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Locomotor training (LT) is intended to improve walking function and can also reduce spasticity in motor-incomplete spinal cord injury (MISCI). Transcutaneous spinal stimulation (TSS) also influences these outcomes. We assessed feasibility and preliminary efficacy of combined LT + TSS during inpatient rehabilitation in a randomized, sham-controlled, pragmatic study. Eighteen individuals with subacute MISCI (2-6 months post-SCI) were enrolled and randomly assigned to the LT + TSS or the LT + TSSsham intervention group. Participants completed a 4-week program consisting of a 2-week wash-in period (LT only) then a 2-week intervention period (LT + TSS or LT + TSSsham). Before and after each 2-week period, walking (10 m walk test, 2-min walk test, step length asymmetry) and spasticity (pendulum test, clonus drop test, modified spinal cord injury-spasticity evaluation tool) were assessed. Sixteen participants completed the study. Both groups improved in walking speed and distance. While there were no significant between-groups differences, the LT + TSS group had significant improvements in walking outcomes following the intervention period; conversely, improvements in the LT + TSSsham group were not significant. Neither group had significant changes in spasticity, and the large amount of variability in spasticity may have obscured ability to observe change in these measures. TSS is a feasible adjunct to LT in the subacute stage of SCI and may have potential to augment training-related improvements in walking outcomes.

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Control of muscles about the ankle joint is an important component of locomotion and balance that is negatively impacted by spinal cord injury (SCI). Volitional control of the ankle dorsiflexors (DF) is impaired by damage to pathways descending from supraspinal centers. Concurrently, spasticity arising from disrupted organization of spinal reflex circuits, further erodes control. The association between neurophysiological changes (corticospinal and spinal) with volitional ankle control (VAC) and spasticity remains unclear. The goal of this scoping review was to synthesize what is known about how changes in corticospinal transmission and spinal reflex excitability contribute to disrupted ankle control after SCI. We followed published guidelines for conducting a scoping review, appraising studies that contained a measure of corticospinal transmission and/or spinal reflex excitability paired with a measure of VAC and/or spasticity. We examined studies for evidence of a relationship between neurophysiological measures (either corticospinal tract transmission or spinal reflex excitability) with VAC and/or spasticity. Of 1,538 records identified, 17 studies were included in the review. Ten of 17 studies investigated spinal reflex excitability, while 7/17 assessed corticospinal tract transmission. Four of the 10 spinal reflex studies examined VAC, while 9/10 examined ankle spasticity. The corticospinal tract transmission studies examined only VAC. While current evidence suggests there is a relationship between neurophysiological measures and ankle function after SCI, more studies are needed. Understanding the relationship between neurophysiology and ankle function is important for advancing therapeutic outcomes after SCI. Future studies to capture an array of corticospinal, spinal, and functional measures are warranted.

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Spasticity affects approximately 65% of persons with spinal cord injury (SCI) and negatively impacts function and quality of life. Whole body vibration (WBV) appears to reduce spasticity and improve walking function; however, the optimal dose (frequency/duration) is not known. We compared single-session effects of four different WBV frequency/duration dose conditions on spasticity and walking speed, in preparation for a planned multi-session study. Thirty-five participants with motor-incomplete SCI received four different doses of WBV: high frequency (50 Hz)/short duration (180 s), high frequency/long duration (360 s), low frequency (30 Hz)/short duration, and low frequency/long duration, plus a control intervention consisting of sham electrical stimulation. In all conditions, participants stood on the WBV platform for 45-s bouts with 1 min rest between bouts until the requisite duration was achieved. The frequency/duration dose order was randomized across participants; sessions were separated by at least 1 week. Quadriceps spasticity was measured using the pendulum test at four time points during each session: before, immediately after, 15 min after, and 45 min after WBV. Walking speed was quantified using the 10-m walk test at three time points during each session: baseline, immediately after, and 45 min after WBV. In the full group analysis, no frequency/duration combination was significantly different from the sham-control condition. In participants with more severe spasticity, a greater reduction in stretch reflex excitability was associated with the high frequency/long duration WBV condition. The sham-control condition was associated with effects, indicating that the activity of repeated sitting and standing may have a beneficial influence on spasticity. TRIAL REGISTRATION: NCT02340910 (assigned 01/19/2015).

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While priming is most often thought of as a strategy for modulating neural excitability to facilitate voluntary motor control, priming stimulation can also be utilized to target spinal reflex excitability. In this application, priming can be used to modulate the involuntary motor output that often follows central nervous system injury. Individuals with spinal cord injury (SCI) often experience spasticity, for which antispasmodic medications are the most common treatment. Physical therapeutic/electroceutic interventions offer an alternative treatment for spasticity, without the deleterious side effects that can accompany pharmacological interventions. While studies of physical therapeutic/electroceutic interventions have been published, a systematic comparison of these approaches has not been performed. The purpose of this study was to compare four non-pharmacological interventions to a sham-control intervention to assess their efficacy for spasticity reduction. Participants were individuals (n = 10) with chronic SCI (≥1 year) who exhibited stretch-induced quadriceps spasticity. Spasticity was quantified using the pendulum test before and at two time points after (immediate, 45 min delayed) each of four different physical therapeutic/electroceutic interventions, plus a sham-control intervention. Interventions included stretching, cyclic passive movement (CPM), transcutaneous spinal cord stimulation (tcSCS), and transcranial direct current stimulation (tDCS). The sham-control intervention consisted of a brief ramp-up and ramp-down of knee and ankle stimulation while reclined with legs extended. The order of interventions was randomized, and each was tested on a separate day with at least 48 h between sessions. Compared to the sham-control intervention, stretching, CPM, and tcSCS were associated with a significantly greater reduction in spasticity immediately after treatment. While the immediate effect was largest for stretching, the reduction persisted for 45 min only for the CPM and tcSCS interventions. tDCS had no immediate or delayed effects on spasticity when compared to sham-control. Interestingly, the sham-control intervention was associated with significant within-session increases in spasticity, indicating that spasticity increases with immobility. These findings suggest that stretching, CPM, and tcSCS are viable non-pharmacological alternatives for reducing spasticity, and that CPM and tcSCS have prolonged effects. Given that the observed effects were from a single-session intervention, future studies should determine the most efficacious dosing and timing strategies.

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Carbon monoxide (CO) is physiologically produced via heme degradation by heme oxygenase enzymes. Whereas CO has been identified as an important physiological signaling molecule, the roles it plays in neuronal development and regeneration are poorly understood. During these events, growth cones guide axons through a rich cellular environment to locate target cells and establish synaptic connections. Previously, we have shown that another gaseous signaling molecule, nitric oxide (NO), has potent effects on growth cone motility. With NO and CO sharing similar cellular targets, we wanted to determine whether CO affected growth cone motility as well. We assessed how CO affected growth cone filopodial length and determined the signaling pathway by which this effect was mediated. Using two well-characterized neurons from the freshwater snail, Helisoma trivolvis, it was found that the CO donor, carbon monoxide releasing molecule-2 (CORM-2), increased filopodial length. CO utilized a signaling pathway that involved the activation of soluble guanylyl cyclase, protein kinase G, and ryanodine receptors. While increases in filopodial length often occur from robust increases in intracellular calcium levels, the timing in which CO increased filopodial length corresponded with low basal calcium levels in growth cones. Taken together with findings of a heme oxygenase-like protein in the Helisoma nervous system, these results provide evidence for CO as a modulator of growth cone motility and implicate CO as a neuromodulatory signal during neuronal development and/or regeneration. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 677-690, 2017.

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Nitric oxide (NO) is a key regulator of neuronal excitability in the nervous system. While most studies have investigated its role as an intercellular messenger/modulator, less is known about potential physiological roles played by NO within NO-producing neurons. We showed previously that intrinsic production of NO within B5 neurons of the pond snail Helisoma trivolvis increased neuronal excitability by acting on three ionic conductances. Here we demonstrate that intrinsically produced NO affected two of the same conductances in another buccal neuron, B19, where it had the opposite, namely inhibitory, effect on neuronal activity. Using single-cell RT-PCR, we show that B19 neurons express NO synthase (NOS) mRNA. The inhibition of intrinsic NO production with NOS inhibitors caused membrane potential depolarization, transient spiking and an increase in input resistance. Inhibition of the main intracellular receptor of NO, soluble guanylyl cyclase, had similar effects on the parameters mentioned above. An investigation of the effects of NO on ion channels revealed that intrinsic NO mediated neuronal hyperpolarization by activating voltage-gated calcium channels that in turn caused the tonic opening of apamin-sensitive calcium-activated potassium channels. The analysis of action potentials in B5 and B19 neurons suggested that the opposite effects on neuronal excitability elicited by intrinsic NO were probably determined by differences in the ionic conductances that shape their action potentials. In summary, we describe a mechanism by which B19 neurons utilise intrinsically produced NO in a cell-type-specific fashion to decrease their neuronal activity, highlighting an important physiological role of NO within NO-producing neurons.

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The electrical activity in developing and mature neurons determines the intracellular calcium concentration ([Ca(2+)]i), which in turn is translated into biochemical activities through various signaling cascades. Electrical activity is under control of neuromodulators, which can alter neuronal responses to incoming signals and increase the fidelity of neuronal communication. Conversely, the effects of neuromodulators can depend on the ongoing electrical activity within target neurons; however, these activity-dependent effects of neuromodulators are less well understood. Here, we present evidence that the neuronal firing frequency and intrinsic properties of the action potential (AP) waveform set the [Ca(2+)]i in growth cones and determine how neurons respond to the neuromodulator nitric oxide (NO). We used two well-characterized neurons from the freshwater snail Helisoma trivolvis that show different growth cone morphological responses to NO: B5 neurons elongate filopodia, while those of B19 neurons do not. Combining whole-cell patch clamp recordings with simultaneous calcium imaging, we show that the duration of an AP contributes to neuron-specific differences in [Ca(2+)]i, with shorter APs in B19 neurons yielding lower growth cone [Ca(2+)]i. Through the partial inhibition of voltage-gated K(+) channels, we increased the B19 AP duration resulting in a significant increase in [Ca(2+)]i that was then sufficient to cause filopodial elongation following NO treatment. Our results demonstrate a neuron-type specific correlation between AP shape, [Ca(2+)]i, and growth cone motility, providing an explanation to how growth cone responses to guidance cues depend on intrinsic electrical properties and helping explain the diverse effects of NO across neuronal populations.

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Nitric oxide (NO) is an unconventional membrane-permeable messenger molecule that has been shown to play various roles in the nervous system. How NO modulates ion channels to affect neuronal functions is not well understood. In gastropods, NO has been implicated in regulating the feeding motor program. The buccal motoneuron, B19, of the freshwater pond snail Helisoma trivolvis is active during the hyper-retraction phase of the feeding motor program and is located in the vicinity of NO-producing neurons in the buccal ganglion. Here, we asked whether B19 neurons might serve as direct targets of NO signaling. Previous work established NO as a key regulator of growth cone motility and neuronal excitability in another buccal neuron involved in feeding, the B5 neuron. This raised the question whether NO might modulate the electrical activity and neuronal excitability of B19 neurons as well, and if so whether NO acted on the same or a different set of ion channels in both neurons. To study specific responses of NO on B19 neurons and to eliminate indirect effects contributed by other cells, the majority of experiments were performed on single cultured B19 neurons. Addition of NO donors caused a prolonged depolarization of the membrane potential and an increase in neuronal excitability. The effects of NO could mainly be attributed to the inhibition of two types of calcium-activated potassium channels, apamin-sensitive and iberiotoxin-sensitive potassium channels. NO was found to also cause a depolarization in B19 neurons in situ, but only after NO synthase activity in buccal ganglia had been blocked. The results suggest that NO acts as a critical modulator of neuronal excitability in B19 neurons, and that calcium-activated potassium channels may serve as a common target of NO in neurons.

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In addition to acting as a classical neurotransmitter in synaptic transmission, acetylcholine (ACh) has been shown to play a role in axonal growth and growth cone guidance. What is not well understood is how ACh acts on growth cones to affect growth cone filopodia, structures known to be important for neuronal pathfinding. We addressed this question using an identified neuron (B5) from the buccal ganglion of the pond snail Helisoma trivolvis in cell culture. ACh treatment caused pronounced filopodial elongation within minutes, an effect that required calcium influx and resulted in the elevation of the intracellular calcium concentration ([Ca]i ). Whole-cell patch clamp recordings showed that ACh caused a reduction in input resistance, a depolarization of the membrane potential, and an increase in firing frequency in B5 neurons. These effects were mediated via the activation of nicotinic acetylcholine receptors (nAChRs), as the nAChR agonist dimethylphenylpiperazinium (DMPP) mimicked the effects of ACh on filopodial elongation, [Ca]i elevation, and changes in electrical activity. Moreover, the nAChR antagonist tubucurarine blocked all DMPP-induced effects. Lastly, ACh acted locally at the growth cone, because growth cones that were physically isolated from their parent neuron responded to ACh by filopodial elongation with a similar time course as growth cones that remained connected to their parent neuron. Our data revealed a critical role for ACh as a modulator of growth cone filopodial dynamics. ACh signaling was mediated via nAChRs and resulted in Ca influx, which, in turn, caused filopodial elongation.

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Serum from seven patients with ordinary scabies and six with crusted scabies were screened by immunoblotting for IgE- and IgG-specific proteins in an extract of the mite, Sarcoptes scabiei variety canis. Sera from atopic individuals without sensitivity to house dust mites were used as controls. Serum from all of the patients with crusted scabies showed strong IgE binding to 11-21 and IgG binding to 1-7 scabies proteins. In contrast, three of the seven patients with ordinary scabies showed IgE binding to one to six scabies proteins, and their antibody binding was much weaker. Patients with crusted scabies had serum antibody that reacted with larger molecular weight proteins compared with patients with ordinary scabies. The results of this study indicate that patients with crusted scabies showed a pronounced IgE response to scabies mites, whereas patients with ordinary scabies did not.

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