Conduction of neural impulses in diabetic neuropathy.

OBJECTIVE: To measure the conduction velocity, absolute refractory period and duration of the action potential for individual afferents of the median nerve in diabetic patients and to examine correlations between measures and with temperature and compare this to data from normal subjects. METHODS: The technique of percutaneous microneurography was used to record from individual afferents and intradermal electrical stimuli were applied to generate action potentials in distal axons. RESULTS: Like normal afferents, afferents in diabetic subjects demonstrated temperature sensitivity. Durations of the action potential and refractory periods correlated with temperature (r=-0.59 and r=-0.51). Conduction velocities and durations of the action potential did not differ between diabetic (means of 34 m/s and 0.42 ms) and normal (means of 34 m/s and 0.45 ms) subjects. However, refractory periods were significantly shorter in diabetic (mean 1.3 ms) than in normal (mean 1.8 ms) nerves and the normal correlation between conduction velocity and refractory period was disrupted. CONCLUSIONS: The results reveal disturbances of the axonal recovery process in diabetic patients, possibly due to membrane potential fluctuations after the generation of an action potential. Uncovering specific excitability changes in diabetic nerve facilitates the design of pharmacological interventions for restoring nerve function.

Scanning Kelvin Microscope: a new method for surface investigations.

Based on the well known Kelvin probe for work function measurements a new microstructure analysis system - the Scanning Kelvin Microscope - has been developed. It allows to measure simultaneously with high lateral resolution the distribution of the contact potential difference (CPD) between a conductive sample and a reference probe together with the topographical structure of the sample surface. The measurement is contact free and non-destructive and can be carried out in natural environments. At present the lateral resolution of the measurement approaches 5 microm. The results can be displayed on a computer in three dimensional colour pictures.

Properties of cutaneous afferents during recovery from Guillain-Barré syndrome.

The technique of percutaneous microneurography was used to record from 60 mechanosensitive cutaneous afferents in patients (n = 5) who were recovering from acute Guillain-Barré syndrome (GBS) and who displayed residual sensory deficits in the hands. Recordings were obtained from median and ulnar nerves, between 1 and 31 months following plasma exchange therapy. The behaviour of all four types of cutaneous afferents known to innervate the glabrous skin of the normal hand (rapidly adapting types RA and PC and slowly adapting types SAI and SAII) was studied in response to mechanical skin stimulation. Some of the units could not be fully classified. Additionally, intradermal electrical stimulation was used to study conduction velocity and absolute refractory period. Abnormal response behaviour was encountered in RA, PC and slowly adapting afferents. The abnormalities consisted of a generation of only a single action potential to above threshold stimuli (RA), inability to follow high frequency vibration (PC) and, in slowly adapting afferents, reduced discharge rates during sustained skin indentations or cessation of discharge during indentation. Abnormally responding units were more frequently found in patients with marked, than in those with mild, clinical sensory symptoms. In the former, half of all units in each patient responded abnormally (12 out of 23 in total). In patients with mild symptoms, most units (33 out of 37) were normal in response behaviour as well as in other measures made: threshold to mechanical stimuli, static discharge rate, receptive field size, conduction velocity, absolute refractory period. Spontaneous activity of unknown origin was also encountered in some patients. The activity consisted of highly regular discharge bursts or relatively regular unitary discharges. The data indicate that the encoding capabilities of all types of cutaneous afferents (RA, PC, SAI and SAII) may be affected in GBS, contributing to the sensory deficits of the disease. The abnormal encoding most likely reflects a limited ability of the axons to conduct trains of action potentials.

Nucleus Z: a somatosensory relay to motor thalamus.

1. It was the aim of this study to show that nucleus Z of the cat medulla acts as a relay between the spinal cord and the ventral lateral (VL) nucleus of the motor thalamus. For this purpose, extracellular recordings were made from neurons that were antidromically identified by stimulation in the rostral thalamus, particularly VL, and orthodromically activated by electrical stimulation of the spinal cord and/or natural stimulation of the hindlimb. The electrophysiological work was complemented by anatomic work. Here, wheat germ agglutinin-horseradish peroxidase (WGA-HRP) was injected into nucleus Z and the termination sites of bulbothalamic projections were anterogradely labeled. 2. A total of 120 neurons were antidromically identified as projecting to thalamus: 101 to VL and 19 outside VL. The recording sites in nucleus Z were marked by dye injection or by electrolytic lesion. They were confined to a small region (roughly 1 mm in diameter), 2.8-3.7 mm rostral to obex, 2.9-3.8 mm lateral from the midline, and from the surface of the medulla to a depth of 1 mm. The antidromic latencies ranged between 0.8 and 3.2 ms, with no difference in latencies associated with location of neurons in nucleus Z or thalamic projection sites. 3. Injection of WGA-HRP labeled fibers and axon terminals in the contralateral thalamus. Terminal labeling was densest in the lateral parts of the mid- and caudal region of the VL nucleus and, to a lesser extent, in the adjacent rostrodorsal part of the ventro-posterior lateral (VPL) nucleus. The sites of terminal labeling in VL corresponded with location of antidromic stimulation sites. 4. Orthodromic activation of nucleus Z neurons was tested in response to electrical stimulation of the ipsilateral dorsolateral funiculus (which includes the dorsal spinocerebellar tract) and/or the dorsal columns. All neurons responded to stimulation of the dorsolateral funiculus (45/45). The responsiveness of 44 neurons was tested to stimulation of the dorsal columns. Only 8 of 44 tested responded with a discharge. The orthodromic latencies of unitary discharges ranged from 1.1 to 4.4 ms to stimulation of the dorsolateral funiculus, and from 1.1 to 4.9 ms to stimulation of the dorsal columns. Most responses are likely to be monosynaptic. Differences in latencies were not associated with location of recording sites or thalamic projection sites of nucleus Z neurons. 5. The responsiveness of many neurons (n = 84) was tested to natural stimulation of the ipsilateral hindlimb (which provides the sensory input to nucleus Z).(ABSTRACT TRUNCATED AT 400 WORDS)

Time course of action potentials recorded from single human afferents.

It was the object of this study to measure the time course of the action potential in individual human sensory nerve fibres in relation to conduction properties of the axons. For this purpose, the technique of percutaneous microneurography was combined with intradermal electrical stimulation of distal portions of the axons. Recordings were made at the wrist level from 57 type-identified mechanoreceptive median nerve afferents [mainly rapidly adapting (RA) and slowly adapting type I (SAI)] innervating the glabrous skin of the hand. Measurements were made of the duration and time-to-peak of the positive peak of the diphasic (large positive phase followed by smaller, slower negative phase) action potential typically recorded using microneurography. Durations ranged from 0.31 to 0.75 ms (mean 0.50 ms) and times-to-peak from 0.12 to 0.45 ms (mean 0.21 ms), with no difference between afferent categories (RA, SAI). Time-to-peak was strongly positively correlated with duration (linear r = 0.81). Conduction velocity was measured over the distance extending from the point of intradermal stimulation (typically in the fingertips) to the point of recording at the wrist (distal conduction velocity). Absolute refractory period was measured using paired stimuli applied at the point of intradermal stimulation, within the receptive field of the afferent (distal absolute refractory period). Distal conduction velocities ranged from 15 to 60 m/s (mean 33 m/s), and distal refractory periods from 0.7 to 4.5 ms (mean 2.1 ms), with no difference between afferent types (RA, SAI). Distal absolute refractory period was inversely correlated with distal conduction velocity. The data were slightly better described assuming a non-linear (exponential) relationship; the non-linear correlation coefficient was -0.77. The time course of the action potential varied inversely with distal conduction velocity and directly with distal absolute refractory period. The time-to-peak versus conduction velocity data were slightly better described by a power than a linear relationship. Coefficients of correlation were: duration versus conduction velocity, linear r = -0.76; time-to-peak versus conduction velocity, non-linear r = -0.64; duration versus absolute refractory period, r = 0.70; time-to-peak versus absolute refractory period, r = 0.76. Extensive intercorrelation between the variables duration, distal conduction velocity and absolute refractory period was revealed by multiple correlation techniques. Inter- and intra-subject skin temperature variation was within 5 degrees C. Correcting the time course, conduction velocity and absolute refractory period values for temperature variation within this limited range did not affect the results.(ABSTRACT TRUNCATED AT 400 WORDS)

Spinal input to thalamic VL neurons: evidence for direct spinothalamic effects.

1. The postsynaptic actions of afferents ascending in the ventrolateral quadrant and dorsal columns of the spinal cord were studied in neurons in the ventrolateral nucleus of the thalamus (VL) (n = 138) by use of intracellular recording procedures. Neurons were identified by their monosynaptic input from the cerebellum and, when possible, their antidromic activation from the motor cortex. The possible occurrence of monosynaptic transmission along spinothalamic fibers was investigated by estimating the intrathalamic delay time of postsynaptic responses and by examining the occurrence of temporal facilitation to double-shock stimulation. The experiments were performed in cats anesthetized with alpha-chloralose. 2. The majority of neurons (86%) responded with excitatory or inhibitory postsynaptic potentials to stimulation of the ascending paths. The response latencies of excitation on stimulation of the ventral quadrants at C3 ranged from 2.9 to 18 ms. Evidence for monosynaptic excitation after stimulation of (spinothalamic) afferents ascending in the ventrolateral quadrants was obtained for a number of neurons (n = 30). For these neurons, estimated intrathalamic delays were less than 1 ms and/or the neurons did not display temporal facilitation to double shocks. All the shortest latency responses (from C3) showed evidence of monosynaptic transmission. It is estimated that approximately 19-39% of neurons sampled may receive monosynaptic input. The spinal conduction velocities of the direct projections ranged from 10 to 35 m/s (median 20 m/s). 3. Much of the ascending input was mediated polysynaptically. For afferents ascending in the ventrolateral quadrant, estimated intrathalamic delays were greater than 1.5 ms and/or the postsynaptic responses displayed temporal facilitation to double shocks. The shortest latency from C3 of a polysynaptic response was 5 ms. Spatial interactions were observed between polysynaptic inputs from the ventrolateral quadrants and the dorsal columns, indicating that at least some of the pathways to VL are shared. 4. The data show that many neurons in the VL receive input ascending from the spinal cord via direct and indirect routes. Somatosensory information reaching VL could serve to adjust, during the course of movement execution, the cerebellar commands relayed by VL to the motor cortex.

Dorsal column input to thalamic VL neurons: an intracellular study in the cat.

This study investigated the role of the ventral lateral (VL) nucleus of the thalamus as a lemniscal relay to motor cortex. Intracellular recordings were obtained from thalamic VL relay neurons in cats anesthetized with chloralose, following stimulation of the dorsal column nuclei. VL neurons were identified by their short-latency input from the cerebellar nuclei, their antidromic activation from motor cortex and their anatomical location. A total of 105 neurons was studied. The occurrence of temporal facilitation to double volleys was also examined. It was found that 80/105 (75%) neurons responded with excitation and/or inhibition to stimulation of the dorsal column nuclei. The latencies of the postsynaptic responses ranged from 2.0 to 20 ms (median 10.0 ms). The latencies of nearly all responses (79/80) were greater than 3 ms and nearly all responses (45/47) which were tested for it, displayed temporal facilitation to double shock stimulation, consistent with polysynaptic transmission. Effective stimulation sites were found in the gracile and cuneate nuclei. Recording sites were located throughout VL, including the "border region" with the ventral posterior lateral nucleus (VPL). There was no obvious topographic relationship between location of recording site and latency or polarity (excitation versus inhibition) of the synaptic responses. This is consistent with dorsal column input diffusely distributed over VL. When the recording electrodes penetrated VPL, characteristics of the EPSPs were indicative of monosynaptic transmission (short latency, no temporal facilitation). This clear transition from VL to VPL suggests that it is not necessary to define, on physiological grounds, a separate "border region" between these two nuclei.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurons of the pretectal area convey spinal input to the motor thalamus of the cat.

The aim of this study was to corroborate lesioning work (Mackel and Noda 1989), suggesting the pretectal area of the rostral midbrain acts as a relay between the spinal cord and the ventrolateral (VL) nucleus of the thalamus. For this purpose, extracellular recordings were made from neurons in the pretectal area which were antidromically activated by stimulation in the rostral thalamus, particularly in VL. The neurons were tested for input from the dorsal columns of the spinal cord, the dorsal column nuclei, and the ventral quadrant of the spinal cord. Latencies of the antidromic responses ranged between 0.6 and 3.0 ms (median 1.0 ms): no differences in latencies were associated with either location of the neurons in the pretectal area or with the site of their thalamic projection. Orthodromic responses to stimulation of ascending pathways were seen in the majority of neurons throughout the pretectal area sampled. Latencies of orthodromic responses varied considerably, with ranges of 0.9-9 ms, 6-20 ms, and 2.5-20 ms upon stimulating the dorsal column nuclei, dorsal columns, and ventrolateral quadrant, respectively. The shortest-latency responses to stimulation of the dorsal column nuclei or of the ventral quadrant were likely to be monosynaptic. Temporal and spatial facilitation of the responses to ascending input were common. The data show that neurons of the pretectal area are capable of relaying somatosensory input ascending from the spinal cord to the rostral thalamus. It is suggested that the pretectofugal output to VL converges with cerebellar input in VL neurons and becomes incorporated in cerebello-cerebral interactions and, ultimately, the control of movement.

Properties of cutaneous afferents in diabetic neuropathy.

The technique of percutaneous microneurography was used to study the response properties of 68 cutaneous afferents in 8 diabetic patients and, for comparison, of 104 afferents in 12 normal control subjects. The diabetic patients were neurologically asymptomatic or had a mild sensory neuropathy. Three afferent categories were studied in the diabetic subjects (rapidly adapting type RA and slowly adapting SAI and SAII) in response to mechanical skin stimulation and abnormal responsiveness was encountered in all categories. Distinct abnormalities were seen in about 30% of the RA and in 20% of the SAI type nerve fibres. The abnormalities consisted of the generation of only single action potentials to above threshold stimuli (RA), and of high fatiguability to repetitive stimulation (SAI). A more subtle abnormality was additionally encountered in the slowly adapting SAI and SAII groups. This consisted of low discharge rates to sustained skin indentation, with values statistically significantly different from normal. Absolute mechanical response thresholds and receptive field configurations were similar between diabetic and normal units. The conduction velocities of individual nerve fibres were measured in response to intradermal electrical stimulation. They were similar to normal, regardless of whether the afferents displayed normal or abnormal responsiveness to physiological stimulation of the receptive fields. The data indicate that different cutaneous afferent categories are affected by the disease, and are limited in their ability to transmit trains of action potentials. As a consequence, physiological stimuli may be abnormally encoded in diabetic units. Two hypotheses, one morphological and one biophysical, are proposed for explaining the present findings. The results altogether provide a physiological basis for understanding nerve fibre dysfunction and sensory disturbances in human diabetic neuropathy.

The pretectum as a site for relaying dorsal column input to thalamic VL neurons.

Intracellular recording techniques were used to study dorsal column input to 122 feline ventral thalamus (VL) relay neurons, before (61 cells) and after (61 cells) lesioning the pretectum. Prior to the lesions, 75% (46/61) of the neurons responded with short and longer latency postsynaptic potentials to dorsal column stimulation. Latencies of the postsynaptic potentials ranged from 4 (short) to 20 ms (long). After the lesions, only long latency responses were encountered, and those responses were seen in only 16% (10/61) of the cells. These data indicate that the pretectum may play an important role in mediating dorsal column information to VL, ultimately influencing cerebellar commands to the motor cortex.

Distribution of recurrent inhibition within a motor nucleus. I. Contribution from slow and fast motor units to the excitation of Renshaw cells.

The relation between the size of a monosynaptic reflex (MSR) to triceps surae and the resulting Renshaw cell discharge was used to evaluate the contribution from slow and fast motor units to the excitation of Renshaw cells. It is, however, difficult to interpret these results in terms of excitation contributed by slow and fast motor units because of the following reasons. First, the size of the MSR recorded in ventral roots is not linearly related to the number of recruited motor units, since larger motor axons contribute more to the size of the MSR than smaller ones. Second, the number of spikes evoked in a Renshaw cell burst is not linearly related to the excitatory input because Renshaw cell discharge saturates in the case of large responses. The contribution of small, early-recruited motoneurones to Renshaw cell excitation is consequently overestimated. Procedures were introduced to deal with these problems. It is concluded that the last-recruited motor units (probably 'fast twitch, fast fatiguing') on average contribute four times as much excitation to Renshaw cells as the first recruited ('slow twitch') motor units.

Distribution of recurrent inhibition within a motor nucleus. II. Amount of recurrent inhibition in motoneurones to fast and slow units.

The maximal recurrent inhibition was studied by intracellular recording from 43 triceps surae motoneurones (tentatively type-identified by the biophysical properties of the neurones) and from 67 medial gastrocnemius motoneurones (type-identified by the muscle unit properties; fast fatiguing, FF; fatigue resistant, FR and slow, S). Maximal homonymous recurrent IPSP (RIPSP) and input resistance (RN) were measured at 'resting' membrane potential and close to firing threshold. The 'synaptic current' at the peak of the RIPSP was estimated (RIPSP/RN). At 'resting' membrane potential the RIPSPs increased in the order FF less than FR less than S (0.9, 1.4, and 2.5 mV, respectively). This order was preserved when the 'current' (RIPSP/RN) rather than voltage was considered, although the overall range was much reduced. When investigated close to firing threshold there were no significant differences in synaptic 'current'. This apparent paradox may be explained by systematic differences in firing threshold between motor unit types; it increased in the order S less than FR less than FF (4.6, 8.9 and 13.5 mV, respectively).

Conduction of neural impulses in human mechanoreceptive cutaneous afferents.

1. It was the aim of the present study to isolate and identify the components underlying the human sensory compound action potential and to study their axonal conduction velocities and refractory periods. For this purpose the technique of percutaneous microneurography was combined with intradermal electrical stimulation of nerve fibre terminals. Sixty-four median and ulnar nerve afferents innervating the glabrous skin of the digits were isolated and type identified. 2. The range of axonal conduction velocities was wide (20-60 m/s), but similar for each afferent category (20-60 m/s). Most afferents conducted slower than expected from the intrafascicularly recorded compound potential (50-60 m/s) and their conduction velocities generally decreased from the base to the tip of the digits. 3. The duration of the absolute axonal refractory periods of all types of afferents ranged from 0.7 to 3.5 ms. The duration of the total refractory periods ranged from 3 to 9 ms. Both absolute and total axonal refractory periods were inversely correlated (r = -0.70 and r = -0.67) with their axonal conduction velocities. 4. The size of individual action potentials was significantly correlated with axonal conduction velocities, although the correlation coefficient was relatively low (r = 0.43), even after correction for variability due to electrode resistance (partial correlation r = 0.44). 5. The results showed that different types of cutaneous afferents cannot be separated on the basis of their axonal conduction properties. The data demonstrate features of neural impulse conduction along the entire axonal tree and which are inaccessible to routine electrodiagnostic procedures. The present approach provides a sensitive means for assessing, in health and disease, nerve conduction in terminal axons.

Sensory input to cerebellocerebral relay neurons in the cat thalamus.

Intracellular recording techniques were used to study the synaptic responses of feline ventrolateral neurons to dorsal column, spinothalamic and sensory cortex stimulation. More than 75% of the cells responded with short- and long-latency excitatory or inhibitory postsynaptic potentials to the one or/and other stimulation sites. These findings indicate that a considerable amount of somatosensory integration in the cerebellocerebral circuit occurs in the thalamic relay neurons.

Sensorimotor performance of the hand during peripheral nerve regeneration.

Conventional neurological testing procedures outline the sensory and motor incapasities which occur following peripheral nerve injury, but they provide little practical information on the ability of the patient to use the injured part in daily life activities. In the present study functional tests are introduced which lend themselves to statistical analysis and can be routinely and universally applied. The tests did also permit a study of the role of sensation in motor performance. The tests were able to distinguish between nerve-damaged and normal hands; with all differences being statistically significant. Rating scales were devised to indicate how much a motor or sensory performance deviated from normal: function was assessed as poor, satisfactory, or good. No correlation could be established between the results obtained from functional and routine neurological tests nor between sensorimotor performance and the response behavior of single afferents recorded in the same patients. The results indicate that the functional tests are useful and promising for a more general application. The results do also underline the need for sensation in the successful execution of a sequence of coordinated, skillful movements.