Mary K. Nagai

Inhibition of trimethadione and dimethadione teratogenicity by the cyclooxygenase inhibitor acetylsalicylic acid: A unifying hypothesis for the teratologic effects of hydantoin anticonvulsants and structurally related compounds☆

Teratogenicity of the anticonvulsant phenytoin may be due in part to its bioactivation by prostaglandin synthetase, forming a reactive free radical intermediate. We examined whether teratogenicity of the structurally similar oxazolidinedione anticonvulsants, trimethadione and its N-demethylated metabolite dimethadione, could be inhibited by the prostaglandin synthetase inhibitor acetylsalicylic acid (ASA). Trimethadione, 700 or 1000 mg/kg intraperitoneally (ip), was given to pregnant CD-1 mice during (Gestational Days 12 and 13) or before (Days 11 and 12) the critical period of susceptibility to phenytoin-induced fetal cleft palates. Dimethadione was given similarly on Days 11 and 12, or 12 and 13, in a dose (900 mg/kg ip) that was equimolar to 1000 mg/kg of trimethadione. ASA, 10 or 1 mg/kg ip, was given 2 hr before trimethadione or dimethadione on Days 11 and 12, and before trimethadione on Day 11 only. Dams were killed on Day 19 and fetuses were examined for anomalies. Either dose of trimethadione given on Days 12 and 13 was negligibly teratogenic, as evidenced by a non-dose-related, 1.1% mean incidence of fetal cleft palates. However, when given earlier on Days 11 and 12, trimethadione 1000 mg/kg caused an 8.9% incidence of cleft palates (p less than 0.05). Similarly, dimethadione caused a 3.9-fold higher incidence of cleft palates when given earlier on Days 11 and 12 (17.3-34.9%) than on Days 12 and 13 (4.4%) (p less than 0.05). At equimolar doses, dimethadione caused a 1.9- to 3.9-fold higher incidence of cleft palates compared to trimethadione (p less than 0.05), suggesting that dimethadione may be the proximate teratogen. Either dose of ASA given on both days before trimethadione totally prevented cleft palates, and ASA 10 mg/kg given only on Day 11 reduced the incidence of trimethadione-induced cleft palates to 1.1% (p less than 0.05). ASA reduced the incidence of cleft palates caused by dimethadione given on Days 11 and 12 from 34.9 to 20.3% (p less than 0.05). These results suggest that the teratogenic potential of trimethadione may depend at least in part upon its prior N-demethylation to dimethadione, which then can be bioactivated by prostaglandin synthetase to a teratogenic reactive intermediate, possibly involving a free radical located in the oxazolidinedione ring. This would provide a unifying hypothesis for the teratogenicity of hydantoins, as well as structurally related teratogens like trimethadione, which lack the molecular configuration necessary for the formation of a teratogenic arene oxide intermediate.

Erratum to “Influence of the Number and Location of Recording Contacts on the Selectivity of a Nerve Cuff Electrode”

A 56-contact matrix nerve cuff electrode (seven rings with eight contacts each) was used to obtain recordings from the rat sciatic nerve, which were then discriminated as originating from one of three fascicles (tibial, peroneal, and sural branches). The influence of the number and location of the recording contacts on the classification accuracy was studied. The performance of a classifier was shown to be superior when data was available from all 56 contacts, compared to when only the eight contacts of the middle ring were used (as in previously proposed multicontact tripolar cuff designs). By examining the performance variations as contacts were included one at a time (in order of decreasing positive impact on performance), it was further shown that the matrix configuration could outperform the single-ring configuration with only a small number of contacts. We can therefore conclude that the performance improvement is not due to the sheer number of contacts, but rather to the possibility of selecting the most informative locations around the nerve. The results could have important implications for the design and use of multicontact nerve cuff electrodes.

Use of an Experimentally Derived Leadfield in the Peripheral Nerve Pathway Discrimination Problem

The task of discriminating the neural pathways responsible for the activity recorded using a multi-contact nerve cuff electrode has recently been approached as an inverse problem of source localization, similar to EEG source localization. A major drawback of this method is that it requires a model of the nerve, and that the localization performance is highly dependent on the accuracy of this model. Using recordings from a 56-contact “matrix” cuff electrode placed on a rat sciatic nerve, we investigated a method that eliminates the need for a model, and uses instead an “experimental” leadfield constructed from a training set of experimental recordings. The resulting pathway-identification task is solved using an inverse problem framework. The experimental leadfield approach was able to identify the correct branch in cases in which a single fascicle was active with a success rate of 94.2%, but was not able to reliably identify combinations of fascicles. Nevertheless, the proposed methodology provides a framework for the study of multi-pathway discrimination, within which methods to improve performance can be investigated. Specifically, the influence of nerve anatomy and electrode design should be examined, and regularization approaches better suited to this novel inverse problem should be sought.

Functional Electrical Stimulation Therapy for Recovery of Reaching and Grasping in Severe Chronic Pediatric Stroke Patients

Stroke affects 2.7 children per 100,000 annually, leaving many of them with lifelong residual impairments despite intensive rehabilitation. In the present study the authors evaluated the effectiveness of 48 hours of transcutaneous functional electrical stimulation therapy for retraining voluntary reaching and grasping in 4 severe chronic pediatric stroke participants. Participants were assessed using the Rehabilitation Engineering Laboratory Hand Function Test, Quality of Upper Extremity Skills Test, Pediatric Evaluation of Disability Inventory, and Assisting Hand Assessment. All participants improved on all measures. The average change scores on selected Rehabilitation Engineering Laboratory Hand Function Test components were 14.5 for object manipulation (P = .042), 0.78 Nm for instrumented cylinder (P = .068), and 14 for wooden blocks (P = .068) and on the grasp component of Quality of Upper Extremity Skills Test was 25.93 (P = .068). These results provide preliminary evidence that functional electrical stimulation therapy has the potential to improve upper limb function in severe chronic pediatric stroke patients.

Short‐Term Neuroplastic Effects of Brain‐Controlled and Muscle‐Controlled Electrical Stimulation

Functional electrical stimulation (FES) has been shown to facilitate the recovery of grasping function in individuals with incomplete spinal cord injury. Neurophysiological theory suggests that this benefit may be further enhanced by a more consistent pairing of the voluntary commands sent from the users brain down their spinal cord with the electrical stimuli applied to the users periphery. The objective of the study was to compare brain‐machine interfaces (BMIs)‐controlled and electromyogram (EMG)‐controlled FES therapy to three more well‐researched therapies, namely, push button‐controlled FES therapy, voluntary grasping (VOL), and BMI‐guided voluntary grasping.

Functional electrical stimulation post-spinal cord injury improves locomotion and increases afferent input into the central nervous system in rats.

Abstract Background Functional electrical stimulation (FES) has been found to be effective in restoring voluntary functions after spinal cord injury (SCI) and stroke. However, the central nervous system (CNS) changes that occur in as a result of this therapy are largely unknown. Objective To examine the effects of FES on the restoration of voluntary locomotor function of the CNS in a SCI rat model. Methods SCI rats were instrumented with chronic FES electrodes in the hindlimb muscles and were divided into two groups: (a) FES therapy and (b) sedentary. At day 7 post-SCI, the animals were assessed for locomotion performance by using a Basso, Beattie and Bresnahan (BBB) scale. They were then anesthetized for a terminal in vivo experiment. The lumbar spinal cord and somatosensory cortex were exposed and the instrumented muscles were stimulated electrically. Associated neurovascular responses in the CNS were recorded with an intrinsic optical imaging system. Results FES greatly improved locomotion recovery by day 7 post-SCI, as measured by BBB scores (P < 0.05): (a) FES 10 ± 2 and (b) controls 3 ± 1. Furthermore, the FES group showed a significant increase (P < 0.05) of neurovascular activation in the spinal cord and somatosensory cortex when the muscles were stimulated between 1 and 3 motor threshold (MT). Conclusion Hind limb rehabilitation with FES is an effective strategy to improve locomotion during the acute phase post-SCI. The results of this study indicate that after FES, the CNS preserves/acquires the capacity to respond to peripheral electrical stimulation.

Bioelectric Source Localization in the Rat Sciatic Nerve: Initial Assessment Using an Idealized Nerve Model

Our goal is to determine the spatial origin of bioelectric activity within a peripheral nerve using recordings from a multi-contact nerve cuff electrode. This task is a bioelectric source localization problem, and a natural question is whether or not algorithms developed for the similar problem of EEG source localization can be applied in the peripheral nerve context. This technique requires a model of the nerve, and the present study aims to determine if using an idealized nerve geometry in the finite-element model is sufficient to achieve acceptable localization performance. Using a leadfield derived from the idealized model, the sLORETA algorithm was applied to recordings from a 56-channel “matrix” nerve cuff electrode placed around the rat sciatic nerve. The results show that the method was not able to reliably estimate the number and combination of active fascicles. A summary of the issues that need to be addressed before source localization techniques can be applied to peripheral nerves is provided.

Why Is Functional Electrical Stimulation Therapy Capable of Restoring Motor Function Following Severe Injury to the Central Nervous System

Injury to the central nervous system (CNS) often results in the loss of motor and sensory activity with a tragic impact on quality of life. The anatomic and cellular complexity of the nervous system limits its ability to repair itself, making the effects of the injury permanent. To date, the majority of attempts to restore normal function after damage to the brain or spinal cord have been unsuccessful. Recent studies have demonstrated significant improvements in voluntary motor function in patients with chronic and subacute stroke and spinal cord injury (SCI) using functional electrical stimulation (FES) therapy. In this therapy, patients are asked to perform multitudes of specific motor tasks. During each session, the therapist instructs patients to perform a specific movement at a time, and, after a few seconds of trying, highly controlled electrical stimulation is applied to facilitate that specific movement of the paralyzed limb. After completing this therapy program, individuals are often able to perform the tasks voluntarily, i.e., unassisted by the FES system. Using this approach, we have been able to assist patients with complete and incomplete spinal cord injuries, severe stroke, and pediatric stroke to recover the ability to reach, grasp, stand, and walk. In this chapter, we explain why we believe FES has achieved such extraordinary results.

A framework for the discrimination of neural pathways using multi-contact nerve cuff electrodes

Monitoring the activity of specific neural pathways in a peripheral nerve is a task with numerous applications in implanted neuroprosthetic systems. Achieving selective recording using multi-contact nerve cuff electrodes is appealing because these devices are well suited for chronic use, but no viable general solution to the task of discriminating combinations of active pathways from extra-neural recordings has yet been proposed. Bioelectric source localization approaches have been suggested, but their effectiveness is limited by the accuracy of the nerve model used to solve the forward problem. We propose a model-free alternative to the pathway discrimination task, in which experimental data is used to estimate a solution to the forward problem. The method was evaluated using a 56-channel cuff placed on the rat sciatic nerve. 3 pathways were discriminated with a 94.2% success rate when individually active, whereas further improvements are needed in order to recover combinations of simultaneously active pathways.

Neuron-Type-Specific Utility in a Brain-Machine Interface: a Pilot Study

Context: Firing rates of single cortical neurons can be volitionally modulated through biofeedback (i.e. operant conditioning), and this information can be transformed to control external devices (i.e. brain-machine interfaces; BMIs). However, not all neurons respond to operant conditioning in BMI implementation. Establishing criteria that predict neuron utility will assist translation of BMI research to clinical applications. Findings: Single cortical neurons (n=7) were recorded extracellularly from primary motor cortex of a Long-Evans rat. Recordings were incorporated into a BMI involving up-regulation of firing rate to control the brightness of a light-emitting-diode and subsequent reward. Neurons were classified as ‘fast-spiking’, ‘bursting’ or ‘regular-spiking’ according to waveform-width and intrinsic firing patterns. Fast-spiking and bursting neurons were found to up-regulate firing rate by a factor of 2.43±1.16, demonstrating high utility, while regular-spiking neurons decreased firing rates on average by a factor of 0.73±0.23, demonstrating low utility. Conclusion/Clinical Relevance: The ability to select neurons with high utility will be important to minimize training times and maximize information yield in future clinical BMI applications. The highly contrasting utility observed between fast-spiking and bursting neurons versus regular-spiking neurons allows for the hypothesis to be advanced that intrinsic electrophysiological properties may be useful criteria that predict neuron utility in BMI implementation.