Descending motor pathways and cortical physiology after spinal cord injury assessed by transcranial magnetic stimulation: a systematic review.

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Descending motor pathways and cortical physiology after spinal cord injury assessed by transcranial magnetic stimulation: a systematic review Raffaele Nardonea,b,e,n, Yvonne Ho¨llera,e, Francesco Brigob,c, Andrea Oriolib, Frediano Tezzonb, Kerstin Schwenkera,e, Monica Christovad, Stefan Golaszewskia, Eugen Trinkaa,e a

Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University and Center for Cognitive Neuroscience, Salzburg, Austria b Department of Neurology, Franz Tappeiner Hospital, Merano, Via Rossini 5, 39012 Meran/o (BZ), Italy c Department of Neurological, Neuropsychological, Morphological and Movement Sciences, Section of Clinical Neurology, University of Verona, Italy d Department of Physiology, Medical University of Graz, Graz, Austria e Spinal Cord Injury and Tissue Regeneration Center, Paracelsus Medical University, Salzburg, Austria

art i cle i nfo

ab st rac t

Article history:

We performed here a systematic review of the studies using transcranial magnetic

Accepted 15 September 2014

stimulation (TMS) as a research and clinical tool in patients with spinal cord injury (SCI). Motor evoked potentials (MEPs) elicited by TMS represent a highly accurate diagnostic test

Keywords:

that can supplement clinical examination and neuroimaging findings in the assessment of

Spinal cord injury

SCI functional level. MEPs allows to monitor the changes in motor function and evaluate

Motor evoked potentials

the effects of the different therapeutic approaches. Moreover, TMS represents a useful non-

Transcranial magnetic stimulation

invasive approach for studying cortical physiology, and may be helpful in elucidating the

Repetitive transcranial magnetic

pathophysiological mechanisms of brain reorganization after SCI. Measures of motor

stimulation

cortex reactivity, e.g., the short interval intracortical inhibition and the cortical silent

Central motor conduction

period, seem to point to an increased cortical excitability.

Intracortical inhibition Therapeutic applications

However, the results of TMS studies are sometimes contradictory or divergent, and should be replicated in a larger sample of subjects. Understanding the functional changes at brain level and defining their effects on clinical outcome is of crucial importance for development of evidence-based rehabilitation therapy. TMS techniques may help in identifying neurophysiological biomarkers that can reliably assess the extent of neural damage, elucidate the mechanisms of neural repair, predict clinical outcome, and identify therapeutic targets. Some researchers have begun to therapeutically use repetitive TMS (rTMS) in patients with SCI. Initial studies revealed that rTMS can induce acute and short

n Corresponding author at: Department of Neurology, Franz Tappeiner Hospital, Merano, Via Rossini 5, 39012 Meran/o (BZ), Italy. Fax: þ39 0473 264449. E-mail address: [email protected] (R. Nardone).

http://dx.doi.org/10.1016/j.brainres.2014.09.036 0006-8993/& 2014 Elsevier B.V. All rights reserved.

Please cite this article as: Nardone, R., et al., Descending motor pathways and cortical physiology after spinal cord injury assessed by transcranial magnetic stimulation: a systematic review. Brain Research (2014), http://dx.doi.org/10.1016/j. brainres.2014.09.036

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duration beneficial effects especially on spasticity and neuropathic pain, but the evidence is to date still very preliminary and well-designed clinical trials are warranted. This article is part of a Special Issue entitled SI: Spinal cord injury. & 2014 Elsevier B.V. All rights reserved.

1.

Introduction

The motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) represent a highly accurate diagnostic test with a very high sensitivity value in spinal cord disorders (Di Lazzaro et al., 1999). In most patients affected by traumatic spinal cord injury (SCI) the involvement of spinal cord is clinically evident, and the MEP contribution to the diagnosis is therefore mainly confirmatory. However, in these patients MEP studies may be useful in localizing levels of functional defects, or in detecting a subclinical involvement of central motor pathways, and the neurophysiological evaluation may also provide a useful adjunct to clinical impairment scales and functional correlate to radiological abnormalities. Topographical map reorganization of primary motor cortex (M1) and premotor cortices after SCI has been reported in several experimental and human studies (for a review, see Nardone et al., 2013; Moxon et al., 2014). TMS also represents a useful non-invasive approach for studying cortical physiology (Hallett, 2000). Several studies have been performed to neurophysiologically characterize the functional reorganization that occurs after SCI. Furthermore, preliminary studies revealed that repetitive TMS (rTMS) can induce beneficial effects on sensorimotor functions, as well as in the treatment of spasticity and neuropathic pain. Future well-controlled studies with appropriate methodology in larger patient cohorts are warranted in order to replicate and extend the initial findings. The present review first focuses on studies that assessed the value of MEPs in defining the extent and severity of damage to corticospinal tract. We also performed a systematic review of the most important TMS reports that have assessed changes in cortical excitability and plasticity in humans after SCI. Finally, we briefly reviewed and critically appraised the preliminary studies that have therapeutically used rTMS in SCI patients. To the best of our knowledge, this is the first comprehensive review that covers all these aspects of TMS/rTMS in subjects with SCI.

2.

Principal findings

2.1.

Motor conduction studies

Subjects with incomplete cervical or thoracic SCI were more likely to demonstrate volitional and TMS-evoked contractions in distal lower limb muscles controlling their foot and ankle compared to proximal lower limb muscles (Calancie et al., 1999). When TMS did evoke responses in muscles innervated at levels caudal to the spinal cord lesion, MEP latencies of

muscles in the lower limbs muscles were delayed equally for persons with cervical or thoracic SCI, thus suggesting normal central motor conduction in motor axons caudal to the lesion. In contrast, subjects with SCI at the thoracolumbar level showed a higher probability of preserved volitional movements, TMS-evoked contractions in proximal muscles of the lower limb, and absent responses in distal muscles. When motor responses to TMS were seen in this group, the latencies were not significantly longer than those of ablebodied subjects; this finding was thought to be suggestive of “root sparing” as a basis for motor function in subjects with SCI at or caudal to the T11 vertebral body. Moreover, a good correlation was described between MEP findings and motor function in patients with SCI (Meyer and Zentner, 1992; Zentner and Rieder, 1990). Several motor conductions studies have been employed to explore the functional implications of impaired transmission in the corticospinal tract on gait after SCI. Barthelemy and coworkers reported that the amplitude of the MEPs at rest and their latency during contraction were correlated to the degree of foot drop (inability to dorsiflex ankle) in 24 persons with incomplete cervical or lumbar SCI (Barthélemy et al., 2010). In a successive study the same authors reported that the presence of MEP at rest was indicative of faster speed and longer distance in the 6-min walk test (Barthélemy et al., 2013). Wirth et al., found in patients with incomplete SCI recovering motor function an unchanged corticospinal tract conductivity (as assessed by MEP latencies) and an increased MEP facilitation at stable background EMG, which might indicate improved synchronization of the descending volley and/or responsiveness of motoneurons to supra-spinal inputs (Wirth et al., 2008a). Since there was no relationship between MEP amplitudes, recovery of ambulation and muscle strength, plastic changes in spinal neural circuits and preserved motor units might have contributed to the functional improvement. It has also been demonstrated that patients with SCI and healthy subjects did not significantly differ in timing of ankle dorsiflexion, neither in the supine position nor in gait, while the onset of dorsiflexion in swing during gait (in contrast to ankle timing in supine position) significantly correlated to the dynamic MEP parameters (latency and amplitude) (Wirth et al., 2008b). A rehabilitation strategy to restore gait in neurological disorders utilizes absent or partial body weight support during stepping on a motorized treadmill. A recent study aimed at establishing changes in corticospinal under these conditions. MEPs were reliably recorded at different sessions during stepping in healthy humans (Knikou et al., 2013). The tibialis anterior MEPs were facilitated at heel contact and throughout the swing phase of the step cycle, while it progressively decreased during the stance phase. Conversely, the soleus MEPs were progressively



increased at early-stance, depressed at the stance-to-swing transition and also throughout the swing phase. These findings indicate that the strength of corticospinal drive will not be affected negatively during stepping under conditions of partial body loading. Importantly, in SCI patients with high cervical lesion, MEPs can be recorded from the diaphragm, as well as from the scalenes, the parasternal intercostals and the expiratory rectus abdominis muscles, thus allowing for the investigation of the central motor conduction properties of the respiratory muscles (Lissens and Vanderstraeten, 1996; Zifko et al., 1986). Therefore, MEPs may represent an important adjunctive tool that can be used routinely to monitor patients with impaired central respiratory drive in SCI patients. Furthermore, preliminary investigations into the interaction between corticospinal drive and reflex control of spinal musculature have been published (Craggs et al., 2007; Vasquez et al., 2014). TMS was found to be effective in facilitating the pudendoanal reflex (PAR) elicited by electrical stimulation of the dorsal penile nerve 8 out of 12 patients with incomplete SCI subjects. The presence of cortical facilitation of the PAR was not related to the degree of urinary continence. In SCI patients with urinary neurogenic incontinence also the somatomotor pathway to the urethral compressive musculature (UCM) has been assessed by means of MEPs and simultaneously recorded evoked pressure curves (EPC) (Schmid et al., 2005). Peripheral responses were normal, while in patients with incomplete SCI the central latency was significantly delayed, and patients with a complete SCI showed no UCM reaction after TMS. MEP and EPC from the UCM thus proved to be an useful diagnostic tool in patients with neurogenic incontinence that distinguished central and peripheral lesions (i.e., due to cauda equina lesions) of the motor efferent pathways to the UCM. MEP studies can supplement clinical examination and neuroimaging findings in the assessment of the SCI level, and can define the extent and the severity of corticospinal tract lesions in patients with SCI. The recording from multiple muscles can be used to identify the level of spinal cord lesion, and this is particularly helpful in uncooperative or unconscious patients. It should be considered that even in a few normal subjects MEPs may be absent at rest to the lower limbs, where motor homunculus is deeper and less accessible. For this reason, the contribution of MEPs in the assessment of thoracolumbar SCIs is more limited than for SCI at cervical level. Moreover, this may limits the usefulness of TMS in determining neurophysiological mechanisms underlying training-induced rehabilitation of paretic gait. On the other hand, brain imaging in animals revealed that cortical representation in response to spared forelimb stimulation early enlarges and invades adjacent sensory-deprived hind limb territory; also in humans neuroimaging showed shifts of functional motor and sensory cortical representations that relate to the severity of SCI (for a review, see Nardone et al., 2013; Moxon et al., 2014). MEPs may be useful in the prediction of functional outcome in the acute phase of SCI. MEP recording from abductor digiti minimi (ADM) muscle was found to be highly correlated to the outcome of hand function (Curt and Dietz, 1999). When

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MEPs recorded from ADM muscle were absent, active hand function was not regained. For the reason mentioned above, recording of lower limb MEPs were less effective in predicting the recovery of ambulatory capacity; in fact, some patients with an initial loss of lower limb MEPs showed a recovery of ambulatory capacity (Curt et al., 1998). However, other authors found that assessment of MEPs of the anterior tibial muscle allows stratification of SCI according to lesion severity and functional outcome. Increases in MEP amplitudes over 12 months after SCI were paralleled by a significant improvement of lower extremity motor scores and walking function; MEP latencies remained stable (Petersen et al., 2012). Another study investigated the reliability of the MEP measures of the anterior tibial muscle controlled for dorsal flexion torque and motor task (van Hedel et al., 2007). Overall, the reliability of MEP amplitude was good. The reliability was good to excellent for MEP latency, maximal voluntary contraction (MVC) and for the RMT. The increased facilitation by the dynamic motor task showed the best reliability at 20% MVC. In a single-subject report (Edwards et al., 2013), MEPs were recorded from the right biceps brachii, extensor carpi radialis (ECR), flexor carpi radialis (FCR) and abductor pollicis brevis (APB) muscles in a 31-year-old man with chronic cervical (at C5 level) SCI, classified as grades B according to the American Spinal Cord Injury Association (ASIA) Impairment Scale. TMS consistently elicited MEPs of normal latency, phase and amplitude in the severely affected ECR muscle but not the similarly affected FCR muscle. MEPs with larger amplitude than those in healthy subjects were observed in proximal and unaffected biceps muscle, while no response was recorded from the distal APB muscle. This report shows that TMS can identify residual pathways not apparent from clinical assessment alone, which may have prescriptive value for rehabilitation.

2.2.

Cortical brain mapping

Topka et al. (1991) reported in six human paraplegics with complete SCI at low thoracic level MEP at rest with shorter latency from a large number of scalp positions in muscles immediately rostral to the level of SCI. The results suggest enhanced excitability of motor pathways targeting these muscles, and reflect reorganization of motor pathways either within cortical motor representation areas or at the level of the spinal cord. The data do not allow the determination of the contribution of spinal or cortical mechanisms. Levy et al. (1990) also found in two quadriplegics SCI patients a reorganization of the motor cortical projection system. In these patients, areas which normally control digit movements, instead activated muscles just above the spinal level. The focal TMS elicited compound motor action potentials (CMAPs) from biceps brachii and deltoid muscles, which were the most caudal muscles spared, from a much wider area of scalp than in the normal subjects. CMAPs from these muscles were elicited from a much wider area of scalp than in the normal subjects, and the latencies of CMAPs were inversely related to CMAP amplitude. Streletz et al. (1995) performed a mapping of the motor cortex in four patients with cervical SCI (at level C5–6) within 6–17 days of SCI. The authors found an expanded cortical


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map of the preserved contralateral biceps muscle as early as 6 days after injury. These findings suggest an increase in excitability of corticospinal projections to non-paralyzed muscles above the lesion. However, in contrast with these studies, other authors (Laubis-Herrmann et al., 2000; Lotze et al., 2006) found reduced or unchanged excitability of corticospinal neurons. Laubis-Herrmann et al. studied two arm muscles distant to the SCI levels (T2–L3), the biceps brachii and the abductor pollicis brevis muscles in 13 patients. RMT, facilitatory effects on MEP-amplitudes (FE) with voluntary activation, MEPamplitudes with maximal stimulation (MA) and MEP-RC were measured. Patients exhibited smaller MA from activated biceps brachii muscles, a tendency towards smaller FE and smaller RC-slopes. With clinical recovery FE, MA and RCslopes tended to normalize. In five patients with complete thoracic SCI and one with an incomplete SCI at L1 level an increase of cortical inhibitory circuits, in particular prolonged CSP duration, were observed in muscles more distant to the deafferented area, indicative of reduced cortico-spinal excitability (Lotze et al., 2006). The above mentioned TMS studies are mapping studies performed with conventional scalp reference points. An important limitation of this procedure is the variation in brain anatomy with reference to scalp topography in individual subjects. The navigated TMS allows to integrate individual three-dimensional MRI with TMS such that output maps can be projected directly onto the anatomical surface of each subject's brain, and thus allows a more precise comparison of cortical muscle maps from different individuals (Julkunen et al., 2009). On the basis of their previous MRI study (Freund et al., 2011a), Freund et al. hypothesized that the corticospinal output map of the forelimb representation would shift towards the denervated cortical leg representation. The authors used a three-dimensional mapping to investigate the physiological properties of the corticospinal system in the same SCI patients (Freund et al., 2011b), and were able to demonstrate alterations in the topography and excitability of the corticomotor projection to a forearm muscle, the extensor communis digitorum (EDC). In fact, the Euclidian distance between the EDC center of gravity and the anatomical hand region in M1 was reduced in the patients. The corticospinal neurons projecting to intrinsic hand muscles often send axonal branches to forearm muscles, and the possible increased strength of these connections might shift the center of gravity into the M1 hand area. It can be therefore hypothesized that this reorganization of corticospinal projections might increase motor output and improve voluntary upper limb movement. However, while the fMRI images showed such clear activation of the leg area of M1 during volitional hand movement (Freund et al., 2011a), the same authors did not evoke any MEPs in the EDC after stimulation over that area in the same patients. One possible explanation for this discrepancy was that indirect polysynaptic inputs from the leg area are not activated by single TMS pulses. These could be unmasked by cortico-cortical connections between neurons in the leg area. On the other hand, an eventual reorganization of motor output is likely to be of relatively minor functional relevance.

In this case, the BOLD signal activation of the leg area in fMRI may represent sensory input from the hand, which has reorganized to innervate neurons in the leg representation. Interestingly, intracortical stimulation has recently been used to study cortical re-mapping in rats following SCI. The motor cortex representations and plasticity of the trunk in adult rats with chronic complete low thoracic SCI have been examined by means of this technique (Oza and Giszter, 2014). A significant reorganization of the trunk motor cortex was found, which was not altered by non-stepping treadmill training or non-stepping robot assisted treadmill training, but is shifted further from normal topography by the training. Cortical stimulation studies may thus provide supporting evidence for the reorganization measured using TMS, which is less specific in its activation patterns.

2.3.

Motor cortex excitability

Freund et al. (2011b) also found that AMT and the duration of the CSP were increased in the SCI subjects. There was also a negative association, as evaluated by multiple linear regression analysis between spinal cord atrophy and both, AMT and CSP duration. Increased AMT may reflect the reduced density of motoneurons and/or interneurons in low segments of the cervical cord that innervate the EDC. However, another explanation is that the reduced density of surviving corticospinal neurons requires a higher intensity of TMS to recruit a given corticospinal output (Di Lazzaro et al.,2004); this hypothesis is supported by the negative correlation between increased AMT and spinal cord atrophy at C2. These AMT changes might also reflect structural or functional abnormalities in the intra-cortical connectivity that result from degenerative processes affecting corticospinal neurons. The reduced afferent excitatory cortico-cortical and thalamo-cortical drive to the motor cortex, due to the degeneration of corticospinal axons and soma shrinkage of pyramidal cells (Beaud et al., 2008; Hains et al., 2003), which induces a shift of cortical excitability towards inhibition, may lead to the increased CSP duration. In line with the findings of Lotze et al. (2006) and Freund et al. (2011b), an increased CSP was found in a patient with isolated lesion in the cervical posterior white columns (Nardone et al., 2008). On the contrary, Shimizu et al. (2000) reported in three patients with cervical SCI a loss of the CSP (Fig. 1). In healthy subjects, CSP increases during a sustained maximal voluntary contraction (MVC) of an intrinsic hand muscle (Mills and Thomson, 1995), of the elbow flexors (Taylor et al., 1999), and of the tibialis anterior muscle (McKay et al., 1996). This physiological lengthening of CSP during fatigue was not observed in SCI patients (Nardone et al., 2013). The authors hypothesized that this reduced intracortical inhibition, probably secondary to decreased activity of the GABAergic inhibitory interneurons that modulate the corticomotoneuronal output, could represent a ‘positive’ neuroplastic response in an attempt to compensate for the loss of corticospinal axons.



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Fig. 1 – Motor evoked potentials (MEP) (black arrow) and cortical silent period (gray arrow) during voluntary contraction of the first dorsal interosseus (upper row) and flexor hallucis brevis (lower row) muscles in patients 1 (A), 2 (B) and 3 (C). Horizontal bars represent 100 ms for each patient. Vertical bars represent 1 mV for patients 1 (A) and 3 (C), and 0.2 mV for patient 2 (B). Adapted with permission from Shimizu et al. (2000).

In some studies, the MEPs and the suppression of voluntary contraction (SVC) or the behavior of single motor units in response to TMS have been evaluated. Davey et al. (1998) found that RMT and SVC elicited by TMS were higher in a group of 10 patients with incomplete cervical SCI (motor level C3–C8). Latency of MEPs, latency of SVC and latency difference (SVC-MEP) was longer in patients than in control subjects. The authors concluded that the longer latency difference between MEPs and SVC in the SCI patients may reflect a weak or absent early component of cortical inhibition. In a successive study (Smith et al., 2000a) the modulation of single motor unit discharges to TMS using peristimulus time histograms (PSTHs) was assessed. This examination was motivated by the aim of improving resolution of the excitatory and inhibitory responses seen previously in surface EMG recordings. Mean threshold for the excitatory peak (excitation) or inhibitory trough (inhibition) in the PSTHs, as well as the mean latencies of excitation and inhibition, were longer in patients than in control subjects. The latency difference (inhibition-excitation) was also significantly longer in patients than in healthy controls. The authors postulated that increased thresholds and latencies of excitation and inhibition may reflect degraded corticospinal transmission in the spinal cord, while the relatively greater increase in the latency of inhibition compared with excitation likely reflects a reduction of corticospinal output in response to TMS. A long pathway is thought to be involved in producing this inhibition, presumably comprising interneurons within the motor cortex. In another study of the same research group (Smith et al., 2000b), electrophysiological tests of corticospinal function were carried out using TMS of the motor cortex and EMG recordings from thenar muscles in 21 patients with incomplete cervical SCI. Both tests were performed on a number of occasions, beginning 19–384 days and ending 124–1109 days post-injury. The group data were pooled into time epochs of 50 or 100 days post-injury for analysis. When the patients were first assessed, the mean latency for MEPs and inhibition

of voluntary EMG were significantly different from control values. The authors concluded that the decreased inhibition observed following SCI is established within the first few days after the SCI. Furthermore, to explore whether crossed facilitatory interactions in the corticospinal pathway are impaired in subjects with SCI, TMS has been used to elicit MEPs in a resting hand, arm, or foot muscle when the contralateral side remained at rest or performed 70% of MVC into index finger abduction, elbow flexion, and ankle dorsiflexion, respectively (Bunday et al., 2013). MEPs remained unchanged in muscles at and within 5 segments below the injury during 70% of MVC compared to rest. Conversely, in muscles beyond 5 segments below the injury the size of MEPs increased similar to controls and was aberrantly high, 2-fold above controls, in muscles distant (415 segments) from the injury. These findings suggest that corticospinal degeneration does not spread rostral to the lesion, and highlight the potential of caudal regions distant from an injury to facilitate residual corticospinal output after SCI.

2.4.

Paired-pulse TMS studies

Saturno et al. (2008) studied cortical excitability in a patient with thoracic SCI using paired-pulse TMS paradigms. During posterior tibial nerve stimulation, the authors observed a contextual flexion of hand fingers contralateral to the stimulated lower limb, which suggests a change in motor cortex excitability. TMS results were consistent with a decreased activity of motor cortex inhibitory circuits. The authors postulated a disinhibition of latent synapses within the motor cortex and the rewriting of a new motor cortical map. Similarly, a paired TMS study in another single patient (Shimizu et al., 2000) showed reduced SICI. Roy et al. (2011) compared SICI during a voluntary contraction in 16 patients with SCI and 14 control subjects, the latter group tested over a larger range of conditioning and test stimulus (CS and TS) intensities to best match the SCI patients data. The main finding was that the average peak


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SICI in the tibialis anterior muscle was typically 3–4 times lower in SCI subjects compared to controls. However, when matched for absolute TS intensity, in terms of maximum stimulator output, both U-shaped SICI recruitment curves were produced by similar CS intensities (Fig. 2). These findings suggest that although the relative excitability profile of cortical SICI networks is unchanged after SCI, the effective inhibition of corticospinal tract output by these neurons is reduced.

3.

Therapeutic applications

3.1.

Repetitive transcranial magnetic stimulation

If delivered repetitively, TMS can influence brain function. Through rTMS a train of TMS pulses of the same intensity are applied to a single brain area at a given frequency ranging from 1 to 20 or more stimuli per second. Depending on the stimulation parameters, particularly the frequency of stimulation, cortical excitability can be modulated, thus obtaining a facilitating or suppressing effect. RTMS can be applied as continuous trains of low-frequency (1 Hz) or bursts of higher frequency ( Z5 Hz). Generally, low-frequency rTMS (stimulus ratesr1 Hz) induces inhibitory effects on motor cortical excitability leading to a reversible ‘virtual lesion’ (PascualLeone et al., 1994; Lee et al., 2003), whereas high-frequency rTMS (5–20 Hz) usually promotes an increase in cortical excitability (Pascual-Leone et al., 1998; Berardelli et al., 1998). This modulation can last for several minutes (depending on the overall duration of the train itself) and provides an index of cortical plasticity. There is evidence for a link between the after-effects induced by rTMS and the induction of synaptic plasticity (Hoogendam et al., 2010).

3.2.

Treatment of sensorimotor deficits and spasticity

In a study in adult rats 10 Hz rTMS was applied daily for 8 weeks after an incomplete high (T4–5) or low (T10–11) thoracic spinal compression-injury (Poirrier et al., 2004). RTMS significantly improved locomotor recovery in lowlesioned rats, but not in rats with high-thoracic injury. The authors proposed that rTMS is beneficial in low thoracic lesions because it activates the central locomotor generator. The benefits of rTMS shown in this experimental pioneer study suggest that this non-invasive intervention strategy should be taken into consideration for clinical studies in human paraplegics/tetraplegics with traumatic SCI. Belci et al. (2004) first tested the efficacy of rTMS in modulating corticospinal inhibition and improving functional recovery in 4 patients with chronic incomplete (ASIA-D) cervical (C5 level) SCI. SICI was reduced during the rTMStreatment week. Perceptual threshold to electrical stimulation of the skin, ASIA clinical measures of motor and sensory function as well as time to complete a peg-board improved during the entire 3-week follow-up period. In another study (Kuppuswamy et al., 2011), subjects with complete or incomplete cervical (or T1) SCI received real sub-threshold 5 Hz rTMS and sham rTMS in a randomised placebo-controlled single-blinded cross-over trial. Outcome

measures comprised MEP and CSP, the ASIA impairment scale (AIS), the Action Research Arm Test (ARAT), a pegboard test, electrical perceptual test (EPT), cardiovascular and sympathetic skin responses. There were no significant differences in AIS outcomes between real and sham rTMS. The ARAT was increased at 1 h after real rTMS compared to baseline. AMT for the most caudally innervated hand muscle was increased at 72 and 120 h compared to baseline. Persistent reductions in EPT occurred in two individuals (Fig. 3). Therefore, the main finding was that changes in cortical motor threshold measures may accompany functional gains to rTMS in SCI subjects. High frequency rTMS applied over the M1 area reduces Hreflex size in healthy subjects (Valero-Cabre et al., 2001; Perez et al., 2005; Quartarone et al., 2005) as well as spasticity in patients with multiple sclerosis (Centonze et al., 2007) or spastic quadriplegia due to cerebral palsy (Valle et al., 2007). A significant clinical improvement in lower limb spasticity (as assessed by the Modified Ashworth Scale, Visual Analog Scale, and the Spinal Cord Injury Spasticity Evaluation Tool) was found in patients with incomplete cervical or thoracic SCI following active rTMS over M1 (Kumru et al., 2010). However, the authors failed to find changes in the examined measures of corticospinal and segmental excitability (Hmax/ Mmax, T reflex, and withdrawal reflex). The same research group also reported that 15 daily sessions of high-frequency (20 Hz) rTMS over the leg motor area can improve motor score, walking speed and spasticity in the lower extremities, thus providing further evidence for the therapeutic potential of rTMS in SCI rehabilitation (Kumru et al., 2013). Recently, Hou et al. (2014) tested the therapeutic effects of early treadmill locomotor training (Tm) initiated at postoperative day 8 and continued for 6 weeks with injury site TMS on spasticity and gait impairments following low C6/7 moderate contusion C-SCI in a rat model. These significant treatment-associated decreases in measures of spasticity and gait impairment were also accompanied by marked treatment-associated up-regulation of dopamine beta-hydroxylase, glutamic acid decarboxylase 67, GABAb receptor and brain-derived neurotrophic factor in the lumbar spinal cord segments of the treatment groups. The authors proposed that the treatment-induced up-regulation of these systems enhanced the adaptive plasticity after SCI. Thus, locomotor exercise may decrease aspects of the spontaneous maladaptive segmental and descending plasticity, and TMS treatment may represent an adjuvant stimulation that further enhances this capacity.

3.3.

Treatment of pain

rTMS can produce analgesic effects, at least partially and transiently, in healthy subjects undergoing laboratory-induced pain and in chronic pain conditions of different etiologies. High-frequency rTMS over the M1 area was applied in 60 patients with drug resistant neurogenic pain, including 12 patients with SCI (Lefaucheur et al., 2004). Overall, rTMS was found to significantly reduce chronic pain, even if transiently. However, these effects depend significantly on pain origin and site. The most favorable conditions were trigeminal



nerve lesions, thalamic stroke, and brachial plexus lesion, while results were worse in patients with spinal cord and brainstem lesions.

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In another study the analgesic effect of rTMS over the M1 on chronic central pain in 11 patients with thoracic SCI and paraplegia was assessed (Defrin et al., 2007). Both real and

Fig. 2 – Short-latency afferent inhibition (SICI) in the tibialis anterior muscle using a test MEP amplitude near ½MEPmax. (A) Raw traces show SICI (at interstimulus interval of 3 ms) in a subject with spinal cord injury (SCI) (traces on left) and an uninjured control (traces on right). Test MEP depicts the single pulse response while the intensities on the left represent the different conditioning stimulus intensities used to elicit SICI. In the SCI subject the MEP was significantly reduced by a CS at 80% active motor threshold (AMT) (black arrow). (B and C) Graphs display the individual subject data from the SCI group and the uninjured control group, expressed as a percentage of the test MEP (which was near ½MEPmax). Thick solid lines and symbols represent the average. The two individual data points not shown in (C) were 231 and 271% at 120% of AMT. (D) Comparison of average SICI recruitment curves in the SCI subjects (closed circles) and the uninjured controls (open triangles). (E) Curves in (D) plotted in terms of maximal stimulator output. Gray symbols and asterisks represent significant differences from the test MEP (B and C). Adapted with permission from Roy et al. (2011). Please cite this article as: Nardone, R., et al., Descending motor pathways and cortical physiology after spinal cord injury assessed by transcranial magnetic stimulation: a systematic review. Brain Research (2014), http://dx.doi.org/10.1016/j. brainres.2014.09.036

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Fig. 3 – Change in AMT for eliciting MEPs in response to repetitive transcranial magnetic stimulation (rTMS) of the motor cortex during 10% of maximal voluntary contraction for first dorsal interosseus (A), thenar (C) and extensor carpi radialis (D) muscles after real (closed symbols) and sham (open symbols) rTMS. Repeated measures ANOVA revealed a significant interaction between time and condition (rTMS/sham) for the first dorsal interosseus muscle. Post-hoc analysis revealed significant differences for rTMS within time with an increase in AMT 72 h and 120 h post-treatment compared to pretreatment. (B) AMT for the FDI muscle before and after rTMS (averages of three measures). All subjects show an increased AMT after rTMS. The changes in AMT for the thenar (C) and extensor carpi radialis (D) muscles following rTMS compared with sham stimulation were statistically insignificant. Reproduced with permission from Kuppuswamy et al. (2011).

sham 10 daily rTMS applications induced similar significant reductions in visual analog scale (VAS) scores immediately after each treatment and in VAS and McGill Pain Questionnaire (MPQ) scores after completion of all the treatment sessions. However, only real rTMS led to a significant increase in heat-pain threshold at the end of the treatment series. Moreover, the reduction in MPQ scores in the patients who received real rTMS continued during the follow-up period, 2–6 weeks after the end of the treatment sessions. The level of depression, as assessed by the Beck Depression Inventory, was reduced in both groups but only continued to improve at follow-up in the real rTMS group. Therefore, while the pain relief induced by a single rTMS treatment is probably related to a placebo effect, SCI patients may benefit from a series of rTMS treatments. In a blinded and randomized crossover study, rTMS was applied (1.000 stimuli/day for 5 consecutive days) over the M1 hand area in 11 patients with complete or incomplete SCI and chronic neuropathic pain at multiple sites, including the lower limbs, trunk, and pelvis (Kang et al., 2009).

Real and sham rTMS sessions were performed, separated by 12 weeks. The outcome measures, that is numeric rating scale (NRS) for average, worst pain and the interference items of the brief pain inventory (BPI) did not differ significantly between real and sham rTMS (one week after the end of the rTMS application). However, the effect of time on the NRS score for worst pain showed a significant reduction only after real stimulation. This finding indicates that more intensive rTMS protocols should be assessed. Lefaucheur et al. (2011) also assessed the value of rTMS targeted over the cortical representation of the painful area to predict the efficacy of the epidural motor cortical stimulation (EMCS) to treat neuropathic pain. In 59 patients who were treated with EMCS for more than 1 year (12 of them were SCI patients) active and sham 10-Hz – rTMS sessions were applied as preoperative tests. VAS scores were calculated to rate the analgesic effects of tTMS; pain scores were significantly reduced by EMCS and active rTMS, but sham rTMS was ineffective. The most salient



finding of this study was that 26 of the 33 patients (79%) who responded to active rTMS and all of the 21 patients (100%) who responded to active-sham stimulation, also responded to EMCS (Fig. 4). The effects of rTMS or EMCS were not related to the side, origin, or duration of pain or to the presence of motor or sensory deficits in the painful area. Poorer results were observed in patients with lower limb pain for rTMS and in older patients for EMCS. Moreover, the analgesic efficacy of rTMS predicts the analgesic effects of EMCS, and a single session of rTMS can be used as a preoperative assessment tool. Therefore, a positive outcome of EMCS can be predicted by a real response to rTMS, and rTMS tests can be used to confirm the indication of EMCS therapy. The authors suggest that new rTMS protocols are necessary to improve the usefulness of preoperative rTMS in EMCS practice. The results of a recent study (Yılmaz et al., 2013) demonstrated that analgesic effect of rTMS on intractable neuropathic pain in SCI was not superior to placebo. However, the middle-term (over 6 weeks) pain relief obtained by rTMS is encouraging and suggests that future studies with a larger sample size are needed. Recently, a literature search was performed to review efficacy, safety and potential predictors of response by assessing the effects of neural stimulation techniques to treat SCI pain (Moreno-Duarte et al., 2014). Chronic pain in SCI is disabling and resistant to common pharmacologic approaches. Electrical and magnetic neural stimulation techniques have been developed to offer a potential tool in the management of these patients. Although some of these techniques are associated with large standardized mean differences to reduce pain, an important variability in these results across studies was found. There is therefore a clear need for the development of methods to decrease treatment variability and increase response to beneficial effects of neural stimulation for pain treatment.

3.4.

Paired associative stimulation

Combining rTMS with peripheral nerve stimulation may also induce plastcity in motor circuits if the interval between the two types of stimulation is appropriate. This has been applied to the human central nervous system by using paired associative stimulation (PAS) and has its basis in the Hebbian theory of spike-timing-dependent plasticity (Stefan et al., 2002). PAS involves repeated pairs of peripheral nerve stimulation followed by TMS applied over the contralateral hand area of the motor cortex. The protocol induces a lasting increased in corticospinal excitability, evident as an increase in MEPs amplitude. A PAS protocol has been employed to determine whether the arrival of a corticospinal volley immediately prior to motoneuron discharge may enhance corticospinal transmission and voluntary motor control in patients with incomplete SCI (Ellaway et al., 2014). A short period of paired pulse stimulation (100 pairs at 0.1 Hz), timed such that a corticospinal volley arrived 1–2 ms before antidromic invasion of action potentials in motoneurons of the flexor digitorum longus, resulted in a MEP facilitation lasting 30 min after PAS treatment. These findings indicate that spike

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timing-dependent plasticity of residual corticospinalmotoneuronal synapses provides a mechanism to improve motor function after SCI. The authors concluded that modulation of these synapses may present a novel therapeutic target for enhancing voluntary motor output and promoting functional recovery in SCI patients.

4.

Discussion and conclusion

In spinal cord disorders, including traumatic SCI, MEPs are very helpful in determining the functional significance of neuroimaging findings. MEPs also allow to follow the evolution of motor disturbances after SCI and to evaluate the effects of different therapeutic procedures. However, the functional outcome in traumatic SCI did not reliably correlate in the most cases with the strength of MEP signals. In fact, the motor output below the level of SCI is a function of both, the conduction of motor signals through the lesion, usually measured by MEPs, and the processing of those signals by neural circuitry below the level of injury, which can be assessed, i.e., by kinematic and poly-EMG studies. Many important functional aspects of motor control such as coordination, speed of movement, and sensory integration, may be affected by different patterns of strength, spasticity (hypertonia, hyperreflexia, dysynergias) or sensory function/ neuropathic pain (such dysesthesias, hyperalgesia, allodynia). Another limitation of this technique is that cortical stimulation produces both a direct corticospinal and an indirect corticobulbar and then bulbospinal signal. Since the latter is polysynaptic, the variably delayed monosynaptic signals that may emerge after SCI or be present after treatment should be distinguished from those polysynaptic responses. TMS may also be helpful in elucidating the mechanisms of the cortical reorganization processes which occur after SCI in humans. Most TMS studies suggest that decreased intracortical inhibition or a reduced descending supraspinal inhibitory influence on spinal circuits may be a prerequisite for the recovery of useful motor function. Previous studies evaluating motor cortex excitability after SCI showed that the activity of inhibitory circuits producing short-interval intracortical inhibition may be reduced after incomplete SCI (Davey et al., 1998; Smith et al., 2000a,b; Shimizu et al., 2000; Saturno et al., 2008). Davey et al. (1998) and Smith et al. (2000a,b) studied this inhibition using the application of sub-threshold TMS, a technique that temporarily inhibits the ongoing EMG, likely through the activation of intracortical inhibitory neurons with connections onto fast-conducing corticospinal tract neurons that drive voluntary contractions. Within several weeks of SCI, the onset of EMG suppression is 25 ms longer than the latency of the MEP, while the latency difference is only 13 ms in healthy controls (Davey et al., 1998; Smith et al., 2000a). However, it is conceivable that a greater involvement of slow-conducting corticospinal tract axons to voluntarily activated EMG may also explain the greater delay in EMG suppression (Davey et al., 1998; Roy et al., 2011). Two singlesubject reports have shown that the reduction of a test MEP by a prior sub-threshold conditioning stimulation (Kujirai


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Fig. 4 – The analgesic effect produced by rTMS, according to the difference of efficacy between active and sham conditions, or by implanted epidural motor cortex stimulation corresponding to the pain area did not differ with the side of pain or the presence or absence of motor or sensory deficit. Reproduced with permission from Lefaucheur et al. (2011).



et al., 1993) in hand muscles is diminished after incomplete SCI (Shimizu et al., 2000; Saturno et al., 2008). Notably, SICI was examined only with a single conditioning and test stimulus (CS and TS) intensity. However, there are some problems in measuring the absolute levels of intracortical inhibition networks by pairedpulse inhibition TMS techniques in patients with altered transmission to the corticospinal tract (Roy et al., 2011). On the other hand, studies using the CSP yielded contradictory results (Shimizu et al., 2000; Lotze et al., 2006; Freund et al., 2011b). Moreover, spinal mechanisms contribute to the early phase of the CSP (Inghilleri et al., 1993; Werhahn et al., 1999). TMS methodological issues may account for this variability between studies. In addition, examination of functional changes in subject with SCI is challenging because of the small number of patients, the heterogeneity of spinal cord damage, and sometimes the difficulty of neuroimaging related to the presence of implants. Therefore, we believe that cortical excitability needs to be further investigated, possibly employing other TMS protocols or techniques. Some researchers have begun to therapeutically use rTMS in patients with SCI. Non-invasive neuromodulation could decrease aspects of the spontaneous maladaptive segmental and descending plasticity. High-frequency rTMS over the leg motor area can improve aspects of spasticity in patients with incomplete SCI. In a few studies on a small number of patients, also clinical measures of motor and sensory function were found to improve after rTMS. Interestingly, in a rat model the combination of treadmill locomotor training and TMS was found to be an effective treatment modality for SCIinduced spasticity and gait impairments (Hou et al., 2014). Therefore, the utility of well-designed rTMS protocols in combination with physical medicine and rehabilitation approaches should be explored in future studies. rTMS was found to be effective for relieving neuropathic pain. Pain and phantom sensations are highly disabling clinical conditions that affect a great number of subjects following SCI. Recent guidelines on the use of rTMS (Cruccu et al., 2007) and three meta-analyses on the role of rTMS in the treatment of neuropathic pain (Lefaucheur et al., 2011; Leo and Latif, 2007; Leung et al., 2009) indicate that rTMS delivered to M1 produces significant analgesic effects in 45– 60% of patients. Prolonged pain relief can be obtained by repeating rTMS sessions every day for several weeks. Interestingly, Lefaucheur et al. (2012) demonstrated that the beneficial analgesic effects of “conventional” 10 Hz-TMS delivered to M1 can be enhanced by priming with theta burst stimulation (TBS), a novel rTMS paradigm that produces greater changes in cortical excitability than “conventional” protocols (Huang et al., 2005). Other stimulation parameters, such as TBS and the combination of tDCS and rTMS, need to be further explored. Since therapeutic effect duration is an important issue to be considered, maintenance therapy regimens should be investigated. In their recent review article, Moreno-Duarte et al. (2014) discussed potential methods such as neuroimaging or EEG-guided neural stimulation for the treatment of chronic pain after SCI, and the development of better surrogate markers of response such as TMS-indexed cortical plasticity.

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Even if TMS holds promise as a physiologic biomarker in humans after SCI and to identify therapeutic targets, the evidence is to date still very preliminary. Often therapeutic approaches have been of short duration, the effects are mostly short-lived and should be replicated after longer duration interventions. Ellaway et al. in a recent review have discussed the confounding issues that may arise with the application of rTMS in SCI patients (Ellaway et al., 2014). In particular, a relatively high strength of TMS is required to obtain sustained increases in motor cortical excitability. Such a level of rTMS may cause in the subject, even if transiently, discomfort, pain and distress. Moreover, since high frequency at high intensities rapidly heats magnetic coils, the duration over which rTMS can be applied is limited and consequently often ineffective. The high intensities also raise the possibility of inadvertent excitation of deep brain structures. Even if there are no known lasting effects in terms of safety or well-being in subjects (Rossi et al., 2009), further studies are needed to address safety and efficacy of high intensity magnetic stimulator capable of stimulating brain structures deep to the motor cortex. In this review consideration is also given to the potential for rTMS to be used in the restoration of bladder and bowel sphincter function and functional recovery of the guarding reflex. Future trials with careful experimental design should consider patient selection aspects and must be carried out to determine optimal stimulation parameters. Animal studies revealed that the effects of neuromodulation are dependent on stimulation parameters, and the strongest stimulation parameter (i.e., higher intensity) is not necessarily associated with the largest beneficial effect (Volz et al., 2012). Finally, it should always be considered that rTMS effects depend on the state of activity of the brain at the time of stimulation (Silvanto and Pascual-Leone, 2008). Therefore, an appropriate and thorough examination of cortical physiology is necessary. In conclusion, neurophysiological techniques, in particular TMS, have shed light on the pathophysiological mechanisms of cortical reorganization. The investigation of motor cortex excitability may improve our understanding of the role of exercise therapy in promoting brain reorganization and functional recovery in humans. These studies may lead to therapeutic strategies to enhance sensorimotor recovery after SCI in humans. It is reasonable to expect that strategies aimed at modulating or reversing motor and sensory reorganization may have therapeutic potential in patients with SCI. Whether these approaches might effectively improve sensory or motor function should be proved by well-designed clinical trials.

5.

Experimental procedures

5.1.

Data sources and search strategy

The MEDLINE, accessed by Pubmed (1966–April 2014) and EMBASE (1980–April 2014) electronic databases were searched using the medical subject headings (MeSH) “spinal cord injury”, “transcranial magnetic stimulation”, “repetitive transcranial magnetic stimulation”, “motor evoked potentials”, as


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well as following free terms, combined in multiple search strategies by Boolean operators in order to find relevant articles: “motor threshold”, “central motor conduction”, “motor cortex excitability”, “cortical silent period”, “intracortical inhibition”, and “intracortical facilitation”. Two review authors (YH and FB) screened the titles and abstracts of the initially identified studies to determine if they satisfied the selection criteria. Any disagreement was resolved through consensus. Full-text articles were retrieved for the selected titles, and reference lists of the retrieved articles were searched for additional publications. In case of missing or incomplete data, principal investigators of included trials were contacted and additional information requested. No language restrictions were applied. The methodological quality was assessed and described narratively. The search strategy described above yielded 53 results. Only articles reporting data on studies using TMS techniques in patients with SCI were considered eligible for inclusion; therefore, 49 papers were provisionally selected and contributed to this review: the earliest was published in 1990 and the most recent in 2014.

5.2. Measures of corticospinal function and motor cortical excitability 5.2.1.

Motor threshold

Resting motor threshold (RMT) is defined as the minimum stimulus intensity that produces a motor evoked potential (MEP) of more than 50 μV in 50% of 10 trials in a relaxed muscle, whereas active motor threshold (AMT) is the minimum stimulus intensity required to generate a MEP (about 200 μV in 50% of 10 trials) during isometric contraction of the tested muscle at about 10% maximum. RMT is thought to provide information about a central core of neurons in the muscle representation of the primary motor cortex. RMT is increased by drugs that block voltage-gated sodium channels (Ziemann et al., 1996a) receptors, is not affected by drugs with effect on gamma-aminobutyric acid (GABA) (Ziemann et al., 1996b), and it is lowered by drugs increasing non-N-methyl-D-aspartate (NMDA) glutamatergic transmission (Di Lazzaro et al., 2003). These findings suggest that RMT reflects both neuronal membrane excitability and non-NMDA receptors glutamatergic neurotransmission. In patients, RMT will typically increase if a significant portion of the corticospinal tract is damaged, while it will typically decrease in a hyperexcitable corticospinal system. AMT differs from RMT in that excitability of motoneurons in the spinal cord is enhanced by the voluntary muscle contraction and, thus, provides a measure of corticospinal excitability with greater dependence on the spinal segmental level excitability (Hallett, 2000; Kobayashi and Pascual-Leone, 2003; Chen et al., 2008; Groppa et al., 2012).

5.2.2.

MEP amplitude

The amplitude of the MEP reflects not only the integrity of the corticospinal tract and the excitability of motor cortex and spinal level, but also the conduction along the peripheral motor pathway to the muscles. That is, a dysfunction along the corticospinal tract may therefore reveal abnormal MEPs, while the absence of MEPs abnormalities suggests integrity of

the pyramidal tract (Kobayashi and Pascual-Leone, 2003; Groppa et al., 2012). It has been demonstrated (Delvendahl et al., 2012) that changes of MEP amplitudes and motor threshold represent two different indices of motor cortex plasticity. Whereas increases and decreases in MEP amplitude are assumed to represent long term potentiation(LTP)like or long term depression(LTD)-like synaptic plasticity of motor cortex output neurons, changes of motor threshold may be considered as a correlate of intrinsic plasticity. With increasing stimulus intensity, the amplitude of the MEP increases until it reaches a plateau level in healthy subjects (Hess et al., 1987; Devanne et al., 1997). This increase in MEP amplitude with increasing TMS intensity is referred to as MEP recruitment curve (RC), but is also known as input/ output or stimulus/response curves, since these MEP curves represent the input/output function of the motor cortex (Devanne et al., 1997; Kimiskidis et al., 2005).

5.2.3.

Brain mapping

TMS enables mapping of motor cortical outputs. Cortical mapping procedures, performed through single TMS pulses applied on several scalp positions overlying the motor cortex, can be obtained with an accurate assessment of the number of cortical sites eliciting MEPs in a target muscle, the site of maximal excitability (hot-spot) and the “center of gravity” of motor cortical output, as represented by the excitable scalp sites (Rothwell et al., 1999).

5.2.4.

Central motor conduction

Central motor conduction time (CMCT) is defined as the latency difference between the MEPs induced by motor cortex stimulation and those evoked by spinal (motor root) stimulation. CMCT is calculated by subtracting the peripheral conduction time from spinal cord to muscles from the absolute latency of responses evoked by cortical stimulation with the following formula: MEP latency – (F latencyþM latency1)/2, where F is the minimal F-wave latency, M the latency of the compound muscle action potential and 1 (in ms) the estimated turnaround time for antidromic activation of the spinal motoneuron (Rossini et al., 1994). Lengthening of CMCT suggests demyelination of the fastest-conducting cortico-motoneuronal fibers, central motor pathways, while low amplitude responses with little delay or absence of responses are more suggestive of neuronal or axonal loss (Hallett, 2000).

5.2.5.

Cortical silent period

Besides evoking MEPs, single TMS pulses delivered during voluntary muscle contraction produce a period of EMG suppression known as cortical silent period (CSP). Spinal inhibition contributes to the early phase of the silent period (its first 50–75 ms), whereas the late one reflects a long-lasting cortical inhibition mediated by GABAB, most likely in the motor cortex (Inghilleri et al., 1993; Werhahn et al., 1999).

5.2.6. Intracortical inhibition and facilitation using paired TMS TMS may also be used to investigate the intracortical facilitatory and inhibitory mechanisms in the motor cortex. Some of these TMS techniques involve paired-stimuli based on



a conditioning-test paradigm (Kujirai et al. 1993). Stimulation parameters such as the intensity of the conditioning (CS) and test stimulus (TS), together with the time between them (interstimulus interval, ISI), determine interactions between stimuli. When the CS is below and the TS is above the motor threshold, the CS inhibits the response to TS at ISIs of 1–5 ms (short latency intracortical inhibition, SICI), while it induces an increase in the test MEP amplitude at ISIs of 7–20 ms (intracortical facilitation, ICF). SICI is thought to reflect mostly the excitability of inhibitory GABAergic cortical circuits (Hallett, 2000; Paulus et al., 2008), whereas ICF is considered to depend upon the activity of intracortical glutamatergic excitatory circuits (Liepert et al., 1997; Di Lazzaro et al., 2006); in fact, glutamate is the main excitatory neurotransmitter in the human central nervous system, and mediates synaptic transmission primarily by activation of the α-amino-3-hydroxy-5-methylisoxazole-4propionate (AMPA)/kainate receptors and the NMDA receptors.

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Glossary TMS: transcranial magnetic stimulation rTMS: repetitive transcranial stimulation MEP: motor evoked potential SCI: spinal cord injury MRI: magnetic resonance imaging fMRI: functional magnetic resonance imaging RTM: resting motor threshold AMT: active motor threshold

CMCT: central motor conduction time CSP: cortical silent period SICI: short latency intracortical inhibition CS: conditioning stimulus TS: test stimulus GABA: gamma-aminobutyric acid NMDA: N-methyl-D-aspartate RC¼ recruitment curve PAS: paired associative stimulation M1: primary motor cortex UCM: urethral compressive musculature EPC: evoked pressure curve PAR: pudendo-anal reflex ADM: abductor digiti minimi APB: abductor pollicis brevis ECR: extensor carpi radialis ECD: extensor communis digitorum CMAP: compound motor action potential MVC: maximal voluntary contraction SCV: suppression of voluntary contraction ASIA: American Spinal Cord Injury Association AIS: ASIA impairment scale ARAT: Action Research Arm EPT: Electrical Perceptual Test VAS: visual analog scale MPQ: McGill Pain Questionnaire EMCS: epidural motor cortical stimulation


Reinforcement of subliminal flexion reflexes by transcranial magnetic stimulation of motor cortex in subjects with spinal cord injury.

Descending volley after electrical and magnetic transcranial stimulation in man.

Targeting Lumbar Spinal Neural Circuitry by Epidural Stimulation to Restore Motor Function After Spinal Cord Injury.

Reorganization of Respiratory Descending Pathways following Cervical Spinal Partial Section Investigated by Transcranial Magnetic Stimulation in the Rat.

Motor cortex stimulation suppresses cortical responses to noxious hindpaw stimulation after spinal cord lesion in rats.

The effect of repetitive transcranial magnetic stimulation on refractory neuropathic pain in spinal cord injury.

Cortical projection to erector spinae muscles in man as assessed by focal transcranial magnetic stimulation.

Central fatigue assessed by transcranial magnetic stimulation in ultratrail running.

Review of Epidural Spinal Cord Stimulation for Augmenting Cough after Spinal Cord Injury.

Origins and conducting pathways of motor evoked potentials elicited by transcranial magnetic stimulation in cats.

Reorganisation of descending motor pathways in patients after hemispherectomy and severe hemispheric lesions demonstrated by magnetic brain stimulation.

Whole-hand water flow stimulation increases motor cortical excitability: a study of transcranial magnetic stimulation and movement-related cortical potentials.

Using transcranial magnetic stimulation to quantify electrophysiological changes following concussive brain injury: a systematic review.

Embolism is emerging as a major cause of spinal cord injury after descending and thoracoabdominal aortic repair with a contemporary approach: magnetic resonance findings of spinal cord injury.

Suppression of motor cortical excitability in anesthetized rats by low frequency repetitive transcranial magnetic stimulation.

Onset Latency of Motor Evoked Potentials in Motor Cortical Mapping with Neuronavigated Transcranial Magnetic Stimulation.

Transcranial Magnetic Stimulation with Intermittent Theta Burst Stimulation Alters Corticospinal Output in Patients with Chronic Incomplete Spinal Cord Injury.

Mechanism of GABA receptors involved in spasticity inhibition induced by transcranial magnetic stimulation following spinal cord injury.

Surgical leg rotation: cortical neuroplasticity assessed through brain mapping using transcranial magnetic stimulation.

Motor unit numbers and contractile properties after spinal cord injury.

Incidence of traumatic spinal cord injury worldwide: a systematic review.

Sleep disordered breathing in spinal cord injury: A systematic review.

A meta-analysis of the effects of aging on motor cortex neurophysiology assessed by transcranial magnetic stimulation.

Mortality and longevity after a spinal cord injury: systematic review and meta-analysis.