Phase II/III placebo-controlled randomized trial of safety and efficacy of growth hormone treatment in incomplete chronic traumatic spinal cord injury.

STUDY DESIGN: This is a double blind phase II/III placebo-controlled randomized trial of the safety and efficacy of GH treatment in incomplete chronic traumatic spinal cord injury. OBJECTIVE: The aim of this study was to investigate the possibility to use exogenous GH administration for motor recovery in chronic traumatic incomplete human SCI. The objectives were to establish safety and efficacy of a combined treatment of subcutaneous GH (or placebo) and rehabilitation in this population. SETTING: Hospital Nacional de Parapléjicos METHODS: The pharmacological treatment was a subcutaneous daily dose of growth hormone (GH, Genotonorm 0.4 mg, Pfizer Pharmaceuticals) or placebo for one year. The pharmacological treatment was performed, during the first six months under hospitalization and supervised rehabilitation. RESULTS: The main findings were that the combined treatment of GH plus rehabilitation treatment is feasible and safe, and that GH but not placebo increases the ISNCSCI motor score. On the other hand, the motor-score increment was marginal (after one-year combined treatment, the mean increment of the motor-score was around 2.5 points). Moreover, we found that intensive and long-lasting rehabilitation program per se increases the functional outcome of SCI individuals (measured using SCIM III and WISCI II). CONCLUSIONS: It is important to highlight that our aim was to propose GH as a possible treatment to improve motor functions in incomplete SCI individuals. At least with the doses we used, we think that the therapeutic effects of this approach are not clinically relevant in most subjects with SCI.

Magnetic Resonance Imaging and Anatomical Correlation of Human Temporal Lobe Landmarks, in 3D Euclidean Space: A Study of Control and Alzheimer's Disease Subjects.

BACKGROUND: The medial temporal lobe (MTL), and in particular the hippocampal formation, is essential in the processing and consolidation of declarative memory. The 3D environment of the anatomical structures contained in the MTL is an important issue. OBJECTIVE: Our aim was to explore the spatial relationship of the anatomical structures of the MTL and changes in aging and/or Alzheimer's disease (AD). METHODS: MTL anatomical landmarks are identified and registered to create a 3D network. The brain network is quantitatively described as a plane, rostrocaudally-oriented, and presenting Euclidean/real distances. Correspondence between 1.5T RM, 3T RM, and histological sections were assessed to determine the most important recognizable changes in AD, based on statistical significance. RESULTS: In both 1.5T and 3T RM images and histology, inter-rater reliability was high. Sex and hemisphere had no influence on network pattern. Minor changes were found in relation to aging. Distances from the temporal pole to the dentate gyrus showed the most significant differences when comparing control and AD groups. The best discriminative distance between control and AD cases was found in the temporal pole/dentate gyrus rostrocaudal length in histological sections. Moreover, more distances between landmarks were required to obtain 100% discrimination between control (divided into <65 years or >65 years) and AD cases. DISCUSSION: Changes in the distance between MTL anatomical landmarks can successfully be detected by using measurements of 3D network patterns in control and AD cases.

Quantitative Measurements in the Human Hippocampus and Related Areas: Correspondence between Ex-Vivo MRI and Histological Preparations.

The decrease of volume estimates in different structures of the medial temporal lobe related to memory correlate with the decline of cognitive functions in neurodegenerative diseases. This study presents data on the association between MRI quantitative parameters of medial temporal lobe structures and their quantitative estimate in microscopic examination. Twelve control cases had ex-vivo MRI, and thereafter, the temporal lobe of both hemispheres was sectioned from the pole as far as the level of the splenium of the corpus callosum. Nissl stain was used to establish anatomical boundaries between structures in the medial temporal lobe. The study included morphometrical and stereological estimates of the amygdaloid complex, hippocampus, and temporal horn of the lateral ventricle, as well as different regions of grey and white matter in the temporal lobe. Data showed a close association between morphometric MRI images values and those based on the histological determination of boundaries. Only values in perimeter and circularity of the piamater were different. This correspondence is also revealed by the stereological study, although irregular compartments resulted in a lesser agreement. Neither age (< 65 yr and > 65 yr) nor hemisphere had any effect. Our results indicate that ex-vivo MRI is highly associated with quantitative information gathered by histological examination, and these data could be used as structural MRI biomarker in neurodegenerative diseases.

The ependymal region of the adult human spinal cord differs from other species and shows ependymoma-like features.

Several laboratories have described the existence of undifferentiated precursor cells that may act like stem cells in the ependyma of the rodent spinal cord. However, there are reports showing that this region is occluded and disassembled in humans after the second decade of life, although this has been largely ignored or interpreted as a post-mortem artefact. To gain insight into the patency, actual structure, and molecular properties of the adult human spinal cord ependymal region, we followed three approaches: (i) with MRI, we estimated the central canal patency in 59 control subjects, 99 patients with traumatic spinal cord injury, and 26 patients with non-traumatic spinal cord injuries. We observed that the central canal is absent from the vast majority of individuals beyond the age of 18 years, gender-independently, throughout the entire length of the spinal cord, both in healthy controls and after injury; (ii) with histology and immunohistochemistry, we describe morphological properties of the non-lesioned ependymal region, which showed the presence of perivascular pseudorosettes, a common feature of ependymoma; and (iii) with laser capture microdissection, followed by TaqMan® low density arrays, we studied the gene expression profile of the ependymal region and found that it is mainly enriched in genes compatible with a low grade or quiescent ependymoma (53 genes); this region is enriched only in 14 genes related to neurogenic niches. In summary, we demonstrate here that the central canal is mainly absent in the adult human spinal cord and is replaced by a structure morphologically and molecularly different from that described for rodents and other primates. The presented data suggest that the ependymal region is more likely to be reminiscent of a low-grade ependymoma. Therefore, a direct translation to adult human patients of an eventual therapeutic potential of this region based on animal models should be approached with caution.

Effects of electromyostimulation on muscle and bone in men with acute traumatic spinal cord injury: A randomized clinical trial.

OBJECTIVE: To study the effect of 14 weeks of electromyostimulation (EMS) training (47 minutes/day, 5 days/week) on both muscle and bone loss prevention in persons with recent, complete spinal cord injury (SCI). DESIGN: Prospective, experimental, controlled, single-blind randomized trial with external blind evaluation by third parties. METHODS: Eight men with recent SCI (8 weeks from injury; ASIA Impairment Scale (AIS) "A") were randomized into the intervention or the control groups. Cross-sectional area of the quadriceps femoris (QF) muscle was quantified using magnetic resonance imaging. Bone mineral density changes were assessed with a dual-energy X-ray absorptiometry. Several bone biomarkers (i.e. total testosterone, cortisol, growth hormone, insulin-growth factor I, osteocalcin, serum type I collagen C-telopeptide), lipid, and lipoprotein profiles were quantified. A standard oral glucose tolerance test was performed before and after the 14-week training. All analyses were conducted at the beginning and after the intervention. RESULTS: The intervention group showed a significant increase in QF muscle size when compared with the control group. Bone losses were similar in both groups. Basal levels of bone biomarkers did not change over time. Changes in lipid and lipoprotein were similar in both groups. Glucose and insulin peaks moved forward after the training in the intervention group. CONCLUSIONS: This study indicates that skeletal muscle of patients with complete SCI retains the ability to grow in response to a longitudinal EMS training, while bone does not respond to similar external stimulus. Increases in muscle mass might have induced improvements in whole body insulin-induced glucose uptake.

Time-course response in serum markers of bone turnover to a single-bout of electrical stimulation in patients with recent spinal cord injury.

The objective of the present repeat-measures study was to determine whether plasma serum levels of testosterone, cortisol, osteocalcin or type I collagen C-telopeptide (CT) are acutely affected following an electro-myostimulation (EMS) bout, and their relation to bone mineral density and muscle mass. Ten men with recent (8 weeks) thoracic spinal cord injury (SCI) (ASIA A) and 10 age-matched able-bodied (AB) men performed one EMS bout on the quadriceps femoris muscle. Blood samples were drawn at basal condition, immediately after EMS, and 15 min, 30 min, 24 h and 48 h post-EMS. Muscle cross-sectional area was measured by magnetic resonance imaging. Bone mineral density (BMD) was determined by dual-energy X-ray absorptiometry. In the SCI group, a significant decrease in testosterone, cortisol and CT together with a significant increase in testosterone/cortisol ratio and osteocalcin/CT ratio was observed after EMS. For the AB subjects, only testosterone and CT decreased significantly following EMS. Muscle size was only related to testosterone/cortisol ratio in the SCI sample (R = 0.659, p < 0.05), whereas BMD did not show any relation to any biomarker. Acute EMS in recent spinal cord injured men seems to induce positive effects on bone turnover biomarkers, and anabolic and catabolic hormones.

Analysis of fMRI time series with mutual information.

Neuroimaging plays a fundamental role in the study of human cognitive neuroscience. Functional magnetic resonance imaging (fMRI), based on the Blood Oxygenation Level Dependent signal, is currently considered as a standard technique for a system level understanding of the human brain. The problem of identifying regionally specific effects in neuroimaging data is usually solved by applying Statistical Parametric Mapping (SPM). Here, a mutual information (MI) criterion is used to identify regionally specific effects produced by a task. In particular, two MI estimators are presented for its use in fMRI data. The first one uses a Parzen probability density estimation, and the second one is based on a K Nearest Neighbours (KNN) estimation. Additionally, a statistical measure has been introduced to automatically detect the voxels which are relevant to the fMRI task. Experiments demonstrate the advantages of MI estimators over SPM maps; firstly, providing more significant differences between relevant and irrelevant voxels; secondly, presenting more focalized activation; and, thirdly, detecting small areas related to the task. These findings, and the improved performance of KNN MI estimator in multisubject and multistimuli studies, make the proposed methods a good alternative to SPM.