Nervous propagation along 'central' motor pathways in intact man: characteristics of motor responses to 'bifocal' and 'unifocal' spine and scalp non-invasive stimulation

In 23 healthy adult volunteers motor action potentials (MAPs) were elicited in upper and lower limb muscles during stimulation of appropriate sites at spinal and scalp level, through skin electrodes. 'Bifocal' stimulation of scalp and spine motor tracts was performed with 2 plaques (3.5 cm2 each), delivering single pulses of 440-940 mA, less than 50 microseconds in duration, which elicited high voltage (up to 10 mV) MAPs in arm and leg muscles. 'Unifocal' stimulation of scalp was carried out through a cathode consisting in a belt or in a series of rectangular interconnected plaques secured around the head, 1-2 cm rostral to the nasion-inion plane, and in a circular anode placed on the appropriate scalp site. MAPs with similar amplitude-latency characteristics were recorded with both 'bifocal' and 'unifocal' stimulating methods. However, the 'unifocal' stimulation necessitated 5-10 times less current than the 'bifocal' one. The 'unifocal' device using the interconnected plaques (6-12 in number) provided the most tolerable stimuli with the lowest amount of current (60-106 mA, rectangular pulses of 100-150 microseconds). Conduction times and velocities of motor pathways in various 'central' and 'peripheral' districts were calculated. Voluntary contraction of target muscles remarkably enhanced MAP amplitudes during scalp, but not during spine stimulation. A nerve action potential was recorded from ulnar nerve during scalp stimulation. MAPs in hand muscles to scalp stimulation were obliterated by the simultaneous activation of the peripheral fibres innervating the target muscle, because of collision between ortho- and antidromically propagated motor impulses. Anodal stimuli showed liminal values significantly lower than the cathodal ones. Mapping studies have been carried out with 'unifocal' scalp stimulation by using different types of anode and of stimulus parameters.     

Further evidence of involvement of central and peripheral sensory pathways in olivopontocerebellar atrophy

We report the electrophysiological findings of the central and peripheral somatosensory pathways in 20 patients with olivopontocerebellar atrophy. Changes in sensory action potentials of the median nerve were observed in 14 patients and consisted of reduced sensory potential amplitudes associated in 10 cases with an increase in distal latencies. Sixteen out of 20 patients also showed changes in somatosensory evoked potentials after stimulation of the median nerve, consisting of decreased amplitude of N13 (13 cases) and N20 (16 cases) components, associated with increased N9-N13 interpeak latency in 9 and N13-N20 in 14 patients. The origin of these alterations is discussed.     

Examination of central and peripheral motor pathways by standardized magnetic stimulation

A standardized magnetic stimulation procedure for evaluation of central and peripheral motor pathways is described together with the results of motor evoked potential (MEP) recordings from 6 muscles in 50 healthy volunteers aged 18 to 60 years. Facilitation of the neuronal pathways was standardized using the integrated electric activity of the EMG as a gauge. The target muscles were: the brachial biceps (BB), the radial carpal flexor (FCR), the first dorsal interosseus of the hand (FDI), the medial vastus of the quadriceps muscle (VM), the anterior tibial (TA) and the abductor hallucis muscles (AH). The parameters used were the conduction times and the amplitudes of the CMAPs evoked by brain and root stimulation. CMAPs could be recorded from all muscles in all but three subjects in whom cortical stimulation was unsuccessful in one TA and two AHs, while root stimulation was negative in two TAs and one AH. Height and conduction times were significantly correlated, while age and conduction times were not. By linear regression 30-60% of the variation in the conduction times could be explained by the variation in height. The residual variation of the conduction times was less than in most other non-standardized studies and comparable to peripheral electrical motor conduction studies.     

Identification of genes influencing dendrite morphogenesis in developing peripheral sensory and central motor neurons

Background

Developing neurons form dendritic trees with cell type-specific patterns of growth, branching and targeting. Dendrites of Drosophila peripheral sensory neurons have emerged as a premier genetic model, though the molecular mechanisms that underlie and regulate their morphogenesis remain incompletely understood. Still less is known about this process in central neurons and the extent to which central and peripheral dendrites share common organisational principles and molecular features. To address these issues, we have carried out two comparable gain-of-function screens for genes that influence dendrite morphologies in peripheral dendritic arborisation (da) neurons and central RP2 motor neurons.

Results

We found 35 unique loci that influenced da neuron dendrites, including five previously shown as required for da dendrite patterning. Several phenotypes were class-specific and many resembled those of known mutants, suggesting that genes identified in this study may converge with and extend known molecular pathways for dendrite development in da neurons. The second screen used a novel technique for cell-autonomous gene misexpression in RP2 motor neurons. We found 51 unique loci affecting RP2 dendrite morphology, 84% expressed in the central nervous system. The phenotypic classes from both screens demonstrate that gene misexpression can affect specific aspects of dendritic development, such as growth, branching and targeting. We demonstrate that these processes are genetically separable. Targeting phenotypes were specific to the RP2 screen, and we propose that dendrites in the central nervous system are targeted to territories defined by Cartesian co-ordinates along the antero-posterior and the medio-lateral axes of the central neuropile. Comparisons between the screens suggest that the dendrites of peripheral da and central RP2 neurons are shaped by regulatory programs that only partially overlap. We focused on one common candidate pathway controlled by the ecdysone receptor, and found that it promotes branching and growth of developing da neuron dendrites, but a role in RP2 dendrite development during embryonic and early larval stages was not apparent.

Conclusion

We identified commonalities (for example, growth and branching) and distinctions (for example, targeting and ecdysone response) in the molecular and organizational framework that underlies dendrite development of peripheral and central neurons.     

Potassium channel blockers and impulse propagation in murine motor endplate disease

An electrophysiologic study has been performed on motor nerves of mice affected with hereditary "motor endplate disease" (MED). Bath application of potassium channel blockers, such as tetraethylammonium and 3,4-diaminopyridine, which are almost without effect on the monophasic compound action potential of normal nerves, considerably enhanced the action potential duration in nerves from mutant mice. Furthermore, external current recordings from motor endings revealed an absence of the K-dependent waveform component in MED mice, which indicates a similar K current intensity in the terminal part of the endings and in the heminode. These observations suggest that in the mutant, unlike in normal mice, K channels play a role in action potential electrogenesis. Possible relationships with paranodal dysmyelination are discussed.     

Pre-movement facilitation of motor-evoked potentials in man during transcranial stimulation of the central motor pathways

Motor evoked potentials (MEPs) following trans-cranial stimulation (TCS) through unifocal electric or magnetic impulses have been evaluated in the pre-movement period in 8 healthy volunteers. By utilizing a simple reaction time paradigm, progressive amplitude increments and latency decrements of MEPs have been demonstrated in the 100 ms preceding the onset of EMG activity in the muscle examined. By employing surface and depth recordings from various muscles of hand and forearm contralateral to the TCS, it was observed that in the 'early' period of pre-EMG facilitation (100-60 ms before EMG onset) TCS solely recruited the same low-threshold motor units which are fired first during self-paced contractions. In the 'middle and late' epochs of pre-EMG facilitation, TCS served when MEPs were recorded from a relaxed muscle, during TCS of progressively higher intensity. Multiple muscle recordings showed that pre-EMG facilitation was remarkably limited to the muscular group of the hand primarily involved in the intended movement.     

Noninvasive measurement of central sensory and motor conduction

Potentials evoked by median and peroneal nerve stimulation were digitally filtered between 300 and 2,500 Hz to measure early latency components and assess sensory cord conduction velocity. Short (R1) and long (R2) latency reflex responses were recorded from contracting thenar and tibialis anterior muscles. R1 is considered a spinal reflex akin to the H-reflex. Clinical evidence suggests that R2 involves a reflex arc with turnaround at the motor cortex. Sensory-motor cord velocity was derived from the latencies of R1 and R2. The method can be used to compare peripheral and central sensory conduction or conduction in central sensory and motor pathways.     

Transcranial magnetic stimulation of the central and peripheral motor pathways to the lingual muscles in cats.

OBJECTIVE: We have assessed a technique to stimulate the intracranial hypoglossal nerve with ease and reproducibility by using magnetic coils (MCs) and to detect a reliable site of excitation in animal experiments in order to establish a method to evaluate the motor pathway to lingual muscles. METHODS: We recorded the motor responses from the lingual muscles of 5 adult cats under general anesthesia by magnetic and electrical stimulation of the intracranial hypoglossal nerves. Figure of 8 and round MCs were used to investigate the optimal position and direction to evoke the motor responses. RESULTS: The round MC was useful for cortical stimulation. The figure of 8 coil, positioned in the back of the head of the examined side, parallel to the cervical spine, was essential for stimulation of the intracranial hypoglossal nerve. Analysis of the latencies, and the observation that the motor responses disappeared after transection of the nerves at the exit of the hypoglossal canal, demonstrated that the site of the excitation is at the exit of the hypoglossal canal. CONCLUSION: Magnetic stimulation using a figure of 8 coil can elicit tongue motor responses with ease and reliable reproducibility, stimulating the hypoglossal nerve at the exit of the hypoglossal canal.     

Conduction time in central somatosensory pathways in man.

Simultaneous recording of the somatosensory evoked potential (SEP) from the neck and from the scalp allows investigation of conduction of somatosensory impulses within the central nervous system alone. The early components of the SEP produced by stimulation of the median nerve at the wrist were recorded from standardized electrode locations on the scalp and neck in 21 normal subjects. The peak latency of both the initial negative potential from the scalp, N20 (19.4 +/- 1.1 msec), and the major negative negative potential from the neck, N14 (13.8 +/- 0.9 MSEC), CORRElated positively with arm length and with height. The difference between the peak latencies of N20 and N14 (5.6 +/- 0.5 msec) was independent of both arm length and height. As the latency and distribution of N14 indicate that this potential probably arises from the dorsal column nuclei, the N20--N14 latency difference provides a measure of conduction time within central pathways which is independent of conduction time in the limbs and spinal cord. Recording of the SEP from the neck, simultaneously with that from the scalp, also facilitates clinical investigation of the somatosensory system.     

Ultrastructural changes in peripheral nerve in hereditary motor and sensory neuropathy-Lom

Ultrastructural observations have been made on nerve biopsy specimens from five cases of hereditary motor and sensory neuropathy-Lom (HMSNL). A number of features that distinguish it from other hereditary demyelinating neuropathies were identified. Teased fibre studies were not feasible but examination of longitudinal sections by electron microscopy demonstrated demyelination/remyelination. Severe progressive axonal loss was a conspicuous feature. There was no indication of axonal atrophy. Hypertrophic onion bulb changes were present in the younger patients which later regressed, probably secondary to axonal loss. Myelin thickness was generally reduced in relation to axon diameter, indicating hypomyelination, and partial ensheathment of axons by Schwann cells was observed. The Schmidt-Lanterman incisures were atypical in extending for long lengths along the internode. Uncompacted myelin with a periodicity greater than that observed in other neuropathies in which it occurs was a feature, as was the accumulation of pleomorphic material in the adaxonal Schwann cell cytoplasm. An unusual finding was the presence of intra-axonal accumulations of irregularly arranged curvilinear profiles. These resemble those that have been described in experimental vitamin E deficiency. The amount of endoneurial collagen was markedly increased and some endoneurial blood vessels showed a non-specific basal laminal reduplication.     

The refractory period of fast conducting corticospinal tract axons in man and its implications for intraoperative monitoring of motor evoked potentials.

OBJECTIVE: To determine the absolute and relative refractory period (RRP) of fast conducting axons of the corticospinal tract in response to paired high intensity (HI or supramaximal) and moderate intensity (MI or submaximal) electrical stimuli. The importance of the refractory period of fast conducting corticospinal tract axons has to be considered if repetitive transcranial electrical stimulation (TES) is to be effective for eliciting motor evoked potentials (MEPs) intraoperatively. METHODS: Direct (D) waves were recorded from the epidural space of the spinal cord in 14 patients, undergoing surgical correction of spinal deformities. To assess the absolute and RRPs of the corticospinal tract, paired transcranial electrical stimuli at interstimulus intervals (ISI) from 0.7 to 4.1 ms were applied. Recovery of conditioned D wave at short (2 ms) and long (4 ms) ISI was correlated with muscle MEP threshold. The refractory period for peripheral nerve was tested in comparison to that for the corticospinal tract. In four healthy subjects sensory nerve action potentials of the median nerve were studied after stimulation with paired stimuli. RESULTS: HI TES revealed a mean duration of 0.82 ms for the absolute refractory period of the corticospinal tract, while MI stimulation resulted in a mean refractory period duration of 1.47 ms. Stimuli of HI produced faster recovery of D wave amplitude during the RRP. Furthermore, short trains of transcranial electrical stimuli did not elicit MEPs when D wave showed incomplete recovery. A similar influence of stimulus intensity on recovery time was found for the refractory period of peripheral nerve. CONCLUSIONS: The recovery of D wave amplitude is dependent upon stimulus intensity. High intensity produces fast recovery. This is an important factor for the generation of MEPs. When HI TES is used to elicit MEPs, short and long ISIs are equally effective. When MI TES is used to elicit MEPs, only a long ISI of 4 ms is effective.     

Myelinated sensory and alpha motor axon regeneration in peripheral nerve neuromas

Histochemical staining for carbonic anhydrase and cholinesterase (CE) activities was used to analyze sensory and motor axon regeneration, respectively, during neuroma formation in transected and tube-encapsulated peripheral nerves. Median–ulnar and sciatic nerves in the rodent model permitted testing whether a 4 cm greater distance of the motor neuron soma from axotomy site or intrinsic differences between motor and sensory neurons influenced regeneration and neuroma formation 10, 30, and 90 days later. Ventral root radiculotomy confirmed that CE-stained axons were 97% alpha motor axons. Distance significantly delayed axon regeneration. When distance was negligible, sensory axons grew out sooner than motor axons, but motor axons regenerated to a greater quantity. These results indicate regeneration differences between axon subtypes and suggest more extensive branching of motor axons within the neuroma. Thus, both distance from injury site to soma and inherent motor and sensory differences should be considered in peripheral nerve repair strategies. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 1748–1758, 1998     

Age-related changes in peripheral and central nerve conduction in man

Somatosensory evoked potential (SEP) latencies, motor and sensory nerve conduction velocities (CVs), and F-wave latenies were measured in 15 elderly normal subjects (mean age 74.1 years), and the results were used to derive indirect estimates of spinal cord CVs. These measurements were compared to those from 15 younger normal adults (mean age 31.6 years), and the nerve conduction characteristics of all 30 subjects were analyzed with respect to age. Peripheral motor and sensory CVs slowed progressively, and the onset latencies of F-waves and SEPs increased gradually with advancing age. Spinal cord CVs showed little change until approximately age 60, and declined sharply thereafter. In addition, the latencies of F-waves and SEPs were positively associated with height. Human clinical and experimental studies utilizing SEP and F-wave measurements must allow for morphologic differences between individuals, and for the systematic changes which accompany normal aging.     

Deficiency of electroneutral K+–Cl− cotransporter 3 causes a disruption in impulse propagation along peripheral nerves

Nerve conduction requires the fine tuning of ionic currents through delicate interactions between axons and Schwann cells. The K⁺–Cl⁻ cotransporter (KCC) family includes four isoforms (KCC1–4) that play an important role in the maintenance of cellular osmotic homeostasis via the coupled electroneutral movement of K⁺ and Cl⁻ with concurrent water flux. Mutation in SLC12A6 gene encoding KCC3 results in an autosomal recessive disease, known as agenesis of the corpus callosum associated with peripheral neuropathy. Nevertheless, the role of KCC3 in nerve function remains a puzzle. In this study, the microscopic examination of KCC isoforms expressed in peripheral nerves showed high expression of KCC2–4 in nodal segments of the axons and in the perinucleus and microvilli of Schwann cells. The KCC inhibitor [[(dihydroindenyl)oxy]alkanoic acid] but not the Na⁺–K⁺–2Cl⁻‐cotransport inhibitor (bumetanide) dose‐dependently suppressed the amplitude and area of compound muscle action potential, indicating the involvement of KCC activity in peripheral nerve conduction. Furthermore, the amplitude and area under the curve were smaller, and the nerve conduction velocity was slower in nerves from KCC3^−/− mice than in nerves from wild‐type mice, while the expression pattern of KCC2 and KCC4 was similar in KCC3 kockout and wild‐type strains. KCC3^−/− mice also manifested a prominent motor deficit in the beam‐walking test. This is the first study to demonstrate that the K⁺–Cl⁻ cotransporter activity of KCC3 contributes to the propagation of action potentials along peripheral nerves. © 2010 Wiley‐Liss, Inc.     

Neurophysiological evaluation of the central nervous impulse propagation in patients with sensorimotor disturbances

Motor evoked potentials (MEPs) to transcranial stimulation (TCS) and somatosensory evoked potentials to median nerve stimulation (MN-SEPs) were examined in 74 patients affected by multiple sclerosis (MS = 49 cases), amyotrophic lateral sclerosis (ALS = 9 cases), cervical cord lesions (7 cases), Parkinson's disease (PD = 5 cases), Huntington's chorea (HC = 2 cases), Wilson's disease (WD = 1 case), subacute combined degeneration (SCD = 1 case). MN-SEPs were altered in 38% of arms in MS with a higher incidence in clinically affected than in clinically 'silent' arms (= 77.8% vs. 27.5%). MEP alterations were found in 54% of examined arms, mostly because of a prolongation of the motor CCT. This index was invariably altered in the affected arms, whilst it was involved in 40% of the 'silent' ones. Twelve out of 18 arms displayed abnormal MEPs in ALS. These were mainly due to an absent response, even if moderate motor CCT prolongation and 'giant' MEPs were also encountered. MN-SEPs were altered in 3/18 arms. By recording MEPs from proximal and distal upper limb muscles, cues on the level of abnormal propagation were obtained in patients suffering from 'focal' lesions of the spinal cord. Combining SEP records enhanced the diagnostic yield in this field. Both MEPs and SEPs were normal in patients with PD and HC, whilst abnormally prolonged CCTs were found in the case with WD. MEP and SEP recording revealed central propagation abnormalities coupled to a severe clinical picture of the peripheral nerve involvement (as in the case of SCD).