Repeated transspinal stimulation decreases soleus H-reflex excitability and restores spinal inhibition in human spinal cord injury

Neurophysiological changes that involve activity-dependent neuroplasticity mechanisms via repeated stimulation and locomotor training are not commonly employed in research even though combination of interventions is a common clinical practice. In this randomized clinical trial, we established neurophysiological changes when transcranial magnetic stimulation (TMS) of the motor cortex was paired with transcutaneous thoracolumbar spinal (transspinal) stimulation in human spinal cord injury (SCI) delivered during locomotor training. We hypothesized that TMS delivered before transspinal (TMS-transspinal) stimulation promotes functional reorganization of spinal networks during stepping. In this protocol, TMS-induced corticospinal volleys arrive at the spinal cord at a sufficient time to interact with transspinal stimulation induced depolarization of alpha motoneurons over multiple spinal segments. We further hypothesized that TMS delivered after transspinal (transspinal-TMS) stimulation induces less pronounced effects. In this protocol, transspinal stimulation is delivered at time that allows transspinal stimulation induced action potentials to arrive at the motor cortex and affect descending motor volleys at the site of their origin. Fourteen individuals with motor incomplete and complete SCI participated in at least 25 sessions. Both stimulation protocols were delivered during the stance phase of the less impaired leg. Each training session consisted of 240 paired stimuli delivered over 10-min blocks. In transspinal-TMS, the left soleus H-reflex increased during the stance-phase and the right soleus H-reflex decreased at mid-swing. In TMS-transspinal no significant changes were found. When soleus H-reflexes were grouped based on the TMS-targeted limb, transspinal-TMS and locomotor training promoted H-reflex depression at swing phase, while TMS-transspinal and locomotor training resulted in facilitation of the soleus H-reflex at stance phase of the step cycle. Furthermore, both transspinal-TMS and TMS-transspinal paired-associative stimulation (PAS) and locomotor training promoted a more physiological modulation of motor activity and thus depolarization of motoneurons during assisted stepping. Our findings support that targeted non-invasive stimulation of corticospinal and spinal neuronal pathways coupled with locomotor training produce neurophysiological changes beneficial to stepping in humans with varying deficits of sensorimotor function after SCI.

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Locomotor training improves reciprocal and nonreciprocal inhibitory control of soleus motoneurons in human spinal cord injury

Journal of Neurophysiology ◽

10.1152/jn.00872.2014 ◽

2015 ◽

Vol 113 (7) ◽

pp. 2447-2460 ◽

Cited By ~ 9

Author(s):

Maria Knikou ◽

Andrew C. Smith ◽

Chaithanya K. Mummidisetty

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Spinal Injury ◽

Reciprocal Inhibition ◽

H Reflex ◽

Medial Gastrocnemius ◽

Locomotor Training ◽

Step Cycle ◽

Human Spinal Cord ◽

Cord Injury

Pathologic reorganization of spinal networks and activity-dependent plasticity are common neuronal adaptations after spinal cord injury (SCI) in humans. In this work, we examined changes of reciprocal Ia and nonreciprocal Ib inhibition after locomotor training in 16 people with chronic SCI. The soleus H-reflex depression following common peroneal nerve (CPN) and medial gastrocnemius (MG) nerve stimulation at short conditioning-test (C-T) intervals was assessed before and after training in the seated position and during stepping. The conditioned H reflexes were normalized to the unconditioned H reflex recorded during seated. During stepping, both H reflexes were normalized to the maximal M wave evoked at each bin of the step cycle. In the seated position, locomotor training replaced reciprocal facilitation with reciprocal inhibition in all subjects, and Ib facilitation was replaced by Ib inhibition in 13 out of 14 subjects. During stepping, reciprocal inhibition was decreased at early stance and increased at midswing in American Spinal Injury Association Impairment Scale C (AIS C) and was decreased at midstance and midswing phases in AIS D after training. Ib inhibition was decreased at early swing and increased at late swing in AIS C and was decreased at early stance phase in AIS D after training. The results of this study support that locomotor training alters postsynaptic actions of Ia and Ib inhibitory interneurons on soleus motoneurons at rest and during stepping and that such changes occur in cases with limited or absent supraspinal inputs.

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Locomotor training improves premotoneuronal control after chronic spinal cord injury

Journal of Neurophysiology ◽

10.1152/jn.00871.2013 ◽

2014 ◽

Vol 111 (11) ◽

pp. 2264-2275 ◽

Cited By ~ 30

Author(s):

Maria Knikou ◽

Chaithanya K. Mummidisetty

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Presynaptic Inhibition ◽

H Reflex ◽

Locomotor Training ◽

Dependent Manner ◽

Step Cycle ◽

Cord Injury ◽

Spinal Inhibition ◽

Presynaptic Facilitation

Spinal inhibition is significantly reduced after spinal cord injury (SCI) in humans. In this work, we examined if locomotor training can improve spinal inhibition exerted at a presynaptic level. Sixteen people with chronic SCI received an average of 45 training sessions, 5 days/wk, 1 h/day. The soleus H-reflex depression in response to low-frequency stimulation, presynaptic inhibition of soleus Ia afferent terminals following stimulation of the common peroneal nerve, and bilateral EMG recovery patterns were assessed before and after locomotor training. The soleus H reflexes evoked at 1.0, 0.33, 0.20, 0.14, and 0.11 Hz were normalized to the H reflex evoked at 0.09 Hz. Conditioned H reflexes were normalized to the associated unconditioned H reflex evoked with subjects seated, while during stepping both H reflexes were normalized to the maximal M wave evoked after the test H reflex at each bin of the step cycle. Locomotor training potentiated homosynaptic depression in all participants regardless the type of the SCI. Presynaptic facilitation of soleus Ia afferents remained unaltered in motor complete SCI patients. In motor incomplete SCIs, locomotor training either reduced presynaptic facilitation or replaced presynaptic facilitation with presynaptic inhibition at rest. During stepping, presynaptic inhibition was modulated in a phase-dependent manner. Locomotor training changed the amplitude of locomotor EMG excitability, promoted intralimb and interlimb coordination, and altered cocontraction between knee and ankle antagonistic muscles differently in the more impaired leg compared with the less impaired leg. The results provide strong evidence that locomotor training improves premotoneuronal control after SCI in humans at rest and during walking.

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Neuronal Actions of Transspinal Stimulation on Locomotor Networks and Reflex Excitability During Walking in Humans With and Without Spinal Cord Injury

Frontiers in Human Neuroscience ◽

10.3389/fnhum.2021.620414 ◽

2021 ◽

Vol 15 ◽

Author(s):

Md. Anamul Islam ◽

Timothy S. Pulverenti ◽

Maria Knikou

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Single Pulse ◽

H Reflex ◽

Spinal Reflex ◽

Emg Activity ◽

Step Cycle ◽

Reflex Excitability ◽

Cord Injury ◽

Modulation Pattern

This study investigated the neuromodulatory effects of transspinal stimulation on soleus H-reflex excitability and electromyographic (EMG) activity during stepping in humans with and without spinal cord injury (SCI). Thirteen able-bodied adults and 5 individuals with SCI participated in the study. EMG activity from both legs was determined for steps without, during, and after a single-pulse or pulse train transspinal stimulation delivered during stepping randomly at different phases of the step cycle. The soleus H-reflex was recorded in both subject groups under control conditions and following single-pulse transspinal stimulation at an individualized exactly similar positive and negative conditioning-test interval. The EMG activity was decreased in both subject groups at the steps during transspinal stimulation, while intralimb and interlimb coordination were altered only in SCI subjects. At the steps immediately after transspinal stimulation, the physiological phase-dependent EMG modulation pattern remained unaffected in able-bodied subjects. The conditioned soleus H-reflex was depressed throughout the step cycle in both subject groups. Transspinal stimulation modulated depolarization of motoneurons over multiple segments, limb coordination, and soleus H-reflex excitability during assisted stepping. The soleus H-reflex depression may be the result of complex spinal inhibitory interneuronal circuits activated by transspinal stimulation and collision between orthodromic and antidromic volleys in the peripheral mixed nerve. The soleus H-reflex depression by transspinal stimulation suggests a potential application for normalization of spinal reflex excitability after SCI.

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Increased spinal reflex excitability is associated with enhanced central activation during voluntary lengthening contractions in human spinal cord injury

Journal of Neurophysiology ◽

10.1152/jn.01074.2014 ◽

2015 ◽

Vol 114 (1) ◽

pp. 427-439 ◽

Cited By ~ 4

Author(s):

Hyosub E. Kim ◽

Daniel M. Corcos ◽

T. George Hornby

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

H Reflex ◽

Spinal Reflex ◽

Electromyographic Activity ◽

Lengthening Contractions ◽

M Wave ◽

Central Activation ◽

Reflex Excitability ◽

Cord Injury

This study of chronic incomplete spinal cord injury (SCI) subjects investigated patterns of central motor drive (i.e., central activation) of the plantar flexors using interpolated twitches, and modulation of soleus H-reflexes during lengthening, isometric, and shortening muscle actions. In a recent study of the knee extensors, SCI subjects demonstrated greater central activation ratio (CAR) values during lengthening (i.e., eccentric) maximal voluntary contractions (MVCs), compared with during isometric or shortening (i.e., concentric) MVCs. In contrast, healthy controls demonstrated lower lengthening CAR values compared with their isometric and shortening CARs. For the present investigation, we hypothesized SCI subjects would again produce their highest CAR values during lengthening MVCs, and that these increases in central activation were partially attributable to greater efficacy of Ia-α motoneuron transmission during muscle lengthening following SCI. Results show SCI subjects produced higher CAR values during lengthening vs. isometric or shortening MVCs (all P < 0.001). H-reflex testing revealed normalized H-reflexes (maximal SOL H-reflex-to-maximal M-wave ratios) were greater for SCI than controls during passive ( P = 0.023) and active (i.e., 75% MVC; P = 0.017) lengthening, suggesting facilitation of Ia transmission post-SCI. Additionally, measures of spinal reflex excitability (passive lengthening maximal SOL H-reflex-to-maximal M-wave ratio) in SCI were positively correlated with soleus electromyographic activity and CAR values during lengthening MVCs (both P < 0.05). The present study presents evidence that patterns of dynamic muscle activation are altered following SCI, and that greater central activation during lengthening contractions is partly due to enhanced efficacy of Ia-α motoneuron transmission.

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Pre- and post-alpha motoneuronal control of the soleus H-reflex during sinusoidal hip movements in human spinal cord injury

Brain Research ◽

10.1016/j.brainres.2006.05.036 ◽

2006 ◽

Vol 1103 (1) ◽

pp. 123-139 ◽

Cited By ~ 10

Author(s):

Maria Knikou ◽

Debjani Chaudhuri ◽

Elizabeth Kay ◽

Brian D. Schmit

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

H Reflex ◽

Human Spinal Cord ◽

Cord Injury

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Impaired Organization of Paired-Pulse TMS-Induced I-Waves After Human Spinal Cord Injury

Cerebral Cortex ◽

10.1093/cercor/bhv048 ◽

2015 ◽

Vol 26 (5) ◽

pp. 2167-2177 ◽

Cited By ~ 23

Author(s):

John Cirillo ◽

Finnegan J. Calabro ◽

Monica A. Perez

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Paired Pulse ◽

Human Spinal Cord ◽

Cord Injury

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An investigation of possible transynaptic neuronal degeneration in human spinal cord injury

Journal of the Neurological Sciences ◽

10.1016/0022-510x(88)90101-3 ◽

1988 ◽

Vol 86 (2-3) ◽

pp. 231-237 ◽

Cited By ~ 24

Author(s):

Cahyono Kaelan ◽

Phillip F. Jacobsen ◽

Byron A. Kakulas

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Neuronal Degeneration ◽

Human Spinal Cord ◽

Cord Injury

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The effects of methylprednisolone and the ganglioside GM1 on acute spinal cord injury in rats

Journal of Neurosurgery ◽

10.3171/jns.1994.80.1.0097 ◽

1994 ◽

Vol 80 (1) ◽

pp. 97-111 ◽

Cited By ~ 248

Author(s):

Shlomo Constantini ◽

Wise Young

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Body Weight Loss ◽

Ganglioside Gm1 ◽

Rat Spinal Cord ◽

Neuroprotective Effects ◽

Content Type ◽

Human Spinal Cord ◽

Cord Injury ◽

Fine Print

✓ Recent clinical trials have reported that methylprednisolone sodium succinate (MP) or the monosialic ganglioside GM1 improves neurological recovery in human spinal cord injury. Because GM1 may have additive or synergistic effects when used with MP, the authors compared MP, GM1, and MP+GM1 treatments in a graded rat spinal cord contusion model. Spinal cord injury was caused by dropping a rod weighing 10 gm from a height of 1.25, 2.5, or 5.0 cm onto the rat spinal cord at T-10, which had been exposed via laminectomy. The lesion volumes were quantified from spinal cord Na and K shifts at 24 hours after injury and the results were verified histologically in separate experiments. A single dose of MP (30 mg/kg), given 5 minutes after injury, reduced 24-hour spinal cord lesion volumes by 56% (p = 0.0052), 28% (p = 0.0065), and 13% (p > 0.05) in the three injury-severity groups, respectively, compared to similarly injured control groups treated with vehicle only. Methylprednisolone also prevented injury-induced hyponatremia and increased body weight loss in the spine-injured rats. When used alone, GM1 (10 to 30 mg/kg) had little or no effect on any measured variable compared to vehicle controls; when given concomitantly with MP, GM1 blocked the neuroprotective effects of MP. At a dose of 3 mg/kg, GM1 partially prevented MP-induced reductions in lesion volumes, while 10 to 30 mg/kg of GM1 completely blocked these effects of MP. The effects of MP on injury-induced hyponatremia and body weight loss were also blocked by GM1. Thus, GM1 antagonized both central and peripheral effects of MP in spine-injured rats. Until this interaction is clarified, the authors recommend that MP and GM1 not be used concomitantly to treat acute human spinal cord injury. Because GM1 modulates protein kinase activity, protein kinases inhibit lipocortins, and lipocortins mediate anti-inflammatory effects of glucocorticoids, it is proposed that the neuroprotective effects of MP are partially due to anti-inflammatory effects and that GM1 antagonizes the effects of MP by inhibiting lipocortin. Possible beneficial effects of GM1 reported in central nervous system injury may be related to the effects on neural recovery rather than acute injury processes.

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