Paper Summaries

Citation:

PÅhlman, M., Gillberg, C., & Himmelmann, K. (2022). Neuroimaging findings in children with cerebral palsy with autism and/or attention-deficit/hyperactivity disorder: a population-based study. Developmental medicine and child neurology, 64(1), 63–69. https://doi.org/10.1111/dmcn.15011

Summary:

This study aimed to compare neuroimaging patterns according to the Magnetic Resonance Imaging Classification System in children with cerebral palsy (CP) with and without autism and/or attention-deficit/hyperactivity disorder (ADHD). The participants consisted of 184 children with CP who had completed comprehensive screening and clinical assessment for neuropsychiatric disorders and undergone neuroimaging. The results showed that Austism and ADHD were common in all of the neuroimaging patterns including normal. Autism and ADHD were not more prevalent in children with bilateral than unilateral lesions, contrary to other associated impairments. Children with predominant white matter injury, related to insults in the late second or early third trimester, had the highest prevalence of autism (40%). Children who had sustained a middle cerebral artery infarction had the highest prevalence of ADHD (62%).

Citation:

Park, E. S., Rha, D. W., Shin, J. S., Kim, S., & Jung, S. (2014). Effects of hippotherapy on gross motor function and functional performance of children with cerebral palsy. Yonsei medical journal, 55(6), 1736–1742. https://doi.org/10.3349/ymj.2014.55.6.1736

Summary:

The study aimed to investigate the effects of hippotherapy on gross motor function and functional performance in children with spastic cerebral palsy (CP). The participants consisted of 34 children with spastic CP who did hippotherapy and 21 children who were the control. They assessed the Gross Motor Function Measure (GMFM)-66, GMFM-88 and the Pediatric Evaluation of Disability Inventory: Functional Skills Scale (PEDI-FSS) before therapy and after the 8-week intervention as outcome measures. The results showed that there were no significant differences between intervention and control groups at baseline on either measure. After the 8-week intervention, the scores on Gross Motor Function measures were significantly improved in both groups. However, the hippotherapy group had significantly greater improvement in dimension E and GMFM-66 total score than the control group. The total PEDI-FSS score and the sub-scores of its 3 domains were significantly improved in the hippotherapy group, but not in the control group.

Citation:

Nardone, R., Sebastianelli, L., Ferrazzoli, D., Brigo, F., Lochner, P., Saltuari, L., Trinka, E., & Versace, V. (2021). Brain functional reorganization in children with hemiplegic cerebral palsy: Assessment with TMS and therapeutic perspectives. Neurophysiologie clinique = Clinical neurophysiology, 51(5), 391–408. https://doi.org/10.1016/j.neucli.2021.09.002

Summary:

This review aimed to investigate the usefulness of TMS to explore cortical excitability, plasticity and connectivity changes in hemiplegic cerebral palsy (HCP). Children with HCP due to unilateral lesions of the corticospinal system had ipsilateral motor evoked potentials (MEPs) similar to those recorded contralaterally. TMS studies demonstrated that occupational and constraint-induced movement therapy were associated with significant improvements in contralateral and ipsilateral corticomotor projection patterns. In addition, after intensive bimanual therapy, children with HCP showed increased activation and size of the motor areas controlling the affected hand. A TMS mapping study revealed a mediolateral location of the upper and lower extremity map motor cortical representations. Deficits in intracortical and interhemispheric inhibitory mechanisms were observed in HCP. Clinical mirror movements (MMs) correlated with disability and CST organization in subjects with HCP and a positive relationship was found between MMs and MEPs strength. Therefore, TMS studies have shed light on important pathophysiological aspects of motor cortex and CST reorganization in HCP patients. Furthermore, repetitive TMS (rTMS) might have therapeutic effects on CST activities, functional connectivity and clinical status in children with HCP.

Citation:

Elkamil, A. I., Andersen, G. L., Salvesen, K. Å., Skranes, J., Irgens, L. M., & Vik, T. (2011). Induction of labor and cerebral palsy: a population-based study in Norway. Acta obstetricia et gynecologica Scandinavica, 90(1), 83–91. https://doi.org/10.1111/j.1600-0412.2010.01022.x

Summary

This study wanted to investigate the association between labor induction and later development of cerebral palsy (CP). They collected perinatal data on all children born in Norway 1996–1998 which was obtained from the Medical Birth Registry of Norway. Unadjusted and adjusted odds ratios were calculated as estimates of the relative risk that a child with CP was born after labor induction. Bilateral cerebral palsy was more frequently observed after induced labor. For children born at term the association between bilateral CP and labor induction was stronger. The association persisted after adjustment for maternal disease, gestational age, standard deviation score for birthweight (z-score) and prelabor rupture of membranes. Among children with CP born at term, four-limb involvement (quadriplegia) was significantly more frequent after induced (45.5%) compared with non-induced labor (8.0%). There was no significant association between labor induction and unilateral CP subtype or CP in preterm born children. In this study population, we found that labor induction at term was associated with excess risk of bilateral spastic CP and in particular CP with four-limb involvement.

Citation:

Keawutan, P., Bell, K. L., Oftedal, S., Ware, R. S., Stevenson, R. D., Davies, P. S. W., & Boyd, R. N. (2017). Longitudinal physical activity and sedentary behaviour in preschool-aged children with cerebral palsy across all functional levels. Developmental medicine and child neurology, 59(8), 852–857. https://doi.org/10.1111/dmcn.13439

Summary:

The study aimed to investigate longitudinal changes of habitual physical activity (HPA) and sedentary time in children with cerebral palsy (CP) aged 1 year 6 months to 5 years across all functional abilities. The participants were 95 children who were classified using the Gross motor function classification system with levels varying from I-V. Participants' physical activity was recorded at four possible time points. The results showed that participants with levels I and II had stable HPA as they aged. HPA decreased significantly at age 5 for participants classified at levels III to V. Sedentary time increased significantly at ages 4 and 5 in all participants.

Citation:

Simon-Martinez, C., Mailleux, L., Ortibus, E., Fehrenbach, A., Sgandurra, G., Cioni, G., Desloovere, K., Wenderoth, N., Demaerel, P., Sunaert, S., Molenaers, G., Feys, H., & Klingels, K. (2018). Combining constraint-induced movement therapy and action-observation training in children with unilateral cerebral palsy: a randomized controlled trial. BMC pediatrics, 18(1), 250. https://doi.org/10.1186/s12887-018-1228-2

Summary:

This study aimed to describe a randomized controlled trial (RCT) protocol investigating the effects of an intensive treatment model, combining modified Constraint-Induced Movement Therapy (mCIMT) and Action-Observation Training (AOT) compared to mCIMT alone on upper limb (UL) function in children with unilateral CP. The participants consisted of 42 children with CP. The participants had to receive mCIMT therapy for 6 hours a day, on 9 out of 11 days, for two weeks. Some of the children received AOT with the mCIMT therapy, but the control group did not. Upper limb function will be assessed at baseline, immediately before and after intervention, and at 6 months follow-up. Brain imaging comprising structural and functional connectivity measures as well as Transcranial Magnetic Stimulation (TMS) to evaluate corticospinal tract wiring will be acquired before the intervention.

Citation:

Nordberg, A., Dahlgren Sandberg, A., & Miniscalco, C. (2015). Story retelling and language ability in school-aged children with cerebral palsy and speech impairment. International journal of language & communication disorders, 50(6), 801–813. https://doi.org/10.1111/1460-6984.12177

Summary:

The study aimed to explore the impact of expressive and receptive language, narrative discourse dimensions (Narrative Assessment Profile measures), auditory and visual memory, theory of mind (ToM) and non-verbal cognition on the retelling ability of children with CP and speech impairment. The participants were 15 cerebral palsy children, with varying levels of gross motor and cognitive function, who spoke with speech impairments. They tested story re-telling skills, receptive language ability, non-verbal cognitive level, memory function, and theory of mind. Each of these skills was measured using a variety of different assessments. The results showed that children had severe problems with retelling ability corresponding to an age equivalent of 5;2-6;9 years. Receptive and expressive language, visuospatial and auditory memory, non-verbal cognitive level, and Theory of mind varied widely within and among the children. Both expressive and receptive language correlated significantly with narrative ability in terms of Narrative assessment profile (NAP) total scores, and so did auditory memory.

Citation:

Harlaar, L., Pouwels, P. J., Geytenbeek, J., Oostrom, K., Barkhof, F., & Vermeulen, R. J. (2013). Language comprehension in young people with severe cerebral palsy in relation to language tracts: a diffusion tensor imaging study. Neuropediatrics, 44(5), 286–290. https://doi.org/10.1055/s-0033-1341600

Summary:

The study aimed to assess the relationship between language tracts and language comprehension or skills in patients with cerebral palsy. The participants were 10 control subjects and 5 subjects with severe cerebral palsy. They assessed language with the Computer-Based instrument for Low motor Language Testing [C-BiLLT]. As well as the language and pyramidal tracts were visualized using diffusion tensor imaging. The results showed that the language tracts were visualized in all 10 control children and in four out of five CP patients. In one CP patient without any objective language comprehension skills, no language tract could be visualized. Both language and pyramidal tracts were smaller in CP patients than in controls.

Citation:

Fosdahl, M. A., Jahnsen, R., Kvalheim, K., & Holm, I. (2019). Stretching and Progressive Resistance Exercise in Children With Cerebral Palsy: A Randomized Controlled Trial. Pediatric physical therapy : the official publication of the Section on Pediatrics of the American Physical Therapy Association, 31(3), 264–271. https://doi.org/10.1097/PEP.0000000000000616

Summary:

The study aimed to evaluate the effects of streching and progressive resistence exercise on the range of motion and muscle strength in children with cerebral palsy. The participants were 37 children with spastic bilateral cerebral palsy and Gross Motor Function Classification System levels I to III. They randomly assigned the children to an intervention and a comparison group. Some of the interventions were stretching of hamstrings and progressive resistance exercise, targeting the lower extremities for 16 weeks, followed by a 16-week maintenance program. Passive and active popliteal angle and muscle strength were evaluated at 0, 16, and 32 weeks. The results showed that after 16 weeks there was nonsignificant improvement found in the passive, active poplititeal angle and quadriceps and hamstring strength.

#10

Citation:

Saether, R., Helbostad, J. L., Adde, L., Brændvik, S., Lydersen, S., & Vik, T. (2014). Gait characteristics in children and adolescents with cerebral palsy assessed with a trunk-worn accelerometer. Research in developmental disabilities, 35(7), 1773–1781. https://doi.org/10.1016/j.ridd.2014.02.011

Summary:

This study aimed to investigate gait characteristics reflecting balance and progression in children with cerebral palsy (CP) compared with typically developing (TD) children. The participants were children in the age range 5–18 years with spastic CP and a gross motor function corresponding to GMFCS I–III and children with TD. The children walked back and forth along a 5 m pathway with a tri-axial accelerometer worn on the lower back to allow assessment of their gait characteristics. Results showed that Gait parameters related to balance, such as AP, ML, and V accelerations, were higher in the children with CP and increased with increasing GMFCS levels. The differences in accelerations in the AP and V directions increased between children with CP and TD children with increasing speed. Also asymmetry in trunk accelerations differed significantly between the two groups in all three directions while interstride regularity differed only slightly between children with CP and TD children, and only in the AP direction. Gait characteristics also differed between children with the spastic subtypes unilateral and bilateral CP, for accelerations and asymmetry in the AP and ML directions. Our results showed significant differences in gait characteristics between children with CP and TD children.

#11

Citation:

Wang, X., Gao, C., Zhong, H., Kong, X., Qiao, R., Zhang, H., . . . Li, B. (2022). TNAP—a potential cytokine in the cerebral inflammation in spastic cerebral palsy. Frontiers in Molecular Neuroscience, doi:https://doi.org/10.3389/fnmol.2022.926791

Summary:
This study aimed to investigate the factors involved in the development of spastic cerebral palsy (CP), which is the most common form of CP. The researchers conducted proteomic analysis on blood samples from children with spastic CP and healthy individuals. Additionally, they induced hypoxic-ischemic encephalopathy (HIE) in rat pups to create a CP model and examined various markers and cytokines in the blood and brain cortex. The study identified downregulation of TNAP (the gene expression product of ALPL) in spastic CP, both in children and the CP model rats. Furthermore, the CP model rats showed increased levels of osteopontin and proinflammatory markers in both blood and the brain cortex on the ischemic side. Serum 25-hydroxyvitamin D and IL-10 were significantly decreased in the CP model rats. The study also found a positive correlation between serum TNAP and serum CRP and IL-10 in the model rats. These findings suggest that TNAP may play a specific and crucial role in neuroinflammation in spastic CP, making it a potential target for diagnosis and treatment of this condition.

#12

Citation:

WEI, M., Wen-bin, J., Qi-jia ZHAN, Sen, L. I., LIU, C., & XIAO, B. (2023). Efficacy and influencing factors of selective dorsal rhizotomy for the treatment of spastic cerebral palsy in children. Chinese Journal of Contemporary Neurology & Neurosurgery, 23(5), 405-411. doi:https://doi.org/10.3969/j.issn.1672-6731.2023.05.005

Summary:

This study aimed to assess the clinical efficacy of selective dorsal rhizotomy (SDR) in treating spastic cerebral palsy (SCP) in children. They examined 131 children with SCP who underwent SDR and used various evaluation measures, including the Gross Motor Function Classification System (GMFCS), Gross Motor Function Measure-66 Items (GMFM-66), and the modified Ashworth Scale. They found that SDR led to a significant decrease in muscle tonus in the lower limb muscle groups. The overall improvement rate of GMFCS classification after SDR was 34.35%, with no cases of worsening in GMFCS classification. Significant differences were observed in GMFM-66 scores before and after surgery across different GMFCS levels, with better improvements in levels I, II, and III compared to level IV, and level I had a better score than level III. Logistic regression analysis identified that SDR performed between the ages of 3-6 years and a preoperative GMFCS level of I-III were favorable factors for significant GMFM-66 score improvement. In conclusion, SDR effectively reduces muscle tonus in lower limb muscle groups and improves gross motor function in children with SCP. The treatment outcome is particularly favorable for children with muscle spasticity in both lower limbs who can cooperate with rehabilitation training (GMFCS level I-III). SDR can also be considered for children with severe cerebral palsy (GMFCS level IV-V) to assist with daily care.

#13

Citation:

Hou, X., Yan, Y., Zhan, Q., Wang, J., Xiao, B., & Jiang, W. (2023). Unsupervised machine learning effectively clusters pediatric spastic cerebral palsy patients for determination of optimal responders to selective dorsal rhizotomy.Scientific Reports (Nature Publisher Group), 13(1), 8095. doi:https://doi.org/10.1038/s41598-023-35021-x

Summary:

In this study, the researchers aimed to improve the outcomes of selective dorsal rhizotomy (SDR) for spastic cerebral palsy (SCP) patients by using unsupervised machine learning to subgroup patients based on pre-operative parameters. The study included 135 pediatric SCP patients who underwent SDR between January 2015 and January 2021. Patients were grouped into three subgroups ("best responders," "good responders," and "moderate responders") based on their response to SDR, using both hierarchical and K-means clustering methods. These subgroups exhibited significantly different clinical characteristics, except for the age at surgery. The post-operative motor function improvement varied among these subgroups. They found that SDR effectively reduced muscle spasticity and improved motor function in all patients. In conclusion, SDR was found to alleviate spasticity and enhance motor function in SCP patients. Machine learning techniques effectively grouped patients into subgroups based on pre-operative characteristics, which could help determine the optimal responders to SDR surgery. This personalized approach has the potential to improve treatment outcomes for SCP patients.

#14

Citation:

Steinbusch, C. V. M., Defesche, A., Bertie van, d. L., Rameckers, E. A. A., Knijnenburg, A. C. S., Vermeulen, J. R. J., & Janssen-Potten, Y. (2023). The effect of bimanual intensive functional training on somatosensory hand function in children with unilateral spastic cerebral palsy: An observational study. Journal of Clinical Medicine, 12(4), 1595. doi:https://doi.org/10.3390/jcm12041595

Summary:

The study focused on children with unilateral spastic cerebral palsy (CP) who often experience sensory impairments alongside motor issues. They conducted intensive bimanual training to enhance daily life bimanual performance without using sensory materials. Twenty-four participants with CP (12–17 years old) underwent 80-90 hours of training. The study measured somatosensory hand function before, immediately after, and six months post-training. Results showed improvements in thumb and wrist position perception, vibration sensation, tactile perception, and stereognosis of the more affected hand after training, which were sustained at the six-month follow-up. However, proprioception, as measured by thumb localization tasks, did not improve significantly. In summary, intensive bimanual training without sensory enrichment can enhance somatosensory function in the more affected hand of children with unilateral spastic CP.

#15

Citation:

Robinson, K. G., Mendonca, J. L., Militar, J. L., Theroux, M. C., Dabney, K. W., Shah, S. A., . . . Akins, R. E. (2013). Disruption of basal lamina components in neuromotor synapses of children with spastic quadriplegic cerebral palsy.PLoS One, 8(8) doi:https://doi.org/10.1371/journal.pone.0070288

Summary:

This study examined neuromuscular junctions (NMJs) and neuromotor maturation in scoliosis patients with spastic CP and idiopathic disease. The study found that in CP samples, there were mismatches in the localization of certain synaptic components, such as acetylcholine esterase (AChE) and laminin β2, within the synaptic basal lamina. However, the distribution of other components, like acetylcholine receptors (AChR) and presynaptic vesicle protein 2 (SV2), remained relatively intact. Further analysis using electron microscopy indicated that NMJs in CP patients were generally mature, with some subtle differences compared to controls, including deeper postsynaptic folds and reduced presynaptic mitochondria. Measures of neuromotor maturation and maturational markers showed similar levels in both groups. Therefore, NMJ disruption in CP appears to primarily involve certain synaptic basal lamina components and subtle structural modifications, rather than neuromotor maturation.

#16

Citation:

Peeters, N., Papageorgiou, E., Hanssen, B., De Beukelaer, N., Staut, L., Degelaen, M., . . . Desloovere, K. (2022). The short-term impact of botulinum neurotoxin-A on muscle morphology and gait in children with spastic cerebral palsy. Toxins, 14(10), 676. doi:https://doi.org/10.3390/toxins14100676

Summary:

This study investigated the effects of intramuscular Botulinum Neurotoxin type-A (BoNT-A) on muscle morphology, gait, and spasticity in children with spastic cerebral palsy (SCP). Gastrocnemius and semitendinosus volume and echogenicity intensity were assessed by 3D-freehand ultrasound, spasticity was quantified through electromyography during passive muscle stretches at different velocities. Ankle and knee kinematics were evaluated by 3D-gait analysis. The study found that BoNT-A reduced muscle volume 8–10 weeks post-injections, but also significantly improved ankle gait kinematics. Spasticity was also reduced, but the effects on knee kinematics were limited. The study concludes that BoNT-A can be an effective treatment for SCP, but close post-treatment follow-up and well-considered treatment selection is advised.

#17

Citation:

Hastings-Ison, T., Blackburn, C., Opie, N., Graham, K., Rawicki, H., Wolfe, R., Simpson, P., Baker, R. (2013). Reproducibility of an instrumented measure for passive ankle dorsiflexion in conscious and anesthetized children with cerebral palsy. Developmental medicine and child neurology. 56. 10.1111/dmcn.12276.

Summary:

This study aimed to determine if an instrumented measure could reduce measurement error in children with cerebral palsy (CP), determine its agreement and reliability in both conscious and anaesthetized participants, and compare it with previously reported measures. Thirty-four ambulant children aged 3 to 9 years with spastic CP were studied in a tertiary-care paediatric hospital. Ankle dorsiflexion at 50% bodyweight was measured in both conscious and anaesthetized participants. The standard error of measurement ranged from 3.9° (anaesthetized) to 6.7° (conscious), compared to previously reported dorsiflexion measures in conscious children with CP. Intrarater reliability was good in both conditions. Passive ankle dorsiflexion using an instrumented measure has face validity and may improve reproducibility under anaesthesia for clinical research. However, it is not better than trained assessors using conventional goniometry when an individual is conscious.

#18

Citation:

Hastings-Ison, T., Blackburn, C., Rawicki, B., Fahey, M., Simpson, P., Baker, R., & Graham, K. (2016). Injection frequency of botulinum toxin A for spastic equinus: a randomized clinical trial. Developmental medicine and child neurology, 58(7), 750–757. https://doi.org/10.1111/dmcn.12962

Summary:

This study was a randomized clinical trial that compared two botulinum toxin A (BoNT-A) injection frequency regimens for spastic equinus in 42 ambulant children with cerebral palsy. The primary outcome measure was passive ankle dorsiflexion. The children were randomized to receive either 12-monthly or 4-monthly BoNT-A injections to the calf over a 26-month period. The study found no significant difference in passive dorsiflexion between the 12-monthly and 4-monthly regimens and no significant differences in secondary outcome measures. However, a significant difference in passive dorsiflexion was found between children with hemiplegia and diplegia. The study recommends BoNT-A injections for spastic equinus on a 12-monthly basis.

#19

Citation:

Hastings-Ison, T., Sangeux, M., Thomason, P., Rawicki, B., Fahey, M., & Graham, H. K. (2018). Onabotulinum toxin-A (Botox) for spastic equinus in cerebral palsy: a prospective kinematic study. Journal of children's orthopaedics, 12(4), 390–397. https://doi.org/10.1302/1863-2548.12.180044

Summary:

This study aimed to investigate the effects of Botulinum toxin-A injections on the gait of children with cerebral palsy. The participants consisted of 37 children; 19 with unilateral and 18 with bilateral involvement. Gait analysis was performed four weeks before and four weeks after Botulinum toxin-A injection. The study found that while maximum ankle dorsiflexion increased for the whole group, there were no significant changes in the Gait Profile Score or ankle Gait Variable Score. Additionally, knee extension was unchanged for the whole group, but knee flexion increased in children with bilateral involvement. Overall, the injections did not result in objective improvements in overall gait, and improvements in ankle dorsiflexion may be offset by deterioration at the knee.

#20

Citation:

McHale, D. P., Mitchell, S., Bundey, S., Moynihan, L., Campbell, D. A., Woods, C. G., Lench, N. J., Mueller, R. F., & Markham, A. F. (1999). A gene for autosomal recessive symmetrical spastic cerebral palsy maps to chromosome 2q24-25. American journal of human genetics, 64(2), 526–532. https://doi.org/10.1086/302237

Summary:

Cerebral palsy is a condition with an incidence of about 1 in 500 births, varying among different ethnic groups. While genetic factors typically account for 1-2% of cases in most populations, they play a more significant role in populations with extensive inbreeding. This study focused on consanguineous families with multiple children affected by symmetrical spastic cerebral palsy to identify recessive genes responsible for the condition. Eight such families in the United Kingdom were examined through clinical assessments and genome-wide linkage analysis using DNA markers. In three families, a region of homozygosity on chromosome 2q24-q25 was identified, suggesting a genetic link to cerebral palsy. The study's findings may pave the way for better management of this challenging condition.

#21

Citation:

Derrick, M., Luo, N. L., Bregman, J. C., Jilling, T., Ji, X., Fisher, K., Gladson, C. L., Beardsley, D. J., Murdoch, G., Back, S. A., & Tan, S. (2004). Preterm fetal hypoxia-ischemia causes hypertonia and motor deficits in the neonatal rabbit: a model for human cerebral palsy?. The Journal of neuroscience : the official journal of the Society for Neuroscience, 24(1), 24–34. https://doi.org/10.1523/JNEUROSCI.2816-03.2004

Summary:

The study addresses the strong association between prenatal hypoxia-ischemia in the developing brain and the subsequent development of hypertonic motor deficits seen in cerebral palsy (CP) in premature and full-term infants with neonatal encephalopathy. To establish an animal model mimicking the hypertonia and motor disturbances observed in CP, researchers created a rabbit model involving in utero placental insufficiency. Preterm rabbit fetuses (67-70% gestation) experienced sustained global hypoxia, and their dams survived, giving birth spontaneously. At postnatal day 1, surviving pups underwent a series of neurobehavioral tests designed specifically for this study and recorded via video for masked scoring. The hypoxic group of newborn pups exhibited significant impairments in various tests assessing spontaneous movement, reflex motor activity, and the coordination of sucking and swallowing. Additionally, increased limb muscle tone was observed in the resting and active states in the preterm insult survivors. Histopathological examinations revealed a distinct pattern of acute injury to subcortical motor pathways, particularly affecting the basal ganglia and thalamus. Persistent damage to the caudate putamen and thalamus at postnatal day 1 was found to be significantly associated with hypertonic motor deficits in the hypoxic group. In summary, this study demonstrates that antenatal hypoxia-ischemia at preterm gestation leads to hypertonia and abnormalities in motor control, offering a valuable behavioral model to investigate the mechanisms and consequences of perinatal brain injury resulting from antenatal hypoxia-ischemia.

#22

Citation:

Synowiec, S., Lu, J., Yu, L., Goussakov, I., Lieber, R., Drobyshevsky, A. (2019). Spinal Hyper-Excitability and Altered Muscle Structure Contribute to Muscle Hypertonia in Newborns After Antenatal Hypoxia-Ischemia in a Rabbit Cerebral Palsy Model. Frontiers in Neurology, Vol. 9.

Summary:

Rabbit kits subjected to global antenatal hypoxic-ischemic injury display motor deficits resembling those seen in humans with cerebral palsy. Researchers conducted a study to explore various mechanisms implicated in spinal hyper-excitability following perinatal brain injury, potentially explaining muscle hypertonia in newborns. They assessed muscle stiffness during passive stretch, electromyogram activity, spinal excitability via the Hoffman reflex, and examined several factors, including muscle architecture, motoneuron morphology, primary afferent density, gliosis, and KCC2 transporter expression in the spinal cord.The findings indicated that while hypertonic kits exhibited decreased knee stiffness after anesthesia, they still had higher residual stiffness compared to controls. Muscle shortening and atrophy were observed in both agonist and antagonist muscles in hypertonic kits, along with longer sarcomere length in the tibialis anterior. Hypertonic kits showed altered reflex characteristics with increased Hmax/Mmax in the H-reflex and decreased rate-dependent depression, suggesting reduced supraspinal inhibitory control contributing to their hypertonia. However, no significant differences were found in motor neuron size or primary afferent density between control and hypertonic kits. Morphological analysis revealed lower dendritic tree length and ramification index in the hypertonic group. Gene expression of KCC2 was reduced in hypertonic kits, but protein content remained similar in both groups. The study suggests that while decreased supraspinal inhibitory control and increased reflex excitability may contribute to the neuronal aspect of hypertonia, the primary cause of increased joint resistance to stretch in hypertonic kits is related to changes in passive muscle and joint properties. Structural evidence for heightened sensory afferent input or motoneuron morphological changes explaining increased excitability was not found, but gliosis in the spinal gray matter may contribute to muscle hypertonia.

#23

Citation:

Cavarsan, C. F., Gorassini, M. A., and Quinlan, K. A. (2019). Animal models of developmental motor disorders: parallels to human motor dysfunction in cerebral palsy. Journal of Neurophysiology 122:3, 1238-1253.

Summary:

Cerebral palsy (CP), a common motor disability in children, has predominantly been researched to reduce the severity of brain injuries. However, limited attention has been given to understanding the cause and improvement of motor symptoms. This focus has influenced the choice of animal models, with many commonly used models not exhibiting CP-like motor problems. Rodent models typically show severe central nervous system injuries in response to CP-related insults but often lack prominent motor symptoms like spasticity and weakness. To better study motor dysfunction resulting from developmental injuries, larger animal models like rabbits, pigs, or nonhuman primates are needed. This research aims to describe and compare various animal models of CP and their potential relevance to the human condition.

#24

Citation:

Reedich, E. J., Genry, L. T., Singer, M. A., Cavarsan, C. F., Mena Avila, E., Boudreau, D. M., Brennan, M. C., Garrett, A. M., Dowaliby, L., Detloff, M. R., & Quinlan, K. A. (2022). Enhanced nociceptive behavior and expansion of associated primary afferents in a rabbit model of cerebral palsy. Journal of neuroscience research, 100(10), 1951–1966. https://doi.org/10.1002/jnr.25108

Summary:

Spastic cerebral palsy (CP) is a movement disorder characterized by muscle stiffness and exaggerated reflexes, often accompanied by pain. This study aimed to investigate the connection between prenatal hypoxia-ischemia (HI) injury, a known cause of CP, and potential alterations in spinal nociceptive circuitry. The researchers examined nociceptive sensory inputs and the sensitivity to mechanical and thermal stimuli in New Zealand White rabbit kits that experienced prenatal HI or underwent a sham surgical procedure.The results showed that HI led to an expansion of peptidergic sensory nerve fibers, identified by the expression of calcitonin gene-related peptide, in both the superficial and deep dorsal horn of the spinal cord in the kits at postnatal day 5. Non-peptidergic nociceptive fibers labeled by isolectin B4 remained unchanged in the HI group, but there was an increased overlap between peptidergic and non-peptidergic nociceptors. The density of glial fibrillary acidic protein in spinal cord white matter regions involved in nociceptive signaling was not affected at this stage. Furthermore, the study found that mechanical and thermal sensitivity to pain was heightened in the HI kits, even in the absence of motor deficits.These findings suggest that prenatal HI injury not only affects motor circuits but also impacts spinal sensory pathways. These changes in spinal nociceptive circuitry may disrupt spinal reflexes and contribute to the pain experienced by individuals with CP.

#25

Citation:

Reedich, E. J., Genry, L. T., Steele, P. R., Avila, E. M., Dowaliby, L., Drobyshevsky, A., Manuel, M., & Quinlan, K. A. (2023). Spinal motoneurons respond aberrantly to serotonin in a rabbit model of cerebral palsy. bioRxiv : the preprint server for biology, 2023.04.05.535691. https://doi.org/10.1101/2023.04.05.535691

Summary:

Cerebral palsy (CP) results from various factors that damage the developing central nervous system and often presents as impaired motor control, including muscle stiffness and spasticity. In rabbits that experience prenatal hypoxic-ischemic (HI) injury at 70-80% gestation, similar motor deficits are observed, along with elevated serotonin (5-HT) levels in the spinal cord. To investigate if serotonergic modulation of spinal motoneurons (MNs) contributes to these motor problems, experiments were conducted on neonatal rabbit spinal cord slices. HI MNs responded differently to the application of α-methyl 5-HT (a 5-HT1/5-HT2 receptor agonist) and citalopram (a selective 5-HT reuptake inhibitor), displaying hyperpolarization of persistent inward currents, altered action potential threshold, reduced maximum firing rate, and changes in spike frequency adaptation, while control MNs did not exhibit such responses. Immunohistochemistry showed that fewer HI MNs expressed inhibitory 5-HT1A receptors compared to age-matched controls. This suggests that the elevated spinal 5-HT concentration in HI rabbits directly excites MNs, leading to MN hyperexcitability and the muscle stiffness and spasticity characteristic of CP. Targeting serotonergic neuromodulation may hold promise for therapeutic strategies in individuals with CP.