu.be/JJH_gAdtwnU). This study clearly showed that mirror movements in the paretic and the non-paretic hand are different phenomena, with mirror movements in the paretic hand being more related to the underlying brain lesion. These results, together with the framework that was presented in the hypothesis and theory article (Jaspers et al., Front Pediatrics, 2016) served as the basis for further studies. The development of a grip force tracking device, the GriFT device, allowed the quantitative assessment of mirror movements (Fig. 1). The characterization, feasibility and validity of the GriFT device was based on data collected from 176 typically developing children (Jaspers et al., IEEE Trans Biomed Eng, under review). Based on these data, a normative database was compiled for mirror movement frequency, strength, and temporal features (synchronization and time lag). To further assess the value of mirror movements with respect to the sensorimotor (CST) wiring pattern, mirror movement data, transcranial magnetic stimulation (TMS) and/or MRI were performed in 56 children and adolescents with unilateral CP (age 7-23 years). This project used both existing clinical databases and prospective data collection in collaboration with the Pediatric Research Group of the Department of Rehabilitation Sciences (KU Leuven, Belgium).
Single pulse TMS over the hand area of the motor cortex in the lesioned and non-lesioned hemisphere is used to elicit a muscle response in the paretic hand of the participant with unilateral CP. With this neurophysiological biomarker, the CST wiring pattern can be categorized based on whether a muscle response in the paretic hand can be elicited from the lesioned hemisphere only (contralateral wiring), from the non-lesioned hemisphere only (pure ipsilateral wiring) or from both hemispheres (bilateral wiring) (Fig. 2). The MRI-protocols included T1/T2-weighted imaging, Diffusion Kurtosis Imaging (DKI), and resting-state functional MRI (rs-fMRI).
The comparison of mirror movements between unilateral CP (n=44, age 7-23 years) and typically developing children showed a clear distinction between “pathological” and “physiological” mirror movements. Mirror movement characteristics were then used to categorize participants with unilateral CP into three groups, based on mirror movement amount and synchronization in the paretic hand. To assess the value of this categorization, its sensitivity and specificity was calculated with respect to the CST wiring pattern as measured with TMS. First results have shown that the mirror movement assessment proved highly discriminative regarding the CST wiring pattern. We hypothesize that knowledge of the structural integrity of the CST might help to further dissociate ipsilateral vs. bilateral CST-wiring patterns.
To assess structural integrity of the CST, we used a novel T1/T2-contrast method (“Myelin Enhanced Contrast” (MEC) method) and diffusion analyses based on DKI. The MEC-method constitutes a sensitive tool for quantifying structural connectivity based on white matter tissue. These calculations were performed in 50 participants with unilateral CP. Current analyses focus on improving the normalization procedure and concurrent segmentation of regions of interest. Diffusion imaging analyses was performed in 40 participants with unilateral CP, with specific focus on diffusion measures such as fractional anisotropy and mean diffusivity at the level of the posterior limb of the internal capsule. This region of interest was manually segmented in both the lesioned and non-lesioned hemisphere and current analyses focuses on its added value as a biomarker to predict the CST wiring pattern.
The investigation of functional connectivity of the sensorimotor maps was based on resting-state fMRI. A new method and analysis pipeline was first developed to create probability maps to reflect the general organization principles of the brain, while taking into account inter-subject variability, which is known to be especially heterogeneous in CP. This analysis pipeline was tested using resting state data of 200 healthy controls and the resulting probability maps of the corticostriatal fingerprint have been published (Jaspers et al., HBM, 2016). The connectivity probability maps will also be calculated using resting state data of 400 typically developing children to identify age-related changes in the probability maps. Next, results will be compared to resting state data in children and adolescents with unilateral CP to identify alterations in the sensorimotor resting-state network in CP and how these alterations are related to sensorimotor function (data collection ongoing).
With this project, I have taken the first crucial steps in the identification of clinically relevant neural biomarkers that go beyond the traditional clinical assessments and that allow categorizing children based on their corticospinal tract wiring pattern. Such categorization will pave the road for larger multicenter clinical trials necessary to determine how sensorimotor rehabilitation can be tailored to the needs of the individual with CP (the science story of this project can be found here: https://youtu.be/1pmPwQfvqs0).
