Reduced Brainstem Volume is Associated with Mobility Impairments in Youth with Cerebral Palsy.

Persons with cerebral palsy (CP) have impaired mobility that has been attributed to changes in structure and function within the nervous system. The brainstem is a region that plays a critical role in locomotion by connecting the cortex and cerebellum to the spinal cord, yet this region has been largely unstudied in persons with CP. The objective of this investigation was to use high-resolution structural MRI and biomechanical analyses to examine whether the volume of the whole brainstem and its constituent elements are altered in CP, and if these alterations relate to the mobility impairments within this population. We assessed the volume of the pons, midbrain, medulla, and superior cerebellar peduncle (SCP) in a cohort of persons with CP (N = 26; Age = 16.3 ± 1.0 yrs; GMFCS levels I-IV, Females = 12) and a cohort of neurotypical (NT) controls (N = 38; Age = 14.3 ± 0.4 yrs, Females = 14) using structural MR imaging of the brainstem. Outside the scanner, a digital mat was used to quantify the spatiotemporal gait biomechanics of these individuals. Our MRI results revealed that there was a significant decrease in volume of the total brainstem, midbrain, and pons in persons with CP in comparison to the NT controls. Furthermore, we found that the altered volumes were related to reduced gait velocity and step length. These results suggest that there are structural changes in the brainstems of persons with CP that may contribute to the mobility impairments that are ubiquitous within this population.

Reduced wrist flexor H-reflex excitability is linked with increased wrist proprioceptive error in adults with cerebral palsy.

Although most neurophysiological studies of persons with cerebral palsy (CP) have been focused on supraspinal networks, recent evidence points toward the spinal cord as a central contributor to their motor impairments. However, it is unclear if alterations in the spinal pathways are also linked to deficits in the sensory processing observed clinically. This investigation aimed to begin to address this knowledge gap by evaluating the flexor carpi radialis (FCR) H-reflex in adults with CP and neurotypical (NT) controls while at rest and during an isometric wrist flexion task. The maximal H-wave (Hmax) and M-wave (Mmax) at rest were calculated and utilized to compute Hmax/Mmax ratios (H:M ratios). Secondarily, the facilitation of the H-wave was measured while producing an isometric, voluntary wrist flexion contraction (i.e., active condition). Finally, a wrist position sense test was used to quantify the level of joint position sense. These results revealed that the adults with CP had a lower H:M ratio compared with the NT controls while at rest. The adults with CP were also unable to facilitate their H-reflexes with voluntary contraction and had greater position sense errors compared with the controls. Further, these results showed that the adults with CP that had greater wrist position sense errors tended to have a lower H:M ratio at rest. Overall, these findings highlight that aberration in the spinal cord pathways of adults with CP might play a role in the sensory processing deficiencies observed in adults with CP.

The vulnerability of spinal motoneurons and soma size plasticity in a mouse model of amyotrophic lateral sclerosis.

KEY POINTS: Motoneuron soma size is a largely plastic property that is altered during amyotrophic lateral sclerosis (ALS) progression. We report evidence of systematic spinal motoneuron soma size plasticity in mutant SOD1-G93A mice at various disease stages and across sexes, spinal regions and motoneuron types. We show that disease-vulnerable motoneurons exhibit early increased soma sizes. We show via computer simulations that the measured changes in soma size have a profound impact on the excitability of disease-vulnerable motoneurons. This study reveals a novel form of plasticity in ALS and suggests a potential target for altering motoneuron function and survival. ABSTRACT: α-Motoneuron soma size is correlated with the cell's excitability and function, and has been posited as a plastic property that changes during cellular maturation, injury and disease. This study examined whether α-motoneuron somas change in size over disease progression in the G93A mouse model of amyotrophic lateral sclerosis (ALS), a disease characterized by progressive motoneuron death. We used 2D- and 3D-morphometric analysis of motoneuron size and measures of cell density at four key disease stages: neonatal (P10 - with earliest known disease changes); young adult (P30 - presymptomatic with early motoneuron death); symptom onset (P90 - with death of 70-80% of motoneurons); and end-stage (P120+ - with full paralysis of hindlimbs). We additionally examined differences in lumbar vs. sacral vs. cervical motoneurons; in motoneurons from male vs. female mice; and in fast vs. slow motoneurons. We present the first evidence of plastic changes in the soma size of spinal α-motoneurons occurring throughout different stages of ALS with profound effects on motoneuron excitability. Somatic changes are time dependent and are characterized by early-stage enlargement (P10 and P30); no change around symptom onset; and shrinkage at end-stage. A key finding in the study indicates that disease-vulnerable motoneurons exhibit increased soma sizes (P10 and P30). This pattern was confirmed across spinal cord regions, genders and motoneuron types. This extends the theory of motoneuron size-based vulnerability in ALS: not only are larger motoneurons more vulnerable to death in ALS, but are also enlarged further in the disease. Such information is valuable for identifying ALS pathogenesis mechanisms.

Experimental Design and Data Analysis Issues Contribute to Inconsistent Results of C-Bouton Changes in Amyotrophic Lateral Sclerosis.

The possible presence of pathological changes in cholinergic synaptic inputs [cholinergic boutons (C-boutons)] is a contentious topic within the ALS field. Conflicting data reported on this issue makes it difficult to assess the roles of these synaptic inputs in ALS. Our objective was to determine whether the reported changes are truly statistically and biologically significant and why replication is problematic. This is an urgent question, as C-boutons are an important regulator of spinal motoneuron excitability, and pathological changes in motoneuron excitability are present throughout disease progression. Using male mice of the SOD1-G93A high-expresser transgenic (G93A) mouse model of ALS, we examined C-boutons on spinal motoneurons. We performed histological analysis at high statistical power, which showed no difference in C-bouton size in G93A versus wild-type motoneurons throughout disease progression. In an attempt to examine the underlying reasons for our failure to replicate reported changes, we performed further histological analyses using several variations on experimental design and data analysis that were reported in the ALS literature. This analysis showed that factors related to experimental design, such as grouping unit, sampling strategy, and blinding status, potentially contribute to the discrepancy in published data on C-bouton size changes. Next, we systematically analyzed the impact of study design variability and potential bias on reported results from experimental and preclinical studies of ALS. Strikingly, we found that practices such as blinding and power analysis are not systematically reported in the ALS field. Protocols to standardize experimental design and minimize bias are thus critical to advancing the ALS field.