Biomedical subjects

David J Bennett

Publications and source records attributed to David J Bennett.

12 recordsLinked to original sources

PubMed2006

Spastic tail muscles recover from myofiber atrophy and myosin heavy chain transformations in chronic spinal rats.

Without intervention after spinal cord injury (SCI), paralyzed skeletal muscles undergo myofiber atrophy and slow-to-fast myofiber type transformations. We hypothesized that chronic spasticity-associated neuromuscular activity after SCI would promote recovery from such deleterious changes. We examined segmental tail muscles of chronic spinal rats with long-standing tail spasticity (7 mo after sacral spinal cord transection; older chronic spinals), chronic spinal rats that experienced less spasticity early after injury (young chronic spinals), and rats without spasticity after transection and bilateral deafferentation (spinal isolated). These were compared with tail muscles of age-matched normal rats. Using immunohistochemistry, we observed myofiber distributions of 15.9 +/- 3.5% type I, 18.7 +/- 10.7% type IIA, 60.8 +/- 12.6% type IID(X), and 2.3 +/- 1.3% type IIB (means +/- SD) in young normals, which were not different in older normals. Young chronic spinals demonstrated transformations toward faster myofiber types with decreased type I and increased type IID(X) paralleled by atrophy of all myofiber types compared with young normals. Spinal isolated rats also demonstrated decreased type I myofiber proportions and increased type II myofiber proportions, and severe myofiber atrophy. After 4 mo of complete spasticity (older chronic spinals), myofiber type transformations were reversed, with no significant differences in type I, IIA, IID(X), or IIB proportions compared with age-matched normals. Moreover, after this prolonged spasticity, type I, IIA, and IIB myofibers recovered from atrophy, and type IID(X) myofibers partially recovered. Our results indicate that early after transection or after long-term spinal isolation, relatively inactive tail myofibers atrophy and transform toward faster myofiber types. However, long-term spasticity apparently produces neuromuscular activity that promotes recovery of myofiber types and myofiber sizes.

Aging↗

PubMed2005

Simulation of Ca2+ persistent inward currents in spinal motoneurones: mode of activation and integration of synaptic inputs.

The goal of this study was to investigate the nature of activation of the dendritic calcium persistent inward current (Ca(2+) PIC) and its contribution to the enhancement and summation of synaptic inputs in spinal motoneurones. A compartmental cable model of a cat alpha-motoneurone was developed comprising the realistic dendritic distribution of Ia-afferent synapses and low-voltage-activated L-type calcium (Ca(v)1.3) channels distributed over the dendrites in a manner that was previously shown to match a wide set of experimental measurements. The level of synaptic activation was systematically increased and the resulting firing rate, somatic and dendritic membrane potentials, dendritic Ca(v)1.3 channel conductance, and dendritic Ca(2+) PIC were measured. Our simulation results suggest that during cell firing the dendritic Ca(2+) PIC is not activated in an all-or-none manner. Instead, it is initially activated in a graded manner with increasing synaptic input until it reaches its full activation level, after which additional increases in synaptic input result in minimal changes in the Ca(2+) PIC (PIC saturated). The range of graded activation of Ca(2+) PIC occurs when the cell is recruited and causes a steep increase in the firing frequency as the synaptic current is increased, coinciding with the secondary range of the synaptic frequency-current (F-I) relationship. Once the Ca(2+) PIC is saturated the slope of the F-I relationship is reduced, corresponding to the tertiary range of firing. When the post-spike afterhyperpolarization (AHP) is blocked, either directly by blocking the calcium-activated potassium channels, or indirectly by blocking the sodium spikes, the PIC is activated in an all-or-none manner with increasing synaptic input. Thus, the AHP serves to limit the depolarization of the cell during firing and enables graded, rather than all-or-none, activation of the Ca(2+) PIC. The graded activation of the Ca(2+) PIC with increasing synaptic input results in a graded (linear) enhancement and linear summation of synaptic inputs. In contrast, the saturated Ca(2+) PIC enhances synaptic inputs by a constant amount (constant current), and leads to less-than linear summation of multiple synaptic inputs. These model predictions improve our understanding of the mode of activation of the dendritic Ca(2+) PIC and its role in the enhancement and integration of synaptic inputs.

Animals↗

PubMed2005

Tail muscles become slow but fatigable in chronic sacral spinal rats with spasticity.

Paralyzed skeletal muscle sometimes becomes faster and more fatigable after spinal cord injury (SCI) because of reduced activity. However, in some cases, pronounced muscle activity in the form of spasticity (hyperreflexia and hypertonus) occurs after long-term SCI. We hypothesized that this spastic activity may be associated with a reversal back to a slower, less fatigable muscle. In adult rats, a sacral (S2) spinal cord transection was performed, affecting only tail musculature and resulting in chronic tail spasticity beginning 2 wk later and lasting indefinitely. At 8 mo after injury, we examined the contractile properties of the segmental tail muscle in anesthetized spastic rats and in age-matched normal rats. The segmental tail muscle has only a few motor units (<12), which were easily detected with graded nerve stimulation, revealing two clear motor unit twitch durations. The dominant faster unit twitches peaked at 15 ms and ended within 50 ms, whereas the slower unit twitches only peaked at 30-50 ms. With chronic injury, this slow twitch component increased, resulting in a large overall increase (>150%) in the fraction of the peak muscle twitch force remaining at 50 ms. With injury, the peak muscle twitch (evoked with supramaximal stimulation) also increased in its time to peak (+48.9%) and half-rise time (+150.0%), and decreased in its maximum rise (-35.0%) and decay rates (-40.1%). Likewise, after a tetanic stimulation, the tetanus half-fall time increased by 53.8%. Therefore the slow portion of the muscle was enhanced in spastic muscles. Consistent with slowing, posttetanic potentiation was 9.2% lower and the stimulation frequency required to produce half-maximal tetanus decreased 39.0% in chronic spinals. Interestingly, in spastic muscles compared with normal, whole muscle twitch force was 81.1% higher, whereas tetanic force production was 38.1% lower. Hence the twitch-to-tetanus ratio increased 104.0%. Inconsistent with overall slowing, whole spastic muscles were 61.5% more fatigable than normal muscles. Thus contrary to the classical slow-to-fast conversion that is seen after SCI without spasticity, SCI with spasticity is associated with a mixed effect, including a preservation/enhancement of slow properties, but a loss of fatigue resistance.

Animals↗

PubMed2005

Simulation of dendritic CaV1.3 channels in cat lumbar motoneurons: spatial distribution.

We used computer simulations to study the dendritic spatial distribution of low voltage-activated L-type calcium (Ca(V)1.3 type) channels, which mediate hysteretic persistent inward current (PIC) in spinal motoneurons. This study was prompted by the growing experimental evidence of the functional interactions between synaptic inputs and active conductances over the motoneuron dendritic tree. A compartmental cable model of an adult cat alpha-motoneuron was developed in NEURON simulation environment constituting the detailed morphology of type-identified triceps surae alpha-motoneuron and realistic distribution of group Ia afferent-to-motoneuron contacts. Simulations of different distributions of Ca(V)1.3 channels were conducted and the resultant behavior was compared to experimental data. Our results suggest that Ca(V)1.3 channels do not uniformly cover the whole motoneuron dendritic tree. Instead, their distribution is similar to that of synaptic contacts. We found that Ca(V)1.3 channels are primarily localized to a wide intermediate band overlapping with the dendritic Ia-synaptic territory at dendritic distances of 300 to 850 microm (0.62 +/- 0.21lambda) from the soma in triceps surae alpha-motoneurons. These findings explain the functional interaction between synaptic inputs and the Ca(V)1.3 channels over the motoneuron dendritic tree.

Animals↗

PubMed2005

Persistent inward currents in motoneuron dendrites: implications for motor output.

The dendrites of motoneurons are not, as once thought, passive conduits for synaptic inputs. Instead they have voltage-dependent channels that provide the capacity to generate a very strong persistent inward current (PIC). The amplitude of the PIC is proportional to the level of neuromodulatory input from the brainstem, which is mediated primarily by the monoamines serotonin and norepinephrine. During normal motor behavior, monoaminergic drive is likely to be moderately strong and the dendritic PIC generates many of the characteristic features of motor unit firing patterns. Most of the PIC activates at or below recruitment threshold and thus motor unit firing patterns exhibit a linear increase just above recruitment. The dendritic PIC allows motor unit derecruitment to occur at a lower input level than recruitment, thus providing sustained tonic firing with little or no synaptic input, especially in low-threshold units. However the dendritic PIC can be readily deactivated by synaptic inhibition. The overall amplification due to the dendritic PIC and other effects of monoamines on motoneurons greatly increases the input-output gain of the motor pool. Thus the brainstem neuromodulatory input provides a mechanism by which the excitability of motoneurons can be varied for different motor behaviors. This control system is lost in spinal cord injury but PICs nonetheless recover near-normal amplitudes in the months following the initial injury. The relationship of these findings to the cause of the spasticity syndrome developing after spinal cord injury is discussed.

Action Potentials↗

PubMed2005

An investigation into the potential for activity-dependent regeneration of the rubrospinal tract after spinal cord injury.

We tested whether regeneration of transected rubrospinal tract (RST) axons is facilitated by a prolonged electrical stimulation of these axons. A peripheral nerve was grafted to the transected RST at the cervical level (C4/5) of adult rats, providing a permissive environment for regeneration of rubrospinal axons. Direct antidromic stimulation of the RST was applied immediately after grafting through a microwire inserted just rostral to the RST lesion, using a 1-h 20-Hz supramaximal stimulation protocol. Stimulation caused no direct damage to rubrospinal axons, and was sufficient to recruit the entire rubrospinal tract. In control animals that had a nerve graft and implanted microwire with no stimulation, there were 42.7 +/- 10.2 rubrospinal neurons regenerated into the graft at 8 weeks, as assessed by retrograde labelling. In test animals that were stimulated there were 28.2 +/- 7.4 back-labelled neurons, not significantly different from control, indicating that this stimulation did not improve the regenerative capacity of rubrospinal neurons. Furthermore, reverse-transcriptase polymerase chain reaction and in situ hybridization for brain-derived neurotrophic factor (BDNF) and/or growth-associated protein-43 (GAP-43) expression in rubrospinal neurons revealed no significant difference between stimulated and unstimulated groups at 48 h after injury, with either 1 or 8 h of stimulation. In summary, direct stimulation of the injured RST axons for the periods tested does not increase expression of GAP-43 and BDNF, and ultimately does not promote regeneration of these central nervous system axons.

Animals↗

PubMed2004

Role of persistent sodium and calcium currents in motoneuron firing and spasticity in chronic spinal rats.

After chronic spinal injury, motoneurons spontaneously develop two persistent inward currents (PICs): a TTX-sensitive persistent sodium current (sodium PIC) and a nimodipine-sensitive persistent calcium current (calcium PIC). In the present paper, we examined how these PICs contributed to motoneuron firing. Adult rats were spinalized at the S(2) sacral level, and after 2 months intracellular recordings were made from sacrocaudal motoneurons in vitro. The PICs and repetitive firing were measured with slow triangular voltage and current ramps, respectively. The sodium PIC was examined after blocking the calcium PIC with nimodipine (20 microM; n = 12). It was always activated subthreshold, and during current ramps in nimodipine, it produced a sodium plateau that assisted in initiating and maintaining firing (self-sustained firing). The sodium PIC oscillated off and on during firing and helped initiate each spike, and near threshold this caused abnormally slow firing (2.82 +/- 1.21 Hz). A low dose of TTX (0.5 microM) blocked the sodium PIC, sodium plateau, and very slow firing prior to affecting the spike itself. The calcium PIC was estimated as the current blocked by nimodipine or current remaining in TTX (2 microM; n = 13). In 59% of motoneurons, the calcium PIC was activated subthreshold to firing and produced a plateau that assisted in initiating and sustaining firing because nimodipine significantly increased the firing threshold current and decreased the self-sustained firing. In the remaining motoneurons (41%), the calcium PIC was activated suprathreshold to firing and during current ramps did not initially affect firing but eventually was activated and caused an acceleration in firing followed by self-sustained firing, which were blocked by nimodipine. The frequency-current (F-I) slope was 3.0 +/- 1.0 Hz/nA before the calcium PIC activation (primary range), 6.3 +/- 3.6 Hz/nA during the calcium PIC onset (secondary range; acceleration), and 2.1 +/- 1.3 Hz/nA with the calcium PIC steadily activated (tertiary range). Nimodipine eliminated the secondary and tertiary ranges, leaving a linear F-I slope of 3.7 +/- 1.0 Hz/nA. A single low-threshold shock to the dorsal root evoked a many-second-long discharge, the counterpart of a muscle spasm in the awake chronic spinal rat. This long-lasting reflex was caused by the motoneuron PICs because when the activation of the voltage-dependent PICs was prevented by hyperpolarization, the same dorsal root stimulation only produced a brief excitatory postsynaptic potential (<1 s). Both the calcium and sodium PIC were involved because nimodipine only partly reduced the reflex and there remained very slow firing mediated by the sodium PIC.

Action Potentials↗

PubMed2003

Persistent sodium and calcium currents cause plateau potentials in motoneurons of chronic spinal rats.

After chronic spinal cord injury motoneurons exhibit large plateau potentials (sustained depolarizations triggered by brief inputs) that play a primary role in the development of muscle spasms and spasticity (Bennett et al. 2001a,b). The present study examined the voltage-gated persistent inward currents (PICs) underlying these plateaus. Adult rats were spinalized at the S2 sacral spinal level and after 2 mo, when spasticity developed, intracellular recordings were made from motoneurons below the injury. For recording, the whole sacrocaudal spinal cord was removed and maintained in vitro in normal artificial cerebral spinal fluid (nACSF), without application of neuromodulators. During a slow triangular voltage-clamp command (ramp) a PIC was activated with a threshold of -54.2 +/- 4.8 mV (similar to plateau threshold), with a peak current of 2.88 +/- 0.95 nA and produced a pronounced negative-slope region in the V-I relation. This PIC was in part mediated by Cav1.3 L-type calcium channels because it was low threshold and significantly reduced by 10 to 20 microM nimodipine or 400 microM Cd2+. The PIC that remained during a calcium channel blockade (in Cd2+) was completely and rapidly blocked by tetrodotoxin (TTX; 0.5 to 2 microM), and thus was a TTX-sensitive persistent sodium current. This persistent sodium current was activated rapidly about 7 mV below the spike threshold (spike threshold -46.1 +/- 4.5 mV), contributed approximately 1/2 of the initial peak of the total PIC, inactivated partly to contribute only approximately 1/3 of the sustained PIC (at 5 to 10 s), and deactivated rapidly with hyperpolarization (<50 ms). When TTX was added to the bath first, the nimodipine-sensitive persistent calcium current (L-type) was seen in isolation; it was slowly activated (>250 ms), had a low but variable threshold (either slightly above or below the spike threshold), contributed the other approximately 1/2 of the initial peak of the total PIC (before TTX), did not usually inactivate with time (contributed approximately two-thirds of the sustained PIC), and deactivated slowly with hyperpolarization to rest (in >300 ms). In summary, low-threshold persistent calcium (Cav1.3) and sodium currents spontaneously develop in motoneurons of chronic spinal rats and these enable large, rapidly activated plateaus that ultimately lead to spasticity.

Animals↗

PubMed2002

Stretch reflex gain in cat triceps surae muscles with compliant loads.

The triceps surae (TS) stretch reflex was measured in decerebrate cats during crossed extensor stimulation (tonic contractions) and after spinalization during rhythmic locomotor activity. The TS reflex force in response to a short pulse stretch measured during tonic contractions at low level of background activity was greater than when more background activity was present at the time of application of stretch. In contrast, the reflex force measured during rhythmic contractions was very small at low level of background force (flexion phase) and increased at moderate and high levels of background activity (extension phase). Thus, even in reduced preparations, a task modulation of the stretch reflex occurs. Throughout the experimental procedure, the torque motor used to stretch the muscles behaved like a spring of a preset compliance (from isometric to very compliant). A reflex model was used to simulate the responses obtained experimentally. The gain of the stretch reflex loop was estimated for each load condition and both behavioural tasks. The reflex loop gain was significantly larger as the compliance of the external load increased for both tonic and rhythmic contractions, although to a lesser extent in the phasically activated muscles. During rhythmic locomotor contractions the gain was less than 1, assuring stability of the system. In contrast, during tonic contractions against a compliant load the gain exceeded 1, consistent with the instability (oscillations, clonus) seen at times under these load conditions. However, the high gain and instability was only transient, since repeated stretch reduced the gain. Thus, non-linearities in the system assured vigorous responses at the onset of perturbations, but then weaker responses to ongoing perturbations to reduce the chance of feedback instability (clonus).

Animals↗

PubMed2002

Intrinsic activation of human motoneurons: possible contribution to motor unit excitation.

The main purpose of this study was to estimate the contribution of intrinsic activation of human motoneurons (e.g., by plateau potentials) during voluntary and reflexive muscle contractions. Pairs of motor units were recorded from either the tibialis anterior or soleus muscle during three different conditions: 1) during a brief muscle vibration followed by a slow relaxation of a steady isometric contraction; 2) during a triangular isometric torque contraction; and 3) during passive sinusoidal muscle stretch superimposed on a steady isometric contraction. In each case, the firing rate of a tonically firing control motor unit was used as a measure of the effective synaptic excitation (i.e., synaptic drive) to a slightly higher-threshold test motor unit that was recruited and de-recruited during a contraction trial. The firing rate of the control unit was compared at recruitment and de-recruitment of the test unit. This was done to determine whether the estimated synaptic drive needed to recruit a motor unit was less than the amount needed to sustain firing as a result of an added depolarization produced from intrinsic sources. After test unit recruitment, the firing rate of the control unit could be decreased significantly (on average by 3.6 Hz from an initial recruitment rate of 9.8 Hz) before the test unit was de-recruited during a descending synaptic drive. Similar decreases in control unit rate occurred in all three experimental conditions. This represents a possible 40% reduction in the estimated synaptic drive needed to maintain firing of a motor unit compared with the estimated amount needed to recruit the unit initially. The firing rates of both the control and test units were modulated together in a highly parallel fashion, suggesting that the unit pairs were driven by common synaptic inputs. This tight correlation further validated the use of the control unit firing rate as a monitor of synaptic drive to the test motor unit. The estimates of intrinsically mediated depolarization of human motoneurons ( approximately 40% during moderate contractions) are consistent with values obtained for plateau potentials obtained from intracellular recordings of motoneurons in reduced animal preparations, although various alternative mechanisms are discussed. This suggests that similar intrinsic conductances provide a substantial activation of human motoneurons during moderate physiological activity.

Adult↗

PubMed2002

Intrinsic activation of human motoneurons: reduction of motor unit recruitment thresholds by repeated contractions.

The main purpose of this study was to examine whether facilitation of human motor unit recruitment by repeated voluntary contractions is mediated, in part, by time and activity-dependent increases in the intrinsic excitability of the parent motoneuron. To do this, pairs of tibialis anterior or soleus motor units were recorded during slowly increasing and then decreasing voluntary contractions. The firing rate of the lower-threshold motor unit of the pair (control unit) was used as a measure of effective synaptic excitation (i.e., drive) to the motoneurons. This rate was used to estimate the recruitment threshold of the higher-threshold unit of the pair (test unit). The test unit was repeatedly recruited and de-recruited in a series of contractions, and the interval between the de-recruitment and re-recruitment of the test unit (interactivation interval) was systematically varied between 0.6 and 60 s. An increase in intrinsic excitability of a unit was considered to have occurred if the level of estimated synaptic input (as measured by the firing rate of the control motor unit) needed to recruit a unit was reduced. At short interactivation intervals (1-2 s), the control unit firing frequency was significantly lower when the test unit was recruited on the second contraction, compared with the first (by 3.9 Hz or a 64% reduction). This suggested that the intrinsic excitability of the test motor unit had increased during the second contraction because it could be recruited at a much lower level of estimated synaptic drive. Longer interaction intervals (2-6 s) produced less recruitment facilitation. At even longer interactivation intervals (>6 s) there was no significant facilitation (time constant of effect was 4.8 s). In some motor units, the effect of this short-term facilitation appeared to be so pronounced that it resulted in reversing the order of de-recruitment with the other initially lower-threshold motor units. Such reversals were occasionally observed for orderly re-recruitment. The time course and behavior of the observed short-term facilitation of motor unit discharge was qualitatively similar to the warm-up phenomenon of plateau potentials seen in motoneurons of reduced preparations (e.g., 4-6 s). The possibility of warm-up contributing to the time and activity-dependent facilitation of human motor unit recruitment is discussed.

Adult↗

PubMed2002

Size scaling: retinal or environmental frame of reference?

Previous studies have reported that when subjects are presented with two forms in a same-different task, their reaction times increase with the size ratio. This suggests a "mental scaling" transformation analogous to the "mental rotation" used to compensate for differently oriented forms in similar tasks. However, since the stimuli were presented in isolation, retinal and environmental size ratios were confounded. The present study varied both retinal and environmental size ratios in a same-different simultaneous matching task. In one experiment, random forms were placed at different distances along a textured hallway. A second experiment varied the monocular size information: In one condition the forms were displayed in a textured hallway; a second condition added cast shadows; and a third condition displayed the forms against a frontal wall of indeterminate distance. The results suggest that environmental size is determined prior to mental scaling and form matching.

Adult↗