Andrew Eisen

Cortical projections to spinal motoneurons : Changes with aging and amyotrophic lateral sclerosis

Peristimulus time histograms (PSTHs) of discharging single motor units, recorded from the extensor digitorum communis (EDC) during randomly applied cortical magnetic stimulation, were obtained in 42 normal subjects aged 24 to 83 years and 42 patients with amyotrophic lateral sclerosis (ALS) aged 37 to 84 years. Normal subjects had an early period of increased firing probability occurring at about 20 msec poststimulus, reflecting an underlying compound excitatory postsynaptic potential (EPSP) induced by fast-conducting, descending volleys of the corticomotoneuronal core facilitating the single spinal motoneuron. There was an age-dependent, linear decline in the amplitude of the EPSP (r = 0.673). We estimated that by age 50 years about 35% of corticomotoneurons are lost or nonfunctioning in normal controls. Compared with age-matched controls, the EPSP in most patients with ALS was reduced, and it was unmeasurable in six. We postulate this reflects a loss of corticomotoneurons. Seven (16.7%) patients phenotypically the same as the others had EPSPs that were larger than age-predicted values. This may reflect glutamate-induced excitotoxicity in a subset of ALS. In a single patient with chronic spinal muscular atrophy the EPSP was normal.

IFCN recommended standards for short latency somatosensory evoked potentials. Report of an IFCN committee

Short latency somatosensory evoked potentials (SEPs) are the electrical potentials generated mainly by the large fiber sensory pathways in the peripheral and central portions of the nervous system. SEPs can be elicited from almost any large nerve, although the median and posterior tibial nerves are usually chosen. The short latency responses occur within the first 50 msec after a brief stimulus. Other later middle latency and long latency SEPs also occur, but with a wider range of normal variability making clinical use more difficult. The recommended standards set out below address specifically the short latency median and posterior tibial nerve SEPs. Analogous standards should be applied for testing other nerves such as ulnar or peroneal. The literature contains many reports using techniques that differ from those described here. The peaks, latencies, amplitudes and normal limits in those reports will not necessarily correspond to results described here. Age has a significant effect on the SEP. In young children, the N9 and N13 potentials occur quite early, and the central conduction is relatively slow. Among older adults, normal limits for most latencies are longer by 5-10%, most of this change occurring after age 55 years. Similar changes occur for posterior tibial nerve SEPs. The patients limbs should be kept warmed during testing, since cool limb temperatures can slow the peripheral conduction. Peak latencies are significantly correlated with height, whereas interpeak latencies are affected less. Most medications have little effect on these potentials, and so sedation with a benzodiazepine or similar medication may be employed to aid the subject relaxation. Sleep may change the apparent median nerve N20 latency by increasing the amplitude of a peak component slightly later than that used for scoring for testing during wakefulness. This may cause a slight latency asymmetry to appear when one limb is tested with the patient awake and the other with the patient asleep.

Cortical excitability in amyotrophic lateral sclerosis : a clue to pathogenesis

Motor evoked potentials (MEPs) were recorded from selected non-wasted, non-denervated hand muscles in 40 patients with Amyotrophic Lateral Sclerosis (ALS) with both upper and lower motor neuron signs. In most the compound muscle action potential (CMAP) of the target muscle was normal. Compared to the control group, cortical threshold in ALS varied considerably and there was a significant (r2 = 0.702) inverse, exponential, correlation between cortical threshold and MEP/CMAP ratio. There was a linear correlation between threshold and disease duration (r2 = 0.66) so that early in the disease threshold was normal and later the motor cortex could not be stimulated. It is suggested that early in ALS normal threshold reflects glutamate-induced hyper-excitability of the corticomotoneuron. The findings lend support to the hypothesis that ALS is primarily a disease of the corticomotoneuron.

The motor cortex and amyotrophic lateral sclerosis

On theoretical grounds, abnormalities of the motor cortex in patients with amyotrophic lateral sclerosis (ALS) could lead to anterograde (“dying‐forward”) transneuronal degeneration of the anterior horn cells as suggested by Charcot. Conversely, retrograde (“dying‐back”) degeneration of the corticospinal tracts could affect the motor cortex. Evidence derived from clinical, neuropathological, static, and functional imaging, and physiological studies, favors the occurrence of anterograde degeneration. It is hypothesized that transneuronal degeneration in ALS is an active excitotoxic process in which live but dysfunctional corticomotoneurons, originating in the primary motor cortex, drive the anterior horn cell into metabolic deficit. When this is marked, it will result in more rapid and widespread loss of lower motor neurons. In contrast, slow loss of corticomotoneurons, as occurs in primary lateral sclerosis (PLS), precludes excitotoxic drive and is incompatible with anterograde degeneration. Preservation of slow‐conducting non‐M1 direct pathways in PLS is not associated with excitotoxicity, and anterior horn cells survive for long periods of time.

Magnetic stimulation of the central and peripheral nervous systems.

Since 1985, when the technique of transcranial magnetic stimulation (TMS) was first developed, a wide range of applications in healthy and diseased subjects has been described. Comprehension of the physiological basis of motor control and cortical function has been improved. Modifications of the basic technique of measuring central motor conduction time (CMCT) have included measurement of the cortical silent period, paired stimulation in a conditioning test paradigm, repetitive transcranial magnetic stimulation (rTMS), and peristimulus time histograms (PSTH). These methods allow dissection of central motor excitatory versus inhibitory interplay on the cortical motor neuron and its presynaptic connections at the spinal cord, and have proven to be powerful investigational techniques. TMS can be used to assess upper and lower motor neuron dysfunction, monitor the effects of many pharmacological agents, predict stroke outcome, document the plasticity of the motor system, and assess its maturation and the effects of aging, as well as perform intraoperative monitoring. The recent use of rTMS in the treatment of depression and movement disorders is novel, and opens the way for other potential therapeutic applications.

Evaluation of radiculopathies by segmental stimulation and somatosensory evoked potentials

Thirty-six patients with suspected or myelographically proven radiculopathies were investigated with motor and sensory conductions, F-waves, needle electromyography, and somatosensory evoked potentials (SEPs). SEPs were elicited by cutaneous nerve stimulation representative of input from individual cervical and lumbosacral dorsal roots. A myelographic defect was present in 83% of 30 patients who had myelograms. Overall 78% of patients had one or more abnormal electrophysiologic tests, the needle EMG giving the best diagnostic yield (75%). F-waves and SEPs were abnormal in 43% and 57% of cases respectively. Motor deficit correlated best with abnormal EMGs, whilst abnormal SEPs occurred most frequently when sensory deficit predominated. Prolonged latency of the SEP occurred rarely, reduced amplitude or abnormal morphology being the most useful characteristics. SEPs evoked by cutaneous nerve stimulation are a useful addition to conventionally available electrophysiological methods of evaluating radiculopathies, especially in the absence of motor deficit.

Clinical neurophysiology of ALS

The neurophysiology of amyotrophic lateral sclerosis is important not only in relation to diagnosis, but also in the development of methods to follow progress, and the effects of putative therapies, in the disease. Quantitative techniques can be applied to the measurement of reinnervation using needle electromyogram. The methodology of motor unit number estimation may be useful in measuring loss of functioning motor units in groups of patients but variability in the measurement using current methods limits its sensitivity in the evaluation of individual patients. Conventional neurophysiological measurements, expressed as a multimetric index, may be useful in assessing progress. The cortical and upper motor neuron system can be assessed using transcortical magnetic stimulation protocols, and cortical excitability may be measured by the peristimulus histogram method. In this review the advantages, limitations and promise of these various methods is discussed, in order to indicate the direction for further neurophysiological studies in this disorder.

Inclusion body myositis (IBM) Myopathy or neuropathy

Inclusion body myositis (IBM) is described in six elderly patients (three women) and in a young familial patient. They all showed the morphologically characteristic vacuoles containing osmiophilic membranous whorls and intracvtodasmic or intranuclear inclusions. There is a well-delineated bimodal age spectrum of IBM, with onset in the second and sixth decades, but otherwise the disorder seems to be a specific entky. Clinical, electrophysiologic, and morphologic features suggest a neurogenic origin in some cases.

The somatosensory evoked potential.

Three decades have elapsed since Dawson (1947) recorded the first somatosensory evoked potential (SEP). Simple superimposition of individual responses was possible because the patient had progressive myoclonic epilepsy. In this disease the SEP amplitude is much enhanced (Shibasaki et al, 1978; Kelly et al, 1981). Subsequently Dawson (1951, 1954) presented his averager to the Physiological Society, thereby initiating the present-day explosive growth of evoked potentials. SEPs are made up of components with varying latencies. The components are best identified by latency and polarity as recorded at the scalp (P = positive and N = negative). Nevertheless, the nomenclature of somatosensory evoked potentials can be extremely confusing, mainly because the same component can have a different polarity depending on the electrode montage used. Generally speaking (but this is not a firm rule), far-field (subcortical) potentials are positive in polarity when a non-cephalic reference is used, whereas these same components have a negative polarity when the reference is on the scalp. It is therefore useful to always indicate the recording montage being employed. In addition, use of absolute latencies in the terminology can cause confusion because they are dependent upon length and body height. For example, the brachial plexus component usually occurs at about 9 msec, but may extend to as long as 11 or more msec in a very tall individual. Subsequent components then become difficult to identify in relation to normal means.

Central nervous system amplification: Its potential in the diagnosis of early multiple sclerosis

Ability to record a sizable somatosensory evoked potential (SEP) in the absence of a recordable sensory nerve action potential (SNAP) suggests a normally occurring central nervous system amplifying process. Increments in SEP and SNAP amplitude with increasing stimulus strength between threshold and 2.5 times threshold (maximum) were compared. At threshold (40% of maximum stimulus) and 50% maximum stimulus, amplification measured 2.3 ± 0.7 and 2.0 ± 0.6, respectively. In 21 MS patients, the SEP at threshold stimulation was absent in 15, but normal in 5 of these at maximum stimulation. It is postulated that normal central amplification is markedly attenuated in MS, and this may be a sensitive indicator of early disease.