Neurophysiology of epidurally evoked spinal cord reflexes in clinically motor-complete posttraumatic spinal cord injury

Increased use of epidural Spinal Cord Stimulation (eSCS) for the rehabilitation of spinal cord injury (SCI) has highlighted the need for a greater understanding of the properties of reflex circuits in the isolated spinal cord, particularly in response to repetitive stimulation. Here, we investigate the frequency-dependence of modulation of short- and long-latency EMG responses of lower limb muscles in patients with SCI at rest. Single stimuli could evoke short-latency responses as well as long-latency (likely polysynaptic) responses. The short-latency component was enhanced at low frequencies and declined at higher rates. In all muscles, the effects of eSCS were more complex if polysynaptic activity was elicited, making the motor output become an active process expressed either as suppression, tonic or rhythmical activity. The polysynaptic activity threshold is not constant and might vary with different stimulation frequencies, which speaks for its temporal dependency. Polysynaptic components can be observed as direct responses, neuromodulation of monosynaptic responses or driving the muscle activity by themselves, depending on the frequency level. We suggest that the presence of polysynaptic activity could be a potential predictor for appropriate stimulation conditions. This work studies the complex behaviour of spinal circuits deprived of voluntary motor control from the brain and in the absence of any other inputs. This is done by describing the monosynaptic responses, polysynaptic activity, and its interaction through its input–output interaction with sustain stimulation that, unlike single stimuli used to study the reflex pathway, can strongly influence the interneuron circuitry and reveal a broader spectrum of connectivity

Comparison of Multi-Compartment Cable Models of Human Auditory Nerve Fibers

Background: Multi-compartment cable models of auditory nerve fibers have been developed to assist in the improvement of cochlear implants. With the advancement of computational technology and the results obtained from in vivo and in vitro experiments, these models have evolved to incorporate a considerable degree of morphological and physiological details. They have also been combined with three-dimensional volume conduction models of the cochlea to simulate neural responses to electrical stimulation. However, no specific rules have been provided on choosing the appropriate cable model, and most models adopted in recent studies were chosen without a specific reason or by inheritance. Methods: Three of the most cited biophysical multi-compartment cable models of the human auditory nerve, i.e., Rattay et al. (2001b), Briaire and Frijns (2005), and Smit et al. (2010), were implemented in this study. Several properties of single fibers were compared among the three models, including threshold, conduction velocity, action potential shape, latency, refractory properties, as well as stochastic and temporal behaviors. Experimental results regarding these properties were also included as a reference for comparison. Results: For monophasic single-pulse stimulation, the ratio of anodic vs. cathodic thresholds in all models was within the experimental range despite a much larger ratio in the model by Briaire and Frijns. For biphasic pulse-train stimulation, thresholds as a function of both pulse rate and pulse duration differed between the models, but none matched the experimental observations even coarsely. Similarly, for all other properties including the conduction velocity, action potential shape, and latency, the models presented different outcomes and not all of them fell within the range observed in experiments. Conclusions: While all three models presented similar values in certain single fiber properties to those obtained in experiments, none matched all experimental observations satisfactorily. In particular, the adaptation and temporal integration behaviors were completely missing in all models. Further extensions and analyses are required to explain and simulate realistic auditory nerve fiber responses to electrical stimulation

Synaptic plasticity in medial vestibular nucleus neurons: comparison with computational requirements of VOR adaptation

Background: Vestibulo-ocular reflex (VOR) gain adaptation, a longstanding experimental model of cerebellar learning, utilizes sites of plasticity in both cerebellar cortex and brainstem. However, the mechanisms by which the activity of cortical Purkinje cells may guide synaptic plasticity in brainstem vestibular neurons are unclear. Theoretical analyses indicate that vestibular plasticity should depend upon the correlation between Purkinje cell and vestibular afferent inputs, so that, in gain-down learning for example, increased cortical activity should induce long-term depression (LTD) at vestibular synapses. Methodology/Principal Findings: Here we expressed this correlational learning rule in its simplest form, as an anti-Hebbian, heterosynaptic spike-timing dependent plasticity interaction between excitatory (vestibular) and inhibitory (floccular) inputs converging on medial vestibular nucleus (MVN) neurons (input-spike-timing dependent plasticity, iSTDP). To test this rule, we stimulated vestibular afferents to evoke EPSCs in rat MVN neurons in vitro. Control EPSC recordings were followed by an induction protocol where membrane hyperpolarizing pulses, mimicking IPSPs evoked by flocculus inputs, were paired with single vestibular nerve stimuli. A robust LTD developed at vestibular synapses when the afferent EPSPs coincided with membrane hyperpolarisation, while EPSPs occurring before or after the simulated IPSPs induced no lasting change. Furthermore, the iSTDP rule also successfully predicted the effects of a complex protocol using EPSP trains designed to mimic classical conditioning. Conclusions: These results, in strong support of theoretical predictions, suggest that the cerebellum alters the strength of vestibular synapses on MVN neurons through hetero-synaptic, anti-Hebbian iSTDP. Since the iSTDP rule does not depend on post-synaptic firing, it suggests a possible mechanism for VOR adaptation without compromising gaze-holding and VOR performance in vivo

Functional Changes in Muscle Afferent Neurones in an Osteoarthritis Model: Implications for Impaired Proprioceptive Performance

Impaired proprioceptive performance is a significant clinical issue for many who suffer osteoarthritis (OA) and is a risk factor for falls and other liabilities. This study was designed to evaluate weight-bearing distribution in a rat model of OA and to determine whether changes also occur in muscle afferent neurones.Intracellular recordings were made in functionally identified dorsal root ganglion neurones in acute electrophysiological experiments on the anaesthetized animal following measurements of hind limb weight bearing in the incapacitance test. OA rats but not naïve control rats stood with less weight on the ipsilateral hind leg (P = 0.02). In the acute electrophysiological experiments that followed weight bearing measurements, action potentials (AP) elicited by electrical stimulation of the dorsal roots differed in OA rats, including longer AP duration (P = 0.006), slower rise time (P = 0.001) and slower maximum rising rate (P = 0.03). Depolarizing intracellular current injection elicited more APs in models than in naïve muscle afferent neurones (P = 0.01) indicating greater excitability. Axonal conduction velocity in model animals was slower (P = 0.04).The present study demonstrates changes in hind limb stance accompanied by changes in the functional properties of muscle afferent neurones in this derangement model of OA. This may provide a possible avenue to explore mechanisms underlying the impaired proprioceptive performance and perhaps other sensory disorders in people with OA

Communications Biophysics

Contains reports on three research projects.National Institutes of Health (Grant MH-04737-05)National Institutes of Health (Grant NB-05462-02)Joint Services Electronics Programs (U. S. Army, U. S. Navy, and U. S. Air Force) under Contract DA 36-039-AMC-03200(E)National Science Foundation (Grant GP-2495)National Aeronautics and Space Administration (Grant NsG-496

The representation of respiratory movements in the inferior olive

It has been previously proposed that the inferior olive (IO) acts as a 'comparator' signalling to the cerebellum differences (errors) between signals conveying the command for movement from 'higher motor centres' and the activity these signals evoke at spinal 'centres' which also are in reciept of peripheral inputs (Oscarsson, 1973). Validation of this hypothesis has been hindered by the lack of direct access to the command signals. A review of the literature revealed that the respiratory system, as a source of centrally initiated automatic movements, offers a unique opportunity for studying both the command and outcome for a naturally occurring movement. The experiments in the first section of the thesis reinvestigate the interactions between the central respiratory drive and segmental (chest wall) reflexes. Muscle afferent activity was also monitored in intercostal nerve filaments to define proprioceptive inputs to the spinal cord and brainstem during artificial ventilation. Against this background the IO was explored by extracellular recording to seek evidence of central and peripheral-related respiratory activities. Three principal types of respiratory related activities were encountered in the dorsal accessory olive (DAO); 1), respiratory phased, mass activity; 2), respiratory phased, low frequency activity; 3), respiratory pump locked activity. The spatial location of these activities was found to correspond to a narrow, longitudinal strip in the DAO representing the segmental projection of the spino-olivary neurones located in the thoracic spinal cord, as identified anatomically by Matsushita et al. (1992). The source of these activities was investigated by cold block of the cervical spinal cord at C3. Whereas the central respiratory activity was abolished in spinal motoneurones, it persisted in the DAO indicating that the DAO receives a phasic respiratory input of supraspinal origin. Lowering the CO2 while holding the mechanical conditions in the thorax constant, resulted in changes in the olivary discharge, further indicating that the central command is fed to the olive, thus supporting the view that the olivary neurones act as a comparator signalling differences between the command for movement and the outcome

The calyx of Held

The calyx of Held is a large glutamatergic synapse in the mammalian auditory brainstem. By using brain slice preparations, direct patch-clamp recordings can be made from the nerve terminal and its postsynaptic target (principal neurons of the medial nucleus of the trapezoid body). Over the last decade, this preparation has been increasingly employed to investigate basic presynaptic mechanisms of transmission in the central nervous system. We review here the background to this preparation and summarise key findings concerning voltage-gated ion channels of the nerve terminal and the ionic mechanisms involved in exocytosis and modulation of transmitter release. The accessibility of this giant terminal has also permitted Ca2+-imaging and -uncaging studies combined with electrophysiological recording and capacitance measurements of exocytosis. Together, these studies convey the panopoly of presynaptic regulatory processes underlying the regulation of transmitter release, its modulatory control and short-term plasticity within one identified synaptic termina