Escape from homeostasis: spinal microcircuits and progression of amyotrophic lateral sclerosis.

In amyotrophic lateral sclerosis (ALS), loss of motoneuron function leads to weakness and, ultimately, respiratory failure and death. Regardless of the initial pathogenic factors, motoneuron loss follows a specific pattern: the largest α-motoneurons die before smaller α-motoneurons, and γ-motoneurons are spared. In this article, we examine how homeostatic responses to this orderly progression could lead to local microcircuit dysfunction that in turn propagates motoneuron dysfunction and death. We first review motoneuron diversity and the principle of α-γ coactivation and then discuss two specific spinal motoneuron microcircuits: those involving proprioceptive afferents and those involving Renshaw cells. Next, we propose that the overall homeostatic response of the nervous system is aimed at maintaining force output. Thus motoneuron degeneration would lead to an increase in inputs to motoneurons, and, because of the pattern of neuronal degeneration, would result in an imbalance in local microcircuit activity that would overwhelm initial homeostatic responses. We suggest that this activity would ultimately lead to excitotoxicity of motoneurons, which would hasten the progression of disease. Finally, we propose that should this be the case, new therapies targeted toward microcircuit dysfunction could slow the course of ALS

Spinal microcircuits comprising dI3 interneurons are necessary for motor functional recovery following spinal cord transection

The spinal cord has the capacity to coordinate motor activities such as locomotion. Following spinal transection, functional activity can be regained, to a degree, following motor training. To identify microcircuits involved in this recovery, we studied a population of mouse spinal interneurons known to receive direct afferent inputs and project to intermediate and ventral regions of the spinal cord. We demonstrate that while dI3 interneurons are not necessary for normal locomotor activity, locomotor circuits rhythmically inhibit them and dI3 interneurons can activate these circuits. Removing dI3 interneurons from spinal microcircuits by eliminating their synaptic transmission left locomotion more or less unchanged, but abolished functional recovery, indicating that dI3 interneurons are a necessary cellular substrate for motor system plasticity following transection. We suggest that dI3 interneurons compare inputs from locomotor circuits with sensory afferent inputs to compute sensory prediction errors that then modify locomotor circuits to effect motor recovery

The measurement of low pay in the UK labour force survey

Consideration of the National Minimum Wage requires estimates of the distribution of hourly pay. The UK Labour Force Survey (LFS) is a key source of such estimates. The approach most frequently adopted by researchers has been to measure hourly earnings from several questions on pay and hours. The Office for National Statistics is now applying a new approach, based on an alternative more direct measurement introduced in March 1999. These two measures do not produce identical values and this paper investigates sources of discrepancies and concludes that the new variable is more accurate. The difficulty with using the new variable is that it is only available on a subset of respondents. An approach is developed in which missing values of the new variable are replaced by imputed values. The assumptions underlying this imputation approach and results of applying it to LFS data are presented. The relation to weighting approaches is also discussed

Multiple Imputation Methodology for Missing Data, Non-Random Response and Panel Attrition

Modern travel-behavior surveys have become quite complex; they frequently include multiple telephone contacts, travel diaries, and customized stated preference experiments. The complexity and length of these surveys lead to pervasive problems with missing data and non-random response biases. Panel surveys, which are becoming common in transportation research, also suffer from non-random attrition biases. This paper shows how Rubin's (1987a) multiple imputation methodology provides a unified approach to alleviating these problems. Before discussing solutions to problems caused by missing data and selection, it is important to recognize that their presence causes fundamental problems with identifying models and even "simple" population estimates. Section 2 reviews this work and stresses the need to make generally untestable assumptions in order to carry out any inference with missing data