Electrophysiological changes in diabetic neuropathy: from subclinical alterations to disabling abnormalities

Clinical spectrum of diabetic neuropathy is variable; it may be asymptomatic, but once established as polyneuropathy, it is irreversible and may finally be disabling. To estimate the prevalence of subclinical diabetic polyneuropathy in the UAE, we undertook a pilot study by means of nerve conduction study (NCS) of peroneal motor and sural sensory studies in 60 diabetics with no symptoms of neuropathy. Neurological examination revealed clinical abnormalities suggesting polyneuropathy in 26 patients, 43% of the patients. NCS revealed abnormal values in 63% of the whole patients. Abnormal NCS was confirmed in 88% of the positive sign group. As to the negative sign group 44% had abnormalities in NCS. Prolonged F-wave latency was seen in 29% in no sign group and in 66% of the patients with positive signs. We found close association between neurological deficit score and abnormalities in NCS. Among various parameter of systemic nerve conduction study in subclinical patients, prolonged F-wave latency seems the commonest abnormality suggesting morphological changes in subclinical diabetic nerve. Decrease in amplitude of compound sensory action potential of sural nerve is another earlier abnormality, which is, then, accompanied by a fall in motor amplitude of peroneal nerve in advanced patients. Recently, our own group of Hirosaki has demonstrated that somatosensory central conduction time (CCT) between the spinal cord entry time and the arrival time to the sensory cortex is prolonged in diabetics. This abnormality might be partly responsible for the irreversible sensory deficits of diabetic neuropathy.     

End plate spikes in the human electromyogram. Revision of the fusimotor theory.

'End plate spike' (EPS) is a spontaneous action potential of a normal striated muscle. EPSs are found in local 'active spots' of the muscle. The prevailing hypothesis about the origin of EPSs states that when a needle electrode affects a motor nerve branch near the neuromuscular junction at the end plate zone, an increased leakage of acetylcholine to the synaptic cleft ensues. This elicits postsynaptic action potentials of the muscle fibre which can be recorded as EPSs with the same needle electrode. Thus EPSs are thought to be caused by needle injury or irritation of the motor axon. We suggest that EPSs are action potentials of intrafusal muscle fibres and that 'active spots' are in fact muscle spindles. Waveform analysis reveals three types of EPSs: small EPSs, not propagated outside the active spot either: i) with negative onset; or ii) with short positive initial deflection; and iii) large EPSs resembling propagated motor unit potentials (MUPs) but with a typical EPS firing pattern, distinctly different from that of the MUPs. Study of EPS activation in different manoeuvres associates small EPSs with intrafusal gamma motor units and large MUP-like EPSs with beta motor units.     

Detection of motor unit action potentials with surface electrodes: influence of electrode size and spacing

A model of the motor unit action potential was developed to investigate the amplitude and frequency spectrum contributions of motor units, located at various depths within muscle, to the surface detected electromyographic (EMG) signal. A dipole representation of the transmembrane current in a three-dimensional muscle volume was used to estimate detected individual muscle fiber action potentials. The effects of anisotropic muscle conductance, innervation zone location, propagation velocity, fiber length, electrode area, and electrode configuration were included in the fiber action potential model. A motor unit action potential was assumed to be the sum of the individual muscle fiber action potentials. A computational procedure, based on the notion of isopotential layers, was developed which substantially reduced the calculation time required to estimate motor unit action potentials. The simulations indicated that: 1) only those motor units with muscle fibers located within 10–12 mm of the electrodes would contribute significant signal energy to the surface EMG, 2) variation in surface area of electrodes has little effect on the detection depth of motor unit action potentials, 3) increased interelectrode spacing moderately increases detection depth, and 4) the frequency content of action potentials decreases steeply with increased electrode-motor unit territory distance.     

Differences between properties of male and female motor units in the rat medial gastrocnemius muscle.

Differences between motor units in hindlimb locomotor muscles of male and female Wistar rats were studied. The contractile and action potential properties of various types of motor units as well as proportions of these units in the medial gastrocnemius muscle were analyzed. Experiments were based on functional isolation and electrical stimulation of axons of single motor units. Composition of motor units was different for male and female subjects, with higher number of the fast fatigable and lower number of slow type units in male animals. The contraction and the half-relaxation times were significantly longer in male motor units, what might be due to differences in muscle size. Slower contraction of male motor units likely corresponds to lower firing rates of their motoneurons. On the other hand, no significant differences between sexes were observed with respect to force parameters of motor units (the twitch and the maximum tetanus forces), except the fast resistant units (higher force values in male muscles). The mass of the muscle was approximately 1.5 time bigger in male rats. However, the mean ratio of motor unit tetanus force to the muscle mass was almost twice smaller in this group, what indirectly suggests that muscles of male rats are composed of higher number of motor units. Finally, female muscles appeared to have higher fatigue resistance as the effect of higher proportion of resistant units (slow and fast resistant) and higher values of the fatigue index in respective motor unit types. The motor unit action potentials in female rats had slightly lower amplitudes and shorter time parameters although this difference was significant only for fast resistant units.     

Diabetic polyneuropathy. 4. Synopsis of electroneurographic findings in diabetics]

Sensory conduction velocity of the median nerve, motor conduction velocity of both median and tibial nerves, and corresponding distal laterncies are sufficient parameters to establish the diagnosis of polyneuropathy almost with certainty. Considering these six parameters yielded in detection of peripheral nerve dysfunction in 22% of diabetic patients who were free from clinical signs of polyneuropathy. Electroneurographical findings in 340 out of 677 patients with diabetes mellitus were interpreted as evidence of segmental demyelination. Within this group there was the majority of patients with clinical signs of polyneuropathy and with subclinical signs of peripheral nerve dysfunction. There existed a positive correlation between signs of nerve dysfunction with angiopathy, age and duration of the disease. A second group consisting of 243 diabetics with signs of incipient segmental demyelination with or without signs of axonaal degeneration mainly included juvenile patients with a short duration of the disease and with a low frequency of angiopathy.     

Motor Unit Characteristics after Targeted Muscle Reinnervation

Targeted muscle reinnervation (TMR) is a surgical procedure used to redirect nerves originally controlling muscles of the amputated limb into remaining muscles above the amputation, to treat phantom limb pain and facilitate prosthetic control. While this procedure effectively establishes robust prosthetic control, there is little knowledge on the behavior and characteristics of the reinnervated motor units. In this study we compared the m. pectoralis of five TMR patients to nine able-bodied controls with respect to motor unit action potential (MUAP) characteristics. We recorded and decomposed high-density surface EMG signals into individual spike trains of motor unit action potentials. In the TMR patients the MUAP surface area normalized to the electrode grid surface (0.25 ± 0.17 and 0.81 ± 0.46, p < 0.001) and the MUAP duration (10.92 ± 3.89 ms and 14.03 ± 3.91 ms, p < 0.01) were smaller for the TMR group than for the controls. The mean MUAP amplitude (0.19 ± 0.11 mV and 0.14 ± 0.06 mV, p = 0.07) was not significantly different between the two groups. Finally, we observed that MUAP surface representation in TMR generally overlapped, and the surface occupied by motor units corresponding to only one motor task was on average smaller than 12% of the electrode surface. These results suggest that smaller MUAP surface areas in TMR patients do not necessarily facilitate prosthetic control due to a high degree of overlap between these areas, and a neural information—based control could lead to improved performance. Based on the results we also infer that the size of the motor units after reinnervation is influenced by the size of the innervating motor neuron.     

Spatial analysis of motor unit potentials of the rat medial gastrocnemius

The spatial analysis of the potentials of single motor units of the rat medial gastrocnemius muscle evoked by stimulation of the fibres of split ventral roots was carried out with a bipolar electrode moving in the direction perpendicular to the longitudinal axis of the muscle fibres. During this movement of the electrode a variability was observed in the time of the biphasic potential from its maximum to minimum, and in the peak-to-peak amplitude of these potentials. The potentials recorded outside the territory of the motor unit had a lower amplitude in relation to the potentials from the territory of the unit. This made localization of the motor unit on the cross-section of the muscle possible. Differences in the duration of the potential from maximal to minimal amplitude (maximum-minimum amplitude time--M-MAT) of each investigated motor unit from successive recording sites reflected the number of fibres contributing to the action potential and the distance of the recording surface of the electrode from the zone of the motor end-plates of this motor unit. The greatest diameter of the territory of the observed motor units reached 2.5 mm.     

Trunk and hip muscle activity in early walkers with and without cerebral palsy – A frequency analysis

Poor control of postural muscles is a primary impairment in cerebral palsy (CP), yet core trunk and hip muscle activity has not been thoroughly investigated. Frequency analysis of electromyographic (EMG) signals provides insight about the intensity and pattern of muscle activation, correlates with functional measures in CP, and is sensitive to change after intervention. The objective of this study was to investigate differences in trunk and hip muscle activation frequency in children with CP compared to children with similar amounts of walking experience and typical development (TD). EMG data from 31 children (15 with CP, 16 with TD) were recorded from 16 trunk and hip muscles bilaterally. A time–frequency pattern was generated using the continuous wavelet transform and instantaneous mean frequency (IMNF) was calculated at each interval of the gait cycle. Functional principal component analysis (PCA) revealed that IMNF was significantly higher in the CP group throughout the gait cycle for all muscles. Additionally, stride-to-stride variability was higher in the CP group. This evidence demonstrated altered patterns of trunk and hip muscle activation in CP, including increased rates of motor unit firing, increased number of recruited motor units, and/or decreased synchrony of motor units. These altered muscle activation patterns likely contribute to muscle fatigue and decreased biomechanical efficiency in children with CP.     

The range of control of the afferent system of the flexor reflex]

The control processes caused by the action of electric inhibition of the nerve fibres and depolarized and hyperpolarized influences in the neurones structures of the spinal cord are discussed. Three typical bands of the amplitude control of motor apparatus in the multineuronic reflex ring are distinguished. The transmission of the action potentials in the battle control bands is carried out by the double way modulation. The first band is characterized by the most effective control with amplitude of the signal control in the limit of three thresholds. In the third band the transmission of information is possible in the inversion regime with unsteady polarity of the reflex movement. The second band unfits for the transmission of control commands.     

Time Course Analysis of Motor Excitability in a Response Inhibition Task According to the Level of Hyperactivity and Impulsivity in Children with ADHD

Short interval intracortical inhibition (SICI) of motor cortex, measured by transcranial magnetic stimulation (TMS) in a passive (resting) condition, has been suggested as a neurophysiological marker of hyperactivity in attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to determine motor excitability in a go/nogo task at stages of response preparation, activation and suppression in children with ADHD, depending on the level of hyperactivity and impulsivity. Motor evoked potentials were recorded in 29 typically developing children and 43 children with ADHD (subdivided in two groups with higher and lower levels of hyperactivity/impulsivity; H/I-high and H/I-low). In the H/I-high group, SICI was markedly reduced in the resting condition and during response preparation. Though these children were able to increase SICI when inhibiting a response, SICI was still reduced compared to typically developing children. Interestingly, SICI at rest and during response activation were comparable, which may be associated with their hypermotoric behaviour. In the H/I-low group, response activation was accompanied by a pronounced decrease of SICI, indicating reduced motor control in the context of a fast motor response. In summary, different excitability patterns were obtained for the three groups allowing a better understanding of dysfunctional response activation and inhibition processes within the motor cortex in children with ADHD.     

Nerve conduction in childhood diabetes

Sixty-nine diabetic children were studied with respect to the motor nerve conduction velocities, duration of illness and adequacy of control.As a group there was a trend for children with diabetes to have slower MNCV than non-diabetic children, and for the slowing to become progressive as the duration of their disease increased. Poorer quality of diabetes control was also associated with progressive slowing of conduction but the exact relationship is uncertain, since no patient who had diabetes for more than four years was well controlled.Theories of causation of peripheral neuropathy in diabetic patients are reviewed; metabolic changes, rather than other factors, are thought most likely in children.     

Time coupling of skeletomotor discharges in response to pseudo-random transsynaptic and transmembrane stimulation

Firing pattern of skeletomotor neurones innervating triceps surae muscles in response to pseudorandom muscle stretching and white noise modulated transmembrane current stimulation was investigated in decerebrate cats. Pseudo-random muscle stretching (upper cut-off frequency 60 Hz, amplitude (standard deviation) ranging from 18.5 m to 40 m) was applied to triceps surae muscles. Membrane potential changes and action potentials of skeletomotor neurones were recorded intracellularly. White noise modulated current was applied through the same (recording) microelectrode. Sequences of ten identical 5 s periods of either muscle stretching or transmembrane current stimulation were applied. Skeletomotor neurones belonging to slow motor units (rheobase less than 8.5 nA) generated action potentials in response to both pseudo-random muscle stretching and transmembrane current stimulation, while firing threshold of those belonging to fast motor units could not be reached by the muscle stretches applied. Peri-spike averaging of muscle length and injected current records showed that the action potentials appeared at the peak of either depolarizing current wave or muscle stretching both preceded by a change in opposite direction (the spikes coinciding with the peak in muscle length PSA being actually elicited by muscle spindle action potentials triggered at the moment of the peak stretching velocity). Time coupling of action potentials occurred during both muscle stretching and transmembrane stimulation, being more tight in the latter case as well as when larger amplitudes of the stimuli were applied. It is supposed that discharges from muscle spindle primary endings phase-locked to small pseudo-random muscle length changes may, due to the time coupling of skeletomotor action potentials, provoke a synchronous firing of skeletomotor neurones, mostly of those belonging to slow motor units. Possible effects of such a firing pattern on the resulting muscle reflex contraction and the stretch reflex stability as well as a possibility of it being provoked by fusimotor discharges are discussed.     

The methods of surface EMG analysis

The use of surface emg as a tool for quantification is described. First, the specific advantages of the surface emg are discussed. Techniques for analysis of the emg signal which estimate and detect the action potentials of the individual motor units and estimate some global properties of muscle activity are reviewed. A survey of data on relations between the properties of motor unit action potential, the properties of motor unit activity and the results of signal processing are given.     

Appearance of "transitional" motor units in overloaded rat skeletal muscle

The contractile characteristics of single motor units, isolated from rat plantaris muscles subjected to short-term (30 days) compensatory overload, were assessed to determine whether motor units in transition could be detected. In the control plantaris 88% of the motor units were classified as fast. After overload, a large decline (26.5%) in the proportion of typical fast motor units was noted. The estimated contribution of fast fatigable units to whole muscle tetanic tension (Po 200) also declined (from 55 to 25%), whereas that of fast intermediate motor units increased (from 33 to 55%). In the overloaded plantaris, motor units that exhibited unusual "sag" and contraction time characteristics were detected. These motor units, which could be further subdivided into two distinct types by a variety of indexes, exhibited characteristics intermediate to fast and slow units and therefore were termed "transitional." Transitional units accounted for 12% of the estimated whole muscle Po200 after overload. These experiments characterize novel classifications of motor units undergoing transformation and further detail the motor unit shift that accompanies compensatory overload.     

Comparative analysis of motor unit action potentials of the medial gastrocnemius muscle in cats and rats

Properties of motor unit action potentials (MUAPs) were compared for medial gastrocnemius (MG) motor units (MUs) in cats and rats. The experiments on functionally isolated MUs were performed under general anaesthesia, under comparable conditions (surgery, stimulating protocol and recording methods) for both species investigated. The proportions of motor units and contractile properties of the sample used in the study were consistent with previous studies performed on the MG muscle in both animal species, so comparisons of action potentials of individual types of MUs were acknowledged as fully reliable. The most prominent differences concerning MUAPs were observed in total duration and peak-to-peak times which for all MU types were about twice longer in cat MUs, in comparison to the rat MUs. The considerable disproportions were observed between the MUAP amplitudes of FF (fast fatigable), FR (fast resistant to fatigue) and S (slow) MUs in each species (the highest amplitudes were measured for FF and the lowest for S MUs), but there were no significant differences between cat and rat when respective types of MUs were compared. The shapes of MUAPs were commonly characterized by biphasic waveforms composed of two or three turns in all types of units, and no interspecies differences were revealed. Several factors influencing MUAP parameters were discussed indicating most of all importance of variable length of cat and rat muscle fibres and ambiguous influence of motor unit size, thickness of muscle fibres and their density around the recording electrode in the MG muscle of both species.     

Firing rates of motor units in human vastus lateralis muscle during fatiguing isometric contractions.

We investigated the firing rate of motor units in the vastus lateralis muscle in five healthy young men (mean = 21.4 yr, SD = 0.9) during a sequence of isometric constant-torque contractions repeated to exhaustion. The contractions were sustained at 20% of the maximal voluntary level, measured at the beginning of the test sequence. Electromyographic (EMG) signals were recorded via quadrifilar fine-wire electrodes and subsequently decomposed into their constituent motor unit action potentials to obtain the motor unit firing times. In addition, we measured the whole muscle mechanical properties during the fatigue task using electrical stimulation. The firing rate of motor units first decreased within the first 10-20% of the endurance time of the contractions and then increased. The firing rate increase was accompanied by recruitment of additional motor units as the force output remained constant. The elicited twitch and tetanic torque responses first increased and then decreased. The two processes modulated in a complementary fashion at the same time. Our data suggest that, when the vastus lateralis muscle is activated to maintain a constant torque output, its motoneuron pool receives a net excitatory drive that first decreases to compensate for the short-lived potentiation of the muscle force twitch and then increases to compensate for the diminution of the force twitch. The underlying inverse relationship between the firing rate and the recruitment threshold that has been reported for nonfatigued contractions is maintained. We, therefore, conclude that the central nervous system control of vastus lateralis motor units remains invariant during fatigue in submaximal isometric isotonic contractions.     

Post-Tetanic Repetitive Activity in the Cat Soleus Nerve : Its origin, course, and mechanism of generation

Subsequent to conditioning by a high frequency stimulus axons of the cat soleus nerve respond to single stimuli with brief trains of repetitive action potentials. This phenomenon, post-tetanic repetitive activity (PTR), was studied in individual axons and single motor units of an in situ cat soleus nerve-muscle preparation. The occurrence, intensity, and duration of PTR are principally dependent on the frequency and duration of the conditioning tetanus. PTR occurs synchronously in the axon and muscles of single motor units. An analysis of the temporal relationships of the repetitive nerve and muscle potentials showed that PTR is generated in the motor nerve terminal. It is postulated that PTR is produced by a generator potential which is developed in the post-tetanic period between the unmyelinated nerve terminal and the last node of Ranvier.     

Multichannel thin-film electrode for intramuscular electromyographic recordings.

It is currently not possible to record electromyographic (EMG) signals from many locations concurrently inside the muscle in a single wire electrode system. We developed a thin-film wire electrode system for multichannel intramuscular EMG recordings. The system was fabricated using a micromachining process, with a silicon wafer as production platform for polyimide-based electrodes. In the current prototype, the flexible polymer structure is 220 microm wide, 10 microm thick, and 1.5 cm long, and it has eight circular platinum-platinum chloride recording sites of 40-microm diameter distributed along the front and back surfaces with 1,500-microm intersite spacing. The system prototype was tested in six experiments where the electrode was implanted into the medial head of the gastrocnemius muscle of rabbits, perpendicular to the pennation angle of the muscle fibers. Asynchronous motor unit activity was induced by eliciting the withdrawal reflex or sequential crushes of the sciatic nerve using a pair of forceps. Sixty-seven motor units were identified from these recordings. In the bandwidth 200 Hz to 5 kHz, the peak-to-peak amplitude of the action potentials of the detected motor units was 75 +/- 12 muV and the root mean square of the noise was 1.6 +/- 0.4 muV. The noise level and amplitude of the action potentials were similar for measures separated by up to 40 min. The experimental tests demonstrated that thin film is a promising technology for a new type of flexible-wire intramuscular EMG recording system with multiple detection sites.     

A Marker of Early Stages of Diabetic Retinopathy

A comparative estimate of the hormonal status and coagulatory activity was carried out in patients with diabetes mellitus at the functional and subclinical stages of diabetic retinopathy and in those without signs of diabetic retinopathy. In all patients, the blood level of hormones was elevated, while in patients with functional and subclinical stages of diabetic retinopathy, the changes in hormonal status were accompanied by increased local and systemic potentials, disturbed microcirculation, and decreased functional activity of the retina outer layers. The increased hormone level affected the hemostatic potentials and induced their elevation at a certain stage. The reliably increased local hemostatic potential was one of the first signs of pathological action of the increased hormone level, while the increase of systemic hemostatic potential was unreliable. The combination of elevated blood level of hormones and coagulatory activity of the tear fluid is a marker fore revealing the group of risk for development of diabetic retinopathy in patients with diabetes mellitus.