Multiple transmitter systems contribute neurites to individual senile plaques.

Senile plaques (SP), which consist largely of abnormal neuronal processes in proximity to deposits of amyloid, are a characteristic neuropathological feature of Alzheimer's disease. In lesser numbers, SP also occur in the brains of nondemented aged humans and nonhuman primates. To date, it is not known whether neurites in individual SP derive from neurons of one or several neurotransmitter systems. In aged monkeys, two strategies were used to test the hypothesis that individual SP can contain abnormal neurites arising from multiple neuronal systems. First, immunocytochemical methods were used to identify somatostatin-immunoreactive neurites in plaques, and these sections were subsequently stained with silver to visualize other neurites. Numerous plaques contained both somatostatin-positive and somatostatin-negative (i.e. argyrophilic only) neurites, suggesting that more than one transmitter system contributed neurites to each of these plaques. Second, two-color immunocytochemical techniques showed, in a small percentage of plaques, that cholinergic neurites coexist with neuropeptide Y (NPY)-containing neurites or catecholaminergic neurites. These results suggest that the formation of SP may result from events that involve abnormalities of neuronal processes arising from multiple transmitter systems.

Aberrant conduction in human peripheral nerve: ephaptic transmission?

Later motor responses were recorded from the foot muscles of patients with neuropathy after stimulation of the posterior tibial nerve at the ankle. The latencies were too short to involve the spinal cord, but latencies were reduced by more proximal stimulation, indicating that the pathway begins with proximal conduction. The response differed from previously reported "axon reflexes," because it appeared on supramaximal stimulation. It was attributed to reflection of an impulse at a discontinuity of the myelin sheath. In 2 of 32 subjects, stimulation of the medial plantar nerve in the great toe resulted in reproducible motor responses with latencies of 37 and 38 msec in the flexor hallucis brevis. Ephaptic transmission was implied.

Pyridoxine neuropathy in rats: specific degeneration of sensory axons.

When rats received pyridoxine in doses large enough to cause neuropathy in humans, the animals developed gait ataxia that subsided after the toxin was withdrawn. By using quantitative histologic techniques, we found axonal degeneration of sensory system fibers and that the fibers derived from the ventral root were spared. Although the degeneration approached the dorsal root ganglion, neurons in the ganglion did not degenerate. We found no early decrease in oxygen consumption of nerve, suggesting that impaired oxidative metabolism was not the primary event.

A neurophysiological theory for the pain mechanism of tic douloureux.

In attempting to understand the mechanism of pain production in tic douloureux, one must account for the myelination pathology seen in the primary afferent fibers, the cases where trigger is in a different division than the pain, the frequent lack of a fixed neurologic deficit, the effective trigger stimuli corresponding to large caliber axons which would not seem to involve the small axons usually associated with pain production, and similar puzzling features of the disease. We present a theory which satisfactorily predicts, or is consistent with, most known features of tic; it is based upon two mechanistic assumptions, both of which have strong experimental foundations in the literature. The first is the trigeminal dorsal root reflex, and the second is the creation of extra action potentials at sites of altered myelination.

Mechanosensitivity of dorsal root ganglia and chronically injured axons: a physiological basis for the radicular pain of nerve root compression.

The radicular pain of sciatica was ascribed by Mixter and Barr to compression of the spinal root by a herniated intervertebral disc. It was assumed that root compression produced prolonged firing in the injured sensory fibers and led to pain perceived in the peripheral distribution of those fibers. This concept has been challenged on the basis that acute peripheral nerve compression neuropathies are usually painless. Furthermore, animal experiments have rarely shown more than several seconds of repetitive firing in acutely compressed nerves or nerve roots. It has been suggested that "radicular pain" is actually pain referred to the extremity through activation of deep spinal and paraspinal nociceptors. Our experiments on cat lumbar dorsal roots and rabbit sural nerves have confirmed that acute compression of the root or nerve does not produce more than several seconds of repetitive firing. However, long periods of repetitive firing (5-25 min) follow minimal acute compression of the normal dorsal root ganglion. Chronic injury of dorsal roots or sural nerve produces a marked increase in mechanical sensitivity; several minutes of repetitive firing may follow acute compression of such chronically injured sites. Such prolonged responses could be evoked repeatedly in a population of both rapidly and slowly conducting fibers. Since mechanical compression of either the dorsal root ganglion or of chronically injured roots can induce prolonged repetitive firing in sensory axons, we conclude that radicular pain is due to activity in the fibers appropriate to the area of perceived pain.

Acquired oculomotor synkinesis.

Paradoxical patterns of pupillary, lid and eye movement may follow oculomotor nerve palsy or they can develop spontaneously in patients with no known history of oculomotor palsy. The mechanism of this condition, known variously as aberrant regeneration of the third nerve, oculomotor misdirection or acquired oculomotor synkinesis, is not known, although the prevailing opinion has held that it occurs when axons regenerating within an oculomotor nerve become misdirected and innervate muscles for which they were not intended. However, there is evidence against this hypothesis. The authors critically review the various hypotheses and elucidate the controversy concerning the pathogenesis of acquired oculomotor synkinesis.

Central axons in injured cat spinal cord recover electrophysiological function following remyelination by Schwann cells.

Axonal morphometry of the lesion site was studied at 3 months after standardized weight-drop contusion injury of the thoracic spinal cord in adult cats. From a sample of 25 injured animals, 12 examples were found in which all surviving axons in the dorsal column were remyelinated by Schwann cells, at the level of the lesion. The dorsolateral tracts were also peripherally myelinated in 6 of these cases, and there was no central myelination in complete transverse sections through the lesion in four animals. In these cases, Schwann cell myelination was prevalent for several millimeters on either side of the lesion center. The extent of Schwann cell invasion correlated with the intensity of injury, measured by overall axon loss. Cortical somatosensory evoked potentials (CSEP) were recorded from all animals before and at intervals for 12 weeks after injury. CSEP to hindlimb (tibial nerve) stimulation were lost immediately at injury but some recovery took place during the first month. The extent of CSEP recovery correlated negatively but weakly with overall axon loss. Clear SEP were recorded at 3 months post-injury in 3 of the animals in which the dorsal columns were remyelinated by Schwann cells; in one of these, the dorsolateral funiculi were also peripherally myelinated. In another, oligodendrocyte myelination was absent from the entire transverse section of the lesion site. Thus, abnormal remyelination by cells of the peripheral nervous system, which is known to occur in a variety of central demyelinating conditions, is capable of restoring effective action potential conduction in mammalian spinal cord sensory tracts.

Reflex activity and axonal conduction in the L-7 spinal cord segment following experimental compression trauma.

In cats in which the spinal cord was transected at C-1, the exposed L-7 spinal cord segment was compressed with an electromagnetically driven rod applied to the dorsal surface of the segment. With the magnitude of compression constant at 3 mm, the cord was compressed for durations of 50 msec, 0.5 sec, or 1.0 sec. Polysynaptic reflex discharges integrated in the injured segment and action potentials conducted in dorsal column axons traversing the same region were electrophysiologically measured before, during, and for 41/2 hours after trauma. Structural changes were evaluated on frozen serial sections obtained both from compressed segments and from tissue adjacent to the injury. At a compression duration of 50 msec, the amplitude of evoked reflex activity decreased abruptly, and dorsal column axonal conduction was blocked for 1 minute following compression. This early-phase response was followed by partial recovery of both functions which persisted until the end of the experiment. Prolonging compression to 0.5 sec brought about a further decrease of polysynaptic reflex activity. Axonal conduction was also decreased, but not significantly. With compression lasting 1.0 sec, no significant changes in reflex discharges and axonal conduction occurred compared with those measured at 0.5 sec. Neither function was abolished, even after the longest compression time. Prolongation of compression significantly increased both the intensity and the spread of edema, whereas changes in hemorrhage were not significant. Thus, a plateau rather than a progressive increase in severity of functional and structural posttraumatic changes was reached by increasing the duration of compression. This injury model reduces the sources of variability found in other experimental compression trauma models and permits the quantitative assessment of basic spinal cord mechanisms and correlated histopathological changes in the same preparation following trauma.

The pathophysiology of proximal neurofilamentous giant axonal swellings: implications for the pathogenesis of amyotrophic lateral sclerosis.

Neurofilamentous giant axonal swellings are observed in a number of human disorders, although they can manifest at different locations (i.e. proximal or distal) along the axon. Recent advances in understanding the pathogenesis of these changes has resulted from correlations of ultrastructural changes with abnormalities in the axonal transport of neurofilament proteins in experimental models produced by toxic chemicals. Using single, high doses of either acrylamide or 2,5-hexanedione, a reduction in neurofilament transport has been shown in the rat sciatic nerve. In contrast to the distal axonal swellings observed upon repeated exposures to these agents, modest proximal axonal swellings containing increased neurofilament content are found following high dose exposures. Thus, regardless of the location of swelling production, a defect in slow transport appears to underlie swelling formation. beta,beta'-Iminodipropionitrile (IDPN) produces proximal neurofilamentous giant axonal swellings which are indistinguishable from those observed in some patients with amyotrophic lateral sclerosis (ALS). Although not a model for ALS, IDPN provides a means to study the functional consequences of proximal giant axonal swellings. Intracellular recordings from IDPN-intoxicated cats reveal a number of abnormalities which may have electrophysiological counterparts in ALS, suggesting that the swellings may be important in the expression of the disease. Although axonal degeneration is rarely observed in the cat, perikaryal recordings reveal a number of alterations which are strikingly similar to those obtained from chromatolytic motor neurons following nerve transection. A perturbation of "trophic" signals from the periphery may be involved in the generation of axotomy-like changes in IDPN-intoxicated cats.

Hypothermia-induced reversible polyneuropathy: electrophysiologic evidence of axonopathy.

A 2 1/2-year-old child developed peripheral polyneuropathy following exposure to hypothermia. Serial electrophysiologic studies over the next 10 months revealed progressive recovery from severe axonopathy. The literature on cold-induced neuropathy is reviewed. The two electrophysiologic studies reported previously in cold-induced polyneuropathy patients are discussed and compared with findings of our patient.

Interfascicular nerve repair.

The technique of nerve repair that results in the greatest percentage of regeneration of axons into their original end organs will result in the greatest functional return and the best result. Of prime importance is the motor-to-motor and sensory-to-sensory axonal orientation. Anatomic and physiologic data, as well as technical expertise, must be utilized for precise nerve approximation. To this end, fascicular repair under high-power magnification is an attempt to achieve the best alignment and coaptation of the neural elements.

Use of exogenous electric current in the treatment of delayed lesions in peripheral nerves.

A commonly observed clinical problem following nerve injury is the incomplete recovery of function associated with the formation of a neuroma in continuity. In the present study, exogenous direct electric current was tested for its ability to promote growth of axons through a neuroma-like lesion. Neuroma-like structures were created by crushing rat sciatic nerves at two sites 4 mm apart and applying phenol to the intermediate region. A bulbous axonally impenetrable structure is formed 3 weeks later. At that time, silicone cuffs were sewn onto the nerve proximal to the phenol application site and 7 mm distally. In experimental groups, cuffs were attached to wires leading to a subcutaneously implanted Traxon power source, the distal cuff being cathodal. In control groups, cuffs were not electrically connected. In electrically active groups, substantial numbers of myelinated axons were seen distal to the cathode 3 weeks after implantation. Four times fewer fibers were observed in control groups. Footprint patterns from electrically active animals revealed a significant improvement over control neuroma preparations, as quantitated using the Sciatic Functional Index.

Capsaicin prevents histamine-induced itching.

The effects of topical treatment with capsaicin or mustard oil on histamine-induced pruritus, wheal formation and flare response were studied in the human skin. Capsaicin pretreatment resulted in a reversible marked reduction or abolition of the axon reflex flare, but did not influence whealing. Itching was also strongly diminished or even abolished, provided that the flare response was completely blocked. The onset of itching was significantly promoted by pretreatment of the skin with mustard oil, inducing axon reflex vasodilatation. It is concluded that, in addition to the axon reflex flare, capsaicin-sensitive peptide-containing primary afferent neurones are also intimately involved in the mediation of the sensation of itching.