Spatial and Temporal Arrangement of Recurrent Inhibition in the Primate Upper Limb.

Renshaw cells mediate recurrent inhibition between motoneurons within the spinal cord. The function of this circuit is not clear; we previously suggested based on computational modeling that it may cancel oscillations in muscle activity around 10 Hz, thereby reducing physiological tremor. Such tremor is especially problematic for dexterous hand movements, yet knowledge of recurrent inhibitory function is sparse for the control of the primate upper limb, where no direct measurements have been made to date. In this study, we made intracellular penetrations into 89 motoneurons in the cervical enlargement of four terminally anesthetized female macaque monkeys, and recorded recurrent IPSPs in response to antidromic stimulation of motor axons. Recurrent inhibition was strongest to motoneurons innervating shoulder muscles and elbow extensors, weak to wrist and digit extensors, and almost absent to the intrinsic muscles of the hand. Recurrent inhibitory connections often spanned joints, for example from motoneurons innervating wrist and digit muscles to those controlling the shoulder and elbow. Wrist and digit flexor motoneurons sometimes inhibited the corresponding extensors, and vice versa. This complex connectivity presumably reflects the flexible usage of the primate upper limb. Using trains of stimuli to motor nerves timed as a Poisson process and coherence analysis, we also examined the temporal properties of recurrent inhibition. The recurrent feedback loop effectively carried frequencies up to 100 Hz, with a coherence peak around 20 Hz. The coherence phase validated predictions from our previous computational model, supporting the idea that recurrent inhibition may function to reduce tremor.SIGNIFICANCE STATEMENT We present the first direct measurements of recurrent inhibition in primate upper limb motoneurons, revealing that it is more flexibly organized than previous observations in cat. Recurrent inhibitory connections were relatively common between motoneurons controlling muscles that act at different joints, and between flexors and extensors. As in the cat, connections were minimal for motoneurons innervating the most distal intrinsic hand muscles. Empirical data are consistent with previous modeling: temporal properties of the recurrent inhibitory feedback loop are compatible with a role in reducing physiological tremor by suppressing oscillations around 10 Hz.

Plastic Changes in Human Motor Cortical Output Induced by Random but not Closed-Loop Peripheral Stimulation: the Curse of Causality.

Previous work showed that repetitive peripheral nerve stimulation can induce plastic changes in motor cortical output. Triggering electrical stimulation of central structures from natural activity can also generate plasticity. In this study, we tested whether triggering peripheral nerve stimulation from muscle activity would likewise induce changes in motor output. We developed a wearable electronic device capable of recording electromyogram (EMG) and delivering electrical stimulation under closed-loop control. This allowed paired stimuli to be delivered over longer periods than standard laboratory-based protocols. We tested this device in healthy human volunteers. Motor cortical output in relaxed thenar muscles was first assessed via the recruitment curve of responses to contralateral transcranial magnetic stimulation. The wearable device was then configured to record thenar EMG and stimulate the median nerve at the wrist (intensity around motor threshold, rate ~0.66 Hz). Subjects carried out normal daily activities for 4-7 h, before returning to the laboratory for repeated recruitment curve assessment. Four stimulation protocols were tested (9-14 subjects each): No Stim, no stimuli delivered; Activity, stimuli triggered by EMG activity above threshold; Saved, stimuli timed according to a previous Activity session in the same subject; Rest, stimuli given when EMG was silent. As expected, No Stim did not modify the recruitment curve. Activity and Rest conditions produced no significant effects across subjects, although there were changes in some individuals. Saved produced a significant and substantial increase, with average responses 2.14 times larger at 30% stimulator intensity above threshold. We argue that unavoidable delays in the closed loop feedback, due mainly to central and peripheral conduction times, mean that stimuli in the Activity paradigm arrived too late after cortical activation to generate consistent plastic changes. By contrast, stimuli delivered essentially at random during the Saved paradigm may have caused a generalized increase in cortical excitability akin to stochastic resonance, leading to plastic changes in corticospinal output. Our study demonstrates that non-invasive closed loop stimulation may be critically limited by conduction delays and the unavoidable constraint of causality.

Cells in the monkey ponto-medullary reticular formation modulate their activity with slow finger movements.

Recent work has shown that the primate reticulospinal tract can influence spinal interneurons and motoneurons involved in control of the hand. However, demonstrating connectivity does not reveal whether reticular outputs are modulated during the control of different types of hand movement. Here, we investigated how single unit discharge in the pontomedullary reticular formation (PMRF) modulated during performance of a slow finger movement task in macaque monkeys. Two animals performed an index finger flexion­extension task to track a target presented on a computer screen; single units were recorded both from ipsilateral PMRF (115 cells) and contralateral primary motor cortex (M1, 210 cells). Cells in both areas modulated their activity with the task (M1: 87%, PMRF: 86%). Some cells (18/115 in PMRF; 96/210 in M1) received sensory input from the hand, showing a short-latency modulation in their discharge following a rapid passive extension movement of the index finger. Effects in ipsilateral electromyogram to trains of stimuli were recorded at 45 sites in the PMRF. These responses involved muscles controlling the digits in 13/45 sites (including intrinsic hand muscles, 5/45 sites). We conclude that PMRF may contribute to the control of fine finger movements, in addition to its established role in control of more proximal limb and trunk movements. This finding may be especially important in understanding functional recovery after brain lesions such as stroke.

Detecting synfire chains in parallel spike data.

The synfire chain model of brain organization has received much theoretical attention since its introduction (Abeles, 1982, 1991). However there has been no convincing experimental demonstration of synfire chains due partly to limitations of recording technology but also due to lack of appropriate analytic methods for large scale recordings of parallel spike trains. We have previously published one such method based on intersection of the neural populations active at two different times (Schrader et al., 2008). In the present paper we extend this analysis to deal with higher firing rates and noise levels, and develop two additional tools based on properties of repeating firing patterns. All three measures show characteristic signatures if synfire chains underlie the recorded data. However we demonstrate that the detection of repeating firing patterns alone (as used in several papers) is not enough to infer the presence of synfire chains. Positive results from all three measures are needed.

Procedural techniques in sacral nerve modulation.

Sacral neuromodulation involves a staged process, including a screening trial and delayed formal implantation for those with substantial improvement. The advent of the tined lead has revolutionized the technology, allowing for a minimally invasive outpatient procedure to be performed under intravenous sedation. With the addition of fluoroscopy to the bilateral percutaneous nerve evaluation, there has been marked improvement in the placement of these temporary leads. Thus, the screening evaluation is now a better reflection of possible permanent improvement. Both methods of screening have advantages and disadvantages. Selection of a particular procedure should be tailored to individual patient characteristics. Subsequent implantation of the internal pulse generator (IPG) or explantation of an unsuccessful staged lead is straightforward outpatient procedure, providing minimal additional risk for the patient. Future refinement to the procedure may involve the introduction of a rechargeable battery, eliminating the need for IPG replacement at the end of the battery life.

Spinal interneuron circuits reduce approximately 10-Hz movement discontinuities by phase cancellation.

Tremor imposes an important limit to the accuracy of fine movements in healthy individuals and can be a disabling feature of neurological disease. Voluntary slow finger movements are not smooth but are characterized by large discontinuities (i.e., steps) in the tremor frequency range (approximately 10 Hz). Previous studies have shown that these discontinuities are coherent with activity in the primary motor cortex (M1), but that other brain areas are probably also involved. We investigated the contribution of three important subcortical areas in two macaque monkeys trained to perform slow finger movements. Local field potential and single-unit activity were recorded from the deep cerebellar nuclei (DCN), medial pontomedullary reticular formation, and the intermediate zone of the spinal cord (SC). Coherence between LFP and acceleration was significant at 6 to 13 Hz for all areas, confirming the highly distributed nature of the central network responsible for this activity. The coherence phase at 6 to 13 Hz for DCN and pontomedullary reticular formation was similar to our previous results in M1. By contrast, for SC the phase differed from M1 by approximately pi rad. Examination of single-unit discharge confirmed that this was a genuine difference in neural spiking and could not be explained by different properties of the local field potential. Convergence of antiphase oscillations from the SC with cortical and subcortical descending inputs will lead to cancellation of approximately 10 Hz oscillations at the motoneuronal level. This could appreciably limit drive to muscle at this frequency, thereby reducing tremor and improving movement precision.

Coherence between motor cortical activity and peripheral discontinuities during slow finger movements.

Slow finger movements in man are not smooth, but are characterized by 8- to 12-Hz discontinuities in finger acceleration thought to have a central source. We trained two macaque monkeys to track a moving target by performing index finger flexion/extension movements and recorded local field potentials (LFPs) and spike activity from the primary motor cortex (M1); some cells were identified as pyramidal tract neurons by antidromic activation or as corticomotoneuronal cells by spike-triggered averaging. There was significant coherence between finger acceleration in the approximately 10-Hz range and both LFPs and spikes. LFP-acceleration coherence was similar for flexion and extension movements (0.094 at 9.8 Hz and 0.11 at 6.8 Hz, respectively), but substantially smaller during steady holding (0.0067 at 9.35 Hz). The coherence phase showed a significant linear relationship with frequency over the 6- to 13-Hz range, as expected for a constant conduction delay, but the slope indicated that LFP lagged acceleration by 18 +/- 14 or 36 +/- 8 ms for flexion and extension movements, respectively. Directed coherence analysis supported the conclusion that the dominant interaction was in the acceleration to LFP (i.e., sensory) direction. The phase relationships between finger acceleration and both LFPs and spikes shifted by about pi radians in flexion compared with extension trials. However, for a given trial type the phase relationship with acceleration was similar for cells that increased their firing during flexion or during extension trials. We conclude that movement discontinuities during slow finger movements arise from a reciprocally coupled network, which includes M1 and the periphery.

Renshaw cell recurrent inhibition improves physiological tremor by reducing corticomuscular coupling at 10 Hz.

Corticomuscular coherence between the primary motor cortex (M1) and hand muscle electromyograms (EMG) occurs at approximately 20 Hz but is rarely seen at approximately 10 Hz. This is unexpected, because M1 has oscillations at both frequencies, which are effectively transmitted to the spinal cord via the corticospinal tract. We have previously speculated that a specific "neural filter" may selectively reduce coherence at approximately 10 Hz. This would have functional utility in minimizing physiological tremor, which often has a dominant component around this frequency. Recurrent inhibition via Renshaw cells in the spinal cord is a putative neural substrate for such a filter. Here we investigate this system in more detail with a biophysically based computational model. Renshaw cell recurrent inhibition reduced EMG oscillations at approximately 10 Hz, and also reduced corticomuscular coherence at this frequency (from 0.038 to 0.014). Renshaw cell inhibitory feedback also generated synchronous oscillations in the motoneuron pool at approximately 30 Hz. We show that the effects at 10 Hz and 30 Hz can both be understood from the dynamics of the inhibitory feedback loop. We conclude that recurrent inhibition certainly plays an important role in reducing 10 Hz oscillations in muscle, thereby decreasing tremor amplitude. However, our quantitative results suggest it is unlikely to be the only system for tremor reduction, and probably acts in concert with other neural circuits which remain to be elucidated.

Circuits generating corticomuscular coherence investigated using a biophysically based computational model. I. Descending systems.

Recordings of motor cortical activity typically show oscillations around 10 and 20 Hz; only those at 20 Hz are coherent with electromyograms (EMGs) of contralateral muscles. Experimental measurements of the phase difference between approximately 20-Hz oscillations in cortex and muscle are often difficult to reconcile with the known corticomuscular conduction delays. We investigated the generation of corticomuscular coherence further using a biophysically based computational model, which included a pool of motoneurons connected to motor units that generated EMGs. Delays estimated from the coherence phase-frequency relationship were sensitive to the width of the motor unit action potentials. In addition, the nonlinear properties of the motoneurons could produce complex, oscillatory phase-frequency relationships. This was due to the interaction of cortical inputs to the motoneuron pool with the intrinsic rhythmicity of the motoneurons; the response appeared more linear if the firing rate of motoneurons varied widely across the pool, such as during a strong contraction. The model was able to reproduce the smaller than expected delays between cortex and muscles seen in experiments. However, the model could not reproduce the constant phase over a frequency band sometimes seen in experiments, nor the lack of around 10-Hz coherence. Simple propagation of oscillations from cortex to muscle thus cannot completely explain the observed corticomuscular coherence.

Stress urinary incontinence: the evolution of the sling.

Stress urinary incontinence is one of the most prevalent and costly problems encountered by the international medical community. The exact mechanism of stress incontinence remains elusive. Early management relied on behavioral modification but, as more advanced anatomic and urodynamic research surfaced, the focus shifted to surgical correction. Initial innovations provided a compressive force/hammock to support the urethra and bladder neck. For almost a century, the pubovaginal sling provided this support, with 70-90% cure rates at the expense of significant voiding dysfunction. Later work has highlighted the interaction of muscles and ligaments as a midurethral kinking mechanism to prevent leakage. With this knowledge came the advent of tension-free vaginal taping. Further modifications led to the development of other midurethral slings, producing similar cure rates while minimizing complications.

Pelvic hematoma following transobturator tape procedure: case report and review of literature.

OBJECTIVE: The transobturator tape (TOS) procedure is rapidly becoming a preferred treatment for female stress urinary incontinence due to excellent outcomes and minimal morbidity. Though rare, significant bleeding complications can occur. MATERIAL AND METHODS: We review our experience and available literature of pelvic hematoma formation after TOS placement. RESULTS: A 56-year-old woman underwent a TOS procedure for stress incontinence. She returned on postoperative day three with nausea and vague suprapubic discomfort, though voiding without difficulty. Office ultrasound and computed tomographic imaging revealed a bi-lobed 8 cm x 10 cm x 11 cm hematoma in the Space of Retzius. She was treated conservatively with intravenous pain medication and antiemetics and without blood transfusion. Four weeks after the procedure, the patient had no voiding, pain, or bowel complaints. Literature review yielded two other reports of five patients with similar presentations who were successfully treated conservatively. CONCLUSIONS: Pelvic hematoma formation after the TOS procedure is a rare event and can usually be managed conservatively.