Diverse abnormalities of corticomotoneuronal projections in individual patients with amyotrophic lateral sclerosis Masashi Nakajima a,b , Andrew Eisen a,b, *, Heather Stewart a,b a The Neuromuscular Diseases Unit, Vancouver Hospital, 855 West 12th Avenue, Vancouver, BC V5Z 1M9, Canada b University of British Columbia, Vancouver, BC, Canada Accepted for publication: 18 July 1997 Abstract Using peristimulus time histograms (PSTHs), abnormalities of composite excitatory postsynaptic potentials (EPSPs) induced by tran- scranial magnetic stimulation were studied in multiple motor units from individuals with amyotrophic lateral sclerosis (ALS) and normal subjects. We studied 97 motor units in the extensor digitorum communis muscle of 22 patients with sporadic ALS and 47 motor units of 10 healthy control subjects. Four or five motor units were studied in each patient and normal subject. For each unit, macro motor unit potentials (Macro-MUPs) were simultaneously recorded from a surface electrode after spike-triggered averaging. The composite EPSPs in ALS showed a generally bi-directional deviation from the normal curve, with small EPSPs at one end, and larger amplitude EPSPs with a prolonged rise time at the other end. The variability of EPSPs from adjacent motor units in the same individual was significantly larger in ALS than in controls. In normal subjects there is a significant negative correlation between the amplitude of composite EPSPs and the Macro-MUPs. In ALS, the trend is reversed (positive) suggesting that the abnormalities of composite EPSPs are supraspinal in origin. A combination of partial attrition of the corticomotoneuronal core and hyper-excitability of surviving corticomotoneurons projecting to a given spinal motoneuron pool best explains the diversity of the composite EPSP in individuals with ALS.  1997 Elsevier Science Ireland Ltd. Keywords: Motor unit; Amyotrophic lateral sclerosis; Transcranial magnetic stimulation 1. Introduction Recently, in vivo techniques have been used to study the corticomotoneuronal system in amyotrophic lateral sclero- sis (ALS). They include magnetic resonance spectroscopy (Pioro et al., 1994), positron emission tomography (Kew et al., 1993, 1994), and neurophysiologic methods involving corticospinal excitation of single spinal motoneurons with magnetic stimulation (Awiszus and Feistner, 1993, 1995; Mills, 1995; Eisen et al., 1996; Nakajima et al., 1996). Each has provided evidence that there are abnormalities in the motor cortex in ALS that occur independently of, or precede those involving the anterior horn cells. In addition, immuno-histochemistry has revealed abnormalities of glu- tamate receptors (Shaw et al., 1994a,b) or transporters (Rothstein et al., 1992, 1995) in ALS motor cortex and spinal cord. These likely play an important role in initiating some of the physiological abnormalities that have been described (Eisen, 1995). Using peristimulus time histograms (PSTHs), the size of the corticomotoneuronal projection to spinal motoneurons can be estimated by studying how the firing probability of a voluntarily activated motor unit changes as a result of an intervening cortical stimulation. In normal subjects, there is a consistent, early, poststimulus period of significantly increased firing probability induced by transcranial mag- netic stimulation (Amassian et al., 1987; Day et al., 1987, 1989; Bawa and Lemon, 1993). The early period occurs at 20–25 ms after stimulation in the forearm and hand mus- cles, and reflects a composite excitatory postsynaptic poten- Electroencephalography and clinical Neurophysiology 105 (1997) 451–457 0924-980X/97/$17.00  1997 Elsevier Science Ireland Ltd. All rights reserved PII S0924-980X(97)00051-9 EEM 97055 * Corresponding author. Tel.: +1 604 8754405; fax: +1 604 8754668; e-mail: eisen@unixg.ubc.ca