Direct muscle delivery of GDNF with human mesenchymal stem cells improves motor neuron survival and function in a rat model of familial ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which there is a progressive loss of motor neurons and their connections to muscle, leading to paralysis. In order to maintain muscle connections in a rat model of familial ALS (FALS), we performed intramuscular transplantation with human mesenchymal stem cells (hMSCs) used as "Trojan horses" to deliver growth factors to the terminals of motor neurons and to the skeletal muscles. hMSCs engineered to secrete glial cell line-derived neurotrophic factor (hMSC-GDNF) were transplanted bilaterally into three muscle groups. The cells survived within the muscle, released GDNF, and significantly increased the number of neuromuscular connections and motor neuron cell bodies in the spinal cord at mid-stages of the disease. Further, intramuscular transplantation with hMSC-GDNF was found to ameliorate motor neuron loss within the spinal cord where it connects with the limb muscles receiving transplants. While disease onset was similar in all the animals, hMSC-GDNF significantly delayed disease progression, increasing overall lifespan by up to 28 days, which is one of the largest effects on survival noted for this rat model of FALS. This preclinical data provides a novel and practical approach toward ex vivo gene therapy for ALS.

Dose-response relationship between the H-reflex and continuous intrathecal baclofen administration for management of spasticity.

OBJECTIVE: To determine the relationship between the H-reflex (H/M ratio) and continuous intrathecal baclofen (CITB) dose after pump implantation for control of spastic hypertonia. METHODS: Soleus H-reflexes were serially recorded in 34 subjects (19 men, mean age 32 years, mean follow-up 1.7 years) during simple continuous mode of CITB delivery. Different fitting methods were explored to determine which function best described changes in H/M ratio with increasing CITB dose. We then calculated effective CITB doses yielding H/M ratios equal to 75, 50, and 25% (ED75, ED50, ED25) of the baseline recorded before the implant in 22 subjects. RESULTS: We found a significant dose-response relationship between the soleus H/M ratio and CITB dose. A two-decay exponential function was the best fit on each side for pooled data, but a general linear model when controlling for subject. The mean ED75, ED50, ED25 were 30, 70, and 110 mcg/day. Logistical regression predicted with high probability that the H/M ratio should be less than 30% at CITB doses above 150 mcg/day. CONCLUSIONS: H/M ratio is strongly dependent on CITB dose. It sharply decreases up to 150 mcg/day of CITB followed by a plateau. SIGNIFICANCE: Establishing the relationship between the H/M ratio and CITB dose may be useful for dose titration and early identification of an ITB system malfunction.

The effect of transcutaneous electrical stimulation on spinal motor neuron excitability in people without known neuromuscular diseases: the roles of stimulus intensity and location.

BACKGROUND AND PURPOSE: The Hoffmann reflex (H-reflex) is widely acknowledged as an indirect indicator of spinal motor neuron excitability. The purpose of this study was to determine whether transcutaneous electrical stimulation (TES), applied over the dorsiflexors or plantar flexors of the ankle, would alter the soleus muscle's H-reflex. Attention was focused on the roles of stimulus intensity and location. SUBJECTS: Thirty-two volunteers without known neuromuscular diseases (17 women [53%]; mean years of age=27, SD=7.3, range=21-48) were studied. METHODS: Subjects were randomly assigned to 1 of 4 groups, and TES was administered for 15 minutes. Stimulation site and intensity varied according to group assignment. H-reflexes were recorded before and for 10 minutes after TES. RESULTS: H-reflex amplitudes increased following TES at sensory threshold, whereas H-reflex amplitudes did not change following TES at 1.5 times motor threshold. The site of stimulation did not influence the resulting H-reflexes. DISCUSSION AND CONCLUSION: Low-intensity TES increases H-reflex amplitudes (and presumably the excitability of spinal motor neurons to Ia afferent input) in subjects without known neuromuscular diseases. High-intensity TES had little influence on H-reflex amplitudes.

Acute glial activation by stab injuries does not lead to overt damage or motor neuron degeneration in the G93A mutant SOD1 rat model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease where motor neurons within the brain and spinal cord are lost, leading to paralysis and death. Recently, a correlation between head trauma and the incidence of ALS has been reported. Furthermore, new invasive neurosurgical studies are being planned which involve inserting needles directly to the spinal cord. We therefore tested whether acute trauma to the spinal cord via a knife wound injury would lead to accelerated disease progression in rodent models of ALS (SOD1(G93A) rats). A longitudinal stab injury using a small knife was performed within the lumbar spinal cord region of presymptomatic SOD1(G93A) rats. Host glial activation was detected in the lumbar area surrounding a micro-knife lesion at 2 weeks after surgery in both wild type and SOD1(G93A) animals. However, there was no sign of motor neuron loss in the injured spinal cord of any animal and normal motor function was maintained in the ipsilateral limb. These results indicate that motor neurons in presymptomatic G93A animals are not affected by an invasive puncture wound injury involving reactive astrocytes. Furthermore, acute trauma alone does not accelerate disease onset or progression in this ALS model which is important for future strategies of gene and cell therapies directly targeting the spinal cord of ALS patients.

Comparison of clinical and neurophysiologic responses to intrathecal baclofen bolus administration in moderate-to-severe spasticity after acquired brain injury.

OBJECTIVES: To compare clinical and neurophysiologic responses to intrathecal baclofen (ITB) bolus injection in subjects with spasticity after acquired brain injury. DESIGN: Prospective case series. SETTING: Tertiary care rehabilitation center. PARTICIPANTS: Thirty consecutive ITB pump candidates with dysfunctional spasticity caused by traumatic brain injury, hypoxic encephalopathy, or stroke. INTERVENTION: A single 50-microg ITB bolus. MAIN OUTCOME MEASURES: Lower-extremity Ashworth Scale score at 2, 4, and 6 hours after ITB bolus; soleus Hoffmann reflex (H-reflex)/M-wave amplitude (H/M) ratio and abductor hallucis F-wave persistence and F/M ratio at 5 hours. Nonparametric repeated-measures analysis of variance and paired t test were used for statistical analyses. RESULTS: The Ashworth score on the more involved side significantly decreased from 2.4+/-0.7 at baseline to 1.5+/-0.6 and 1.4+/-0.6 at 4- and 6-hour evaluations, respectively (P<.001). H/M ratio significantly decreased bilaterally (more involved side, 62%+/-28% to 14%+/-19%; less involved side, 59%+/-26% to 11%+/-20%; P<.001). F-wave persistence significantly decreased on the more involved side (86%+/-17% to 75%+/-13%, P<.05) with no change in F/M ratio. There was no significant correlation among these outcome measures before or after the ITB bolus injection. CONCLUSIONS: H/M ratio is more sensitive than the Ashworth score or F-wave persistence in detecting a physiologic response to ITB bolus. H-reflex is useful for verification of ITB bolus administration, as an adjunct to clinical evaluation, particularly among patients with moderate spasticity at rest or with small changes in Ashworth score. However, potential application of the marked sensitivity of the H-reflex to other clinically challenging situations, such as early detection of possible ITB system malfunction, awaits further investigation.