Paired Stimulation to Promote Lasting Augmentation of Corticospinal Circuits

After injury, electrical stimulation of the nervous system can augment plasticity of spared or latent circuits through focal modulation. Pairing stimulation of two parts of a spared circuit can target modulation more specifically to the intended circuit. We discuss 3 kinds of paired stimulation in the context of the corticospinal system, because of its importance in clinical neurorehabilitation. The first uses principles of Hebbian plasticity: by altering the stimulation timing of presynaptic neurons and their postsynaptic targets, synapse function can be modulated up or down. The second form uses synchronized presynaptic inputs onto a common synaptic target. We dub this a “convergent” mechanism, because stimuli have to converge on a common target with coordinated timing. The third form induces focal modulation by tonic excitation of one region (e.g., the spinal cord) during phasic stimulation of another (e.g., motor cortex). Additionally, endogenous neural activity may be paired with exogenous electrical stimulation. This review addresses what is known about paired stimulation of the corticospinal system of both humans and animal models, emphasizes how it qualitatively differs from single-site stimulation, and discusses the gaps in knowledge that must be addressed to maximize its use and efficacy in neurorehabilitation.

Focal CO2/H+ alters phrenic motor output response to chemical stimulation of cat pre-Bötzinger complex in vivo

Microinjection ofdl-homocysteic acid (DLH), a glutamate analog, into the pre-Bötzinger complex (pre-BötC) can produce tonic excitation of phrenic nerve discharge. Although this DLH-induced tonic excitation can be modified by systemic hypercapnia, the role of focal increases in pre-BötC CO2/H+ in this modulation of the DLH-induced response remains to be determined. Therefore, we examined the effects of unilateral microinjection of DLH (10 mM; 10–20 nl) into the pre-BötC before and during increased focal pre-BötC CO2/H+ (i.e., focal tissue acidosis) in chloralose-anesthetized, vagotomized, mechanically ventilated cats. Focal tissue acidosis was produced by blockade of carbonic anhydrase with either focal acetazolamide (AZ) or methazolamide (MZ) microinjection. For these experiments, sites were selected in which unilateral microinjection of DLH into the pre-BötC produced a nonphasic tonic excitation of phrenic nerve discharge ( n = 10). Microinjection of 10–20 nl AZ (50 μM) or MZ (50 μM) into these 10 sites in the pre-BötC increased the amplitude and/or frequency of eupneic phrenic bursts, as previously reported. Subsequent microinjection of DLH produced excitation in which phasic respiratory bursts were superimposed on tonic discharge. These DLH-induced phasic respiratory bursts had an increased frequency compared with the preinjection baseline frequency ( P < 0.05). These findings demonstrate that modulation of phrenic motor activity evoked by DLH-induced activation of the pre-BötC is influenced by focal CO2/H+chemosensitivity in this region. Furthermore, these findings suggest that focal increases in pre-BötC CO2/H+may have contributed to the modulation of the DLH-induced responses previously observed during systemic hypercapnia.

Influence of respiratory network drive on phrenic motor output evoked by activation of cat pre-Bötzinger complex

10.1152/ajpregu.00395.2002. We have previously demonstrated that microinjection of dl-homocysteic acid (DLH), a glutamate analog, into the pre-Bötzinger complex (pre-BötC) can produce either phasic or tonic excitation of phrenic nerve discharge during hyperoxic normocapnia. Breathing, however, is influenced by input from both central and peripheral chemoreceptor activation. This influence of increased respiratory network drive on pre-BötC-induced modulation of phrenic motor output is unclear. Therefore, these experiments were designed to examine the effects of chemical stimulation of neurons (DLH; 10 mM; 10–20 nl) in the pre-BötC during hyperoxic modulation of CO2 (i.e., hypercapnia and hypocapnia) and during normocapnic hypoxia in chloralose-anesthetized, vagotomized, mechanically ventilated cats. For these experiments, sites were selected in which unilateral microinjection of DLH into the pre-BötC during baseline conditions of hyperoxic normocapnia [arterial Pco 2 (PaCO2 ) = 37–43 mmHg; n = 22] produced a tonic (nonphasic) excitation of phrenic nerve discharge. During hypercapnia (PaCO2 = 59.7 ± 2.8 mmHg; n= 17), similar microinjection produced excitation in which phasic respiratory bursts were superimposed on varying levels of tonic discharge. These DLH-induced phasic respiratory bursts had an increased frequency compared with the preinjection baseline frequency ( P < 0.01). In contrast, during hypocapnia (PaCO2 = 29.4 ± 1.5 mmHg; n= 11), microinjection of DLH produced nonphasic tonic excitation of phrenic nerve discharge that was less robust than the initial (normocapnic) response (i.e., decreased amplitude). During normocapnic hypoxia (PaCO2 = 38.5 ± 3.7; arterial Po 2 = 38.4 ± 4.4; n= 8) microinjection of DLH produced phrenic excitation similar to that seen during hypercapnia (i.e., increased frequency of phasic respiratory bursts superimposed on tonic discharge). These findings demonstrate that phrenic motor activity evoked by chemical stimulation of the pre-BötC is influenced by and integrates with modulation of respiratory network drive mediated by input from central and peripheral chemoreceptors.

The Effects of Digital Anesthesia on Force Control Using a Precision Grip

A total of 20 right-handed subjects were asked to perform a grasp-lift-and-hold task using a precision grip. The grasped object was a one-degree-of-freedom manipuladum consisting of a vertically mounted linear motor capable of generating resistive forces to simulate a range of object weights. In the initial study, seven subjects (6 women, 1 man; ages 24–56 yr) were first asked to lift and hold the object stationary for 4 s. The object presented a metal tab with two different surface textures and offered one of four resistive forces (0.5, 1.0, 1.5, and 2.0 N). The lifts were performed both with and without visual feedback. Next, the subjects were asked to perform the same grasping sequence again after ring block anesthesia of the thumb and index finger with mepivacaine. The objective was to determine the degree to which an internal model obtained through prior familiarity might compensate for the loss of cutaneous sensation. In agreement with previous studies, it was found that all subjects applied significantly greater grip force after digital anesthesia, and the coordination between grip and load forces was disrupted. It appears from these data, that the internal model alone is insufficient to completely compensate for the loss of cutaneous sensation. Moreover, the results suggest that the internal model must have either continuous tonic excitation from cutaneous receptors or at least frequent intermittent reiteration to function optimally. A subsequent study performed with 10 additional subjects (9 women, 1 man; ages 24–49 yr) indicated that with unimpaired cutaneous feedback, the grasping and lifting forces were applied together with negligible forces and torques in other directions. In contrast, after digital anesthesia, significant additional linear and torsional forces appeared, particularly in the horizontal and frontal planes. These torques were thought to arise partially from the application of excessive grip force and partially from a misalignment of the two grasping fingers. These torques were further increased by an imbalance in the pressure exerted by the two opposing fingers. Vision of the grasping hand did not significantly correct the finger misalignment after digital anesthesia. Taken together, these results suggest that mechanoreceptors in the fingertips signal the source and direction of pressure applied to the skin. The nervous system uses this information to adjust the fingers and direct the pinch forces optimally for grasping and object manipulation.

Analysis of Oscillations in a Reciprocally Inhibitory Network with Synaptic Depression

We present and analyze a model of a two-cell reciprocally inhibitory network that oscillates. The principal mechanism of oscillation is short-term synaptic depression. Using a simple model of depression and analyzing the system in certain limits, we can derive analytical expressions for various features of the oscillation, including the parameter regime in which stable oscillations occur, as well as the period and amplitude of these oscillations. These expressions are functions of three parameters: the time constant of depression, the synaptic strengths, and the amount of tonic excitation the cells receive. We compare our analytical results with the output of numerical simulations and obtain good agreement between the two. Based on our analysis, we conclude that the oscillations in our network are qualitatively different from those in networks that oscillate due to postinhibitory rebound, spike-frequency adaptation, or other intrinsic (rather than synaptic) adaptational mechanisms. In particular, our network can oscillate only via the synaptic escape mode of Skinner, Kopell, and Marder (1994).