William H. Calvin

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

&NA; 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.

Did throwing stones shape hominid brain evolution

Abstract Early hominid evolution may have involved an interaction between lateralization to left brain of rapid motor sequencing (e.g., right handedness) and its selection via one-handed throwing of stones at small prey. Since a more redundant sequencer should permit faster orchestration of muscles, faster (and hence longer range) throws could have selected for encephalization. Secondary uses of the enlarged sequencer may have included tool-sharpening and manual gestures. Because an oral-facial sequencing area just below motor strip forms the core of modern language cortex, there may have been a common origin of handedness and language in redundant sequencing circuits selected by throwing success.

A neurophysiological theory for the pain mechanism of tic douloureux.

&NA; 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 the 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.

Can Neuralgias Arise from Minor Demyelination? Spontaneous Firing, Mechanosensitivity, and Afterdischarge from Conducting Axons

Abstract Mammalian peripheral axons respond to local disruption of their myelin sheath with membrane changes which support continuous conduction of the impulse through the affected region. We report here that sites of demyelination may become foci of spontaneous impulse initiation. Such sites may also generate ectopic discharges upon slow mechanical distortion. Finally, conduction of an impulse train through a demyelinated region may set off an ectopic afterdischarge that may last many seconds. Rhythmic ectopic firing in dysmyelinated but conducting axons is very similar to that observed in regenerating axons and nerve-end neuromas. Although the latter have long been recognized as sources of pathophysiologic sensations, this is the first indication that neuralgias could arise following minor dysmyelination in peripheral nerves without substantial conduction deficits.

Human cortical neurons in epileptogenic foci: Comparison of inter-ictal firing patterns to those of “epileptic” neurons in animals

Abstract 1. 1. Extracellular recordings of the spontaneous firing patterns of cortical neurons were obtained in patients undergoing craniotomy for the surgical excision of an epileptogenic focus. 2. 2. Because many kinds of experimental “epileptic” foci in animals exhibit cells with high frequency (200–500/sec) bursts of action potentials, lasting 5–50 msec and recurring many times per second, we explored the electrocorticographically defined epileptogenic focus in humans in search of bursting firing patterns. 3. 3. In addition to normal firing patterns, many cells near the focus exhibited “epileptic” bursting firing patterns. Sometimes, normal and bursting cells could be recorded simultaneously, indicating that cells in proximity to one another are not uniform in such firing properties. 4. 4. Such high frequency bursts are not typically the result of artifact such as micro-electrode pressure upon a cell, or heartbeat or respiratory movements of the cortex. Most bursting cells were obtained under operating conditions involving local anesthesia, but similar results were seen under general anesthesia. 5. 5. Bursts were not necessarily synchronized with the EEG sharp waves, nor with bursts from other simultaneously recorded neurons. 6. 6. Attempts were made to modify the burst patterns by arousing a sleeping patient and by electrical stimulation of the adjacent cortical surface. While some modifications in the rate of recurrence of the bursts could be obtained, the timing patterns of the first few spikes within a burst did not change readily. 7. 7. High frequency tonic firing was also seen. Some such activity could be observed to undergo spontaneous changes from silence to high frequency tonic firing and then to bursts. 8. 8. Within a burst, the timing of spikes may be very repeatable (stereotyped bursts) in some cases. In a few cases, the structured bursts reported in chronic monkey foci have been observed, where there seems to be a characteristic pause in the firing after the first one or two spikes and then a resumption of high frequency firing in a manner identical to the stereotyped bursts. These structured timing patterns have been considered a clue towards the identification of primarily dysfunctional epileptic neurons (in contrast to normal cells recruited into bursting firing patterns by an abnormally large synaptic input). 9. 9. We would conclude that there is a good correspondence between the chronic alumina “epileptic” foci in animals and the human disease, insofar as the inter-ictal firing patterns of neurons near the focus is concerned.

Structured timing patterns within bursts from epileptic neurons in undrugged monkey cortex

Abstract While normal cortical neurons often show ill-defined, labile bursts during spontaneous firing, stereotyped high-frequency bursts every 50–200 msec are characteristic of the firing patterns of neurons near chronically alumina-induced epileptic foci in sensorimotor cortex of awake, undrugged rhesus monkeys. Computer-assisted analysis of the timing patterns within bursts revealed an unusually long interval between the first and second spikes of these epileptic bursts, with the later spikes of the burst time-locked to the second spike, not the first spike. In some neurons, this stereotyped “remainder” of the burst would begin at a highly variable time following the first spike. In other neurons, this first interval was bimodal, with the remainder of the burst starting either 3 or 4 msec following the first spike. In a third class of epileptic neuron, the first interval was unusually long and remarkably lacking in variability (8.6 ± 0.2 msec). Other neurons, especially those located further away from the epileptogenic focus, showed less stereotyped bursts without the long first intervals. One explanation considered for these phenomena is that the neuron is being stimulated antidromically (first spike) and responds repetitively (remainder of the burst).

Synaptic noise as a source of variability in the interval between action potentials.

The source of variability in the interval between action potentials has been identified in a class of cat spinal motoneurons. The observed random fluctuations in membrane potential (synaptic noise) together with an empirical description of spike generation accurately predict the statistical structure of variability observed to occur in the neurons discharge.

Synaptic potential summation and repetitive firing mechanisms: Input-output theory for the recruitment of neurons into epileptic bursting firing patterns

Abstract Neurons in human epileptic foci (and in the various animal models of epilepsy) tend to discharge in high-frequency bursts. If a normal neuron received enough inputs from such epileptic bursting neurons, the temporal and spatial summation of PSPs might elicit a high-frequency burst from the normal neuron itself. This paper considers quantitative models for PSP summation: The average depolarization is the product of mean PSP rates and the area beneath a single PSP, ignoring non-linearities. The size of PSPs, due to single inputs, in mammalian CNS neurons is reviewed and used to estimate the mean depolarization caused by nominal 20/sec firing rates in an input fiber; from this, it is estimated that 2% of a normal neurons inputs would be required to give enough spatial summation to start low frequency firing, 8% to cause high-frequency responses. Temporal and spatial summation were simulated on a computer using actual spike trains from epileptic neurons bursting at high frequency, thus giving an estimate of the depolarization sequence to be expected in a normal cortical neuron which might receive synapses from an epileptic bursting neuron. Depolarization-to-firing-rate curves from normal cortical neurons were then used to illustrate the firing patterns to be expected from the normal neurons response. It was concluded that a normal neuron could be recruited into a high-frequency bursting firing pattern if about 1% of its inputs possessed such firing patterns. The input spikes need not be synchronous; only the bursts themselves need overlap in time (simultaneous recording from several epileptic neurons often exhibit such overlap of bursts). Bursts lasting longer than several postsynaptic time constants will nearly achieve their maximal mean depolarizations; bursts longer than that may not achieve significantly greater depolarization levels, but will increase the chances of overlap in bursts from different inputs.

Deafferentation Effects in Lateral Cuneate Nucleus of the Cat: Correlation of Structural Alterations with Firing Pattern Changes

Abstract A correlated anatomical and physiological investigation of the effects of unilateral cervicothoracic dorsal rhizotomies upon lateral cuneate nucleus of the cat (LCN) is reported. Pairs of adult cats with identical survival times were selected to correlate structural and functional changes. Two phases are described in the development of alterations of neuronal firing patterns. In the first phase, a relative silence within LCN was associated with depletion of round synaptic vesicles in the presynaptic profiles (LR boutons) of primary dorsal root afferents. The second phase was characterized by a development of spontaneous electrical hyperactivity which corresponded anatomically to the presence of denuded postsynaptic specializations, transient increase of adjacent extracellular space and an apparent decrease in the number of dendritic spines. There was a persistence of an unaltered population of small presynaptic boutons with flattened vesicles (SF boutons). The LCN neuronal membrane is viewed as having an intrinsic tendency for repetitive firing which is enhanced by the functional effects of denuded postsynaptic specialization. A marked similarity was found between some of the spontaneous firing patterns of normal animals (doublets) and the high frequency bursting firing pattern in deafferented preparation. Three models for repetitive spike production are considered in our analysis: oscillator-produced spikes; EPSP-produced spikes; and spike-evoked spikes. The spike-evoked spikes model is considered to be the origin of normal doublet activity and a candidate for the deafferented burst activity. Abnormal hyperactivity after deafferentation may be a function of changes in the membrane characteristics occurring at or near the denuded postsynaptic specializations.

Doublet and burst firing patterns within the dorsal column nuclei of cat and man

Abstract We have examined extracellularly the firing pattern of neurons in the cat external cuneate nucleus and in the human main cuneate nucleus, focusing upon both the spontaneous firing patterns and its modification by natural stimulation. Many of these neurons exhibit stereotyped doublet or burst firing patterns, e.g., the interval between the spikes might be 1.0 ± 0.1 msec in a given cell. For most cells, this characteristic doublet interval was between 0.8 and 2.0 msec, with a few extending to 5 msec. While doublets were most common, the number of spikes per burst ranged to six or more. When the external cuneate neurons were synaptically driven by forelimb position changes, the firing rate increased but the proportion of spikes occurring within bursts (the “burst index”) often fell. The doublets that occurred became broader during synaptic drive. This paradoxical behavior (the peak instantaneous firing rate falling as the average firing rate rises) is analogous to the doublet firing patterns occasionally observed in spinal motoneurons; there, the doublet is caused by a large depolarizing afterpotential (postspike hump) which rises through the falling threshold at the end of the relative refractory period to elicit an “extra spike.”