Corticomotorneuronal hyper-excitability in amyotrophic lateral sclerosis

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Abstract

We have analysed how the behaviour of a voluntarily activated motor unit changes when subjected to 100–150 threshold cortical stimuli using peristimulus time histograms (PSTHs). This is a measure of the integrity of the corticomotoneuronal core innervating a single anterior horn cell. One hundred and thirty units in 29 patients with ALS and 35 units in eight age-matched normal controls were studied. PSTHs were constructed using 1-ms bins of stimulus triggered sweeps with a total analysis time of 250 ms (50 ms before and 200 ms after the stimulus). In ALS the primary peak of the PSTH was delayed in onset and prolonged in duration. The primary peak was further analysed by finer 0.2-ms bins, which showed in ALS there were more sub-components than normally occur. Additional sub-components in the PSTH primary peak implies a hyper-excitable corticomotoneuron that fires excessively. Excitability could be glutamate induced and/or due to failure of GABA inhibitory mechanisms. Some glutamate antagonsits may be therapeutic in ALS because of their anticonvulsant or GABergic properties rather than their anti-glutamate properties. GABAB agonists might have a role in future therapeutic combined therapies for ALS.

Introduction

In humans, each anterior horn cell, excepting those innervating the extra-ocular muscles and bladder wall, receive mono-synaptic input from a core of corticomotoneurons. The size of the core is plastic. It declines with age [16]and varies with the complexity of the motor function performed 20, 24. There is growing in vivo evidence suggesting that the motor cortex, with its numerous corticomotneuronal cores, is hyper-excitable in amyotrophic lateral sclerosis (ALS). For example positron emission tomography using [18F]-2-fluoro-2-deoxy-d-glucose (FDG) and other ligands, have demonstrated a significantly increased metabolic activity in response to contralateral hand movement as compared to controls 1, 23. A variety of electrophysiologic experiments involving excitation of the corticospinal pathways also indicate the ALS motor cortex is hyperexcitable. The intensity required to stimulate the motor cortex in ALS is frequently reduced 12, 13, 27, the cortical silent period, a measure of cortical inhibition, is shortened 12, 34, and magnetic stimulation using a conditioning-test paradigm with a short interstimulus interval (<4 ms) fails to inhibit the test response in ALS [37]. It is not clear how these findings relate to the type or severity of neurological deficit (upper versus lower motor neuron), or disease duration. However, they imply that in ALS either the corticomotoneurons and/or their pre-synaptic terminals are overly active and that their modulation by local circuit inhibitory interneurons is impaired.

When the core of corticomotoneurons that converge on a single spinal motoneuron is activated a descending volley of impulses is generated, which if adequately summated, will depolarize the anterior cell membrane and induce an excitatory postsynaptic potential (EPSP) 3, 6, 8, 31, 33. The size of the EPSP is a reflection of the number of corticomotoneurons activated and, as we show here, the complexity of the EPSP gives information about how frequently the cell discharges. These measurements can be determined using peristimulus time histograms (PSTHs). The PSTH identifies changes in the firing probability of a voluntarily activated motor unit 10, 19. When the activated unit is subjected to an intervening cortical stimulus, its firing changes dramatically.In normal subjects the PSTH shows a consistent early post-stimulus period of significantly increased firing of an indexed motor unit. This is referred to as the primary peak 9, 25. In this study we have analysed the primary peak in detail and in ALS it is more complex than normal. There are additional sub-components, likely the result of a hyper-excitable corticomotoneuron which fires repetitively.

Section snippets

Subjects and methods

Informed consent was provided from 29 patients with ALS aged from 27 to 79 years (mean 60.4±14.8 years) and eight age-matched normal subjects (four men and four women) aged from 38 to 82 years (mean 54.3±15.6 years). Preliminary results from these subjects have been reported elsewhere [30]. None of the subjects were on medication that would alter cortical excitability. The patients fulfilled the El Escorial criteria for definite ALS [7], but had early stage disease, particularly with respect to

Result

In Table 1 are summarized the differences in the primary peak in ALS compared to normal. The mean onset latency of the primary peak in ALS was significantly longer than normal. The mean amplitude and duration of control and ALS primary peaks were not significantly different. However, as is shown in Fig. 1 the range of the amplitude and duration was widely distributed in ALS (amplitude range 0.36–6.71 mV and duration range 1–9 ms, respectively). This compared to controls values of 0.75–7.5 mV

Discussion

The onset of the primary peak in the PSTH derived from forearm or hand motor units is about 20 ms. This latency is in keeping with a fast-conducting descending volley as is typical of the corticomotoneuronal projection [33]. Several abnormalities in the primary peak of the PSTH have recently been described in ALS 4, 5, 15, 16, 25, 26, 28, 29, 30. The peak may be small, dispersed and prolonged in latency. The abnormalities are at least in part supraspinal in origin and may well result from

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