The authors thank Professor Winston Byblow and Harry Jordan for their valuable contribution to this work. This work was funded by the Health Research Council of New Zealand.

All research conducted with human participants must have human ethics approval by the appropriate institutional ethics committee and the study must be conducted in accordance with the declaration of Helsinki.
1. Patient Screening
<ol>
	<li>Screen all patients for PREP2 suitability within 72 h of stroke onset. 
	NOTE: Patients are suitable if they have had a unilateral ischemic or hemorrhagic stroke within the last 72 h, have new UL weakness, and are 18 years or older.</li>
</ol>
2. SAFE Score
NOTE: Ensure that patients with inattention or fatigue are focused on the arm to enable an accurate assessment of strength.
<ol>
	<li>Position the patient with their back fully supported and upright either in bed or in a chair and their paretic arm by their side with the elbow in extension.</li>
	<li>Demonstrate shoulder abduction. Ask the patient to lift their arm sideways and up towards their ear. Use the Medical Research Council (MRC) grades to score shoulder abduction strength. 
	NOTE: MRC grades are described as follows: 0 = no palpable muscle activity; 1 = palpable muscle activity but no movement; 2 = limited range of movement without gravity; 3 = full range of motion against gravity but no resistance; 4 = full range of motion against gravity and resistance but weaker than the other side; 5 = normal power.</li>
	<li>To score shoulder abduction grades 4 or 5, place your hand over the patient&#39;s arm, proximal to the elbow and apply resistance. 
	NOTE: The patient must be able to achieve full range of motion against resistance to be awarded a score of 4 or higher.</li>
	<li>Place the paretic forearm in pronation with the fingers fully flexed and provide support under the wrist.</li>
	<li>Demonstrate finger extension. Ask the patient to straighten their fingers and use the Medical Research Council grades to score finger extension strength.</li>
	<li>To score finger extension grades 4 or 5, apply resistance over the dorsum of the fingers, distal to the metacarpophalangeal joints, throughout the movement. 
	NOTE: The patient must be able to achieve full extension against resistance to be awarded a score of 4 or higher.</li>
	<li>To score fingers with unequal strength, use the majority rule. If three fingers have the same score, use this score. If two fingers have a lower score than the other two fingers, use the lower score.</li>
	<li>Add the MRC grades for shoulder abduction and finger extension together for a SAFE score out of 10. If the patient has a SAFE score of 5 or more on day 3 poststroke they can be assumed to have a functional corticospinal tract and TMS is not required. If the patient has a SAFE score less than 5 on day 3 poststroke, TMS is required to determine their MEP status.</li>
</ol>
3. Transcranial Magnetic Stimulation (TMS)
<ol>
	<li>Evaluate patient suitability for TMS.
	<ol>
		<li>Complete a TMS safety checklist with the patient to identify absolute and relative contraindications to TMS24. 
		NOTE: This information should be gathered through patient and family interview and from the medical records. See representative results section for more detail.</li>
		<li>Ask the patient&#39;s physician to review the TMS checklist and approve it if appropriate.</li>
		<li>On the day of the TMS test, review the patient&#39;s medical status with the clinical team and the patient to ensure there have been no changes since the checklist was signed. 
		NOTE: Events to consider include fall with head injury, seizure, if the patient has become medically unwell, is hypoglycemic, or has unstable blood pressure. Ensure the patient has taken all prescribed medication prior to the test.</li>
	</ol>
	</li>
	<li>Prepare the environment.
	<ol>
		<li>Remove furniture from around the bed. Move the bed away from the wall to allow space for the TMS unit.</li>
		<li>Place the TMS unit at the head of the bed towards the side opposite the paretic limb. Angle the TMS unit so that the person delivering TMS can easily see the screen.</li>
		<li>Test the TMS setup to check it is working appropriately. 
		NOTE: This protocol uses a single-pulse TMS unit. The electromyography (EMG) signal can be sampled at 2 kHz and filtered with 10 Hz high-pass and 1,000 Hz low-pass filters. The EMG equipment needs to be triggered by the TMS unit such that the EMG trace begins at least 50 ms prior to the TMS stimulus and ends at least 50 ms after the TMS stimulus.</li>
		<li>Ensure familiarity with the protocol for summoning emergency assistance in the TMS assessment room in case this is required.</li>
	</ol>
	</li>
	<li>Prepare the patient. 
	NOTE: Patients with intravenous (IV) lines, nasogastric feeding, or low concentrations of supplementary oxygen via a nasal cannula can be tested with TMS provided that they are considered medically stable by the treating physician. Supplemental oxygen should continue throughout the TMS session. Suspending and disconnecting nasogastric feeding and non-essential fluids through IV lines will make it easier to conduct the TMS assessment.
	<ol>
		<li>Remove any clothing covering the forearms. Remove any items covering the paretic wrist such as a watch or identification bracelet to enable the EMG electrode placement.</li>
		<li>Position the paretic arm on a pillow with the forearm pronated and fully supported from the elbow to the hand.</li>
		<li>Palpate the paretic forearm to locate the muscle belly for the extensor carpi radialis (ECR) muscle. Identify positions for two surface EMG electrodes over the muscle belly, allowing for factors such as the position of IV cannula or dressings. 
		NOTE: It is essential that at least one electrode is positioned over the muscle belly. This may require discussion with the nursing staff about repositioning dressings before the test if possible.</li>
		<li>Clean the skin at each electrode site with an alcohol skin-cleansing wipe. Shave each electrode site to remove any hair. Lightly abrade the electrode sites with an abrasive cream or tape. Take care with patients who have fragile skin and avoid any areas of broken skin.</li>
		<li>Securely apply self-adhesive disposable recording electrodes to each site.</li>
		<li>Locate the electrode sites for the first dorsal interosseus muscle (FDI). One electrode will be placed on the FDI muscle belly and one on the dorsum of the hand. 
		NOTE: Electrode placement may vary depending on patient factors such as the position of an IV cannula or dressings.</li>
		<li>Prepare the skin and apply the self-adhesive recording electrodes as previously described.</li>
		<li>Place the reference electrode strap around the arm just proximal to the elbow. Alternatively, prepare the skin and place a self-adhesive reference electrode over the lateral epicondyle of the humerus.</li>
	</ol>
	</li>
	<li>Position the patient in bed for the test.
	<ol>
		<li>Lower the bed rails. Move the patient as high up the bed as possible and towards the edge of the bed on the non-paretic side. 
		NOTE: The patient should only be moved by trained staff.</li>
		<li>Put the bed rail back up on the paretic side for safety. Remove the headboard of the bed if possible and remove any unused IV poles attached to the bed that may obstruct the coil position.</li>
		<li>Raise the head of the bed as high as possible. Position pillows behind the patient&#39;s back to bring them into an upright sitting position without their head contacting the bed. Do not put a pillow behind the head. If possible, raise the knees to prevent the patient from slipping down the bed during testing.</li>
		<li>Ensure the paretic forearm is in pronation and fully supported by a pillow from the elbow to the wrist. Check for adequate TMS coil access by holding the TMS coil against the patient&#39;s head. Make adjustments to the patient&#39;s position as required.</li>
	</ol>
	</li>
	<li>Position the patient in a chair or wheelchair for the test (alternative option).
	<ol>
		<li>Ensure the patient is sitting upright and comfortably in the chair. Place a pillow under each arm. Ensure the paretic forearm is pronated and fully supported by the pillow.</li>
	</ol>
	</li>
	<li>Check the EMG trace: Connect the cables between the patient and the EMG unit. Check to make sure the EMG signal is free from any electrical noise.</li>
	<li>Deliver TMS.
	<ol>
		<li>Two trained staff should be present for the TMS test. Instruct the patient to look straight ahead, keeping their head still and eyes open.</li>
		<li>The person holding the coil should stand next to the patient&#39;s head on their non-paretic side and position the center of the coil over the location of the primary motor cortex of the stroke-affected hemisphere. This is approximately 4 cm lateral from the vertex on the interaural line. 
		NOTE: Another way to identify the starting coil position is to measure approximately a third of the distance from the vertex to the front of the ear.</li>
		<li>Orient the coil with the handle pointing backwards, at an approximately 45&#176; angle in the midsagittal plane to produce a posterior-to-anterior current in the underlying tissue. 
		NOTE: The coil used in this protocol is a flat figure-eight coil, but a branding coil or circular coil can also be used.</li>
		<li>Adjust the bed height for the coil holder&#39;s comfort. Use a step if necessary. The second person (not the coil holder) is responsible for monitoring patient comfort throughout the TMS session. They may stand at the foot of the bed to monitor the patient and ensure the patient maintains a neutral head position or monitor the patient from the bedside while adjusting the TMS unit controls as necessary. 
		NOTE: This will depend on the individual TMS setup used. The patient should be monitored for comfort levels, alertness, and any adverse effects such as vasovagal responses to the TMS.</li>
		<li>Begin with a stimulus intensity of 30% maximum stimulator output (MSO). Increase intensity in 10% MSO steps with three to five stimuli at each intensity and scalp location.</li>
		<li>Move the coil systematically in 1 cm steps in each direction (anterior, posterior, medial, lateral) to find the optimal location for producing MEPs in the recorded muscles. Small adjustments to the coil rotation may also be necessary.</li>
		<li>Continue increasing the stimulus intensity and moving the coil until the MEPs are consistently observed in one or both muscles or until 100% MSO is reached.</li>
		<li>If 100% MSO is reached with no MEPs observed, use active facilitation to increase corticomotor excitability and the likelihood of eliciting a MEP. Ask the patient to hug a pillow to their chest with both arms, attempting to activate their paretic UL as much as possible. For patients with no distal UL activity, ask them to elevate and retract at the shoulder girdle.</li>
	</ol>
	</li>
	<li>Classify the MEP status of the patient.
	<ol>
		<li>Classify the patient as MEP+ if MEPs of any amplitude are observed with a consistent latency in response to at least five stimuli. This can be either at rest or during voluntary facilitation. FDI latencies are typically 20&#8211;30 ms while ECR latencies are typically 15&#8211;25 ms. MEPs do not have to exceed a peak-to-peak amplitude of 50 &#181;V.</li>
		<li>Classify the patient as MEP- if a MEP cannot be elicited at 100% MSO either at rest or while attempting voluntary facilitation.</li>
	</ol>
	</li>
	<li>Remove electrodes and wipe the skin with an alcohol wipe. The skin may be slightly red but this usually resolves without any treatment.</li>
</ol>

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	<li>Veerbeek, J. M., Kwakkel, G., van Wegen, E. E., Ket, J. C., Heymans, M. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Early+prediction+of+outcome+of+activities+of+daily+living+after+stroke:+a+systematic+review.">Early prediction of outcome of activities of daily living after stroke: a systematic review.</a> Stroke. 42 (5), 1482-1488 (2011).</li><li>Lohse, K. R., Schaefer, S. Y., Raikes, A. C., Boyd, L. A., Lang, C. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Asking+New+Questions+with+Old+Data:+The+Centralized+Open-Access+Rehabilitation+Database+for+Stroke.">Asking New Questions with Old Data: The Centralized Open-Access Rehabilitation Database for Stroke.</a> Frontiers in Neurology. 7, 153 (2016).</li><li>Stinear, C., Ackerley, S., Byblow, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rehabilitation+is+initiated+early+after+stroke,+but+most+motor+rehabilitation+trials+are+not:+a+systematic+review.">Rehabilitation is initiated early after stroke, but most motor rehabilitation trials are not: a systematic review.</a> Stroke. 44 (7), 2039-2045 (2013).</li><li>Stinear, C. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prediction+of+recovery+of+motor+function+after+stroke.">Prediction of recovery of motor function after stroke.</a> Lancet Neurology. 9 (12), 1228-1232 (2010).</li><li>Byblow, W. D., Stinear, C. M., Barber, P. A., Petoe, M. A., Ackerley, S. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Proportional+recovery+after+stroke+depends+on+corticomotor+integrity.">Proportional recovery after stroke depends on corticomotor integrity.</a> Annals of Neurology. 78 (6), 848-859 (2015).</li><li>Stinear, C. 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P., Kurczych, K., Karli Nski, M., Czlonkowska, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+prognostic+value+of+motor-evoked+potentials+in+motor+recovery+and+functional+outcome+after+stroke+-+a+systematic+review+of+the+literature.">The prognostic value of motor-evoked potentials in motor recovery and functional outcome after stroke - a systematic review of the literature.</a> Functional Neurology. 27 (2), 79-84 (2012).</li><li>Smania, N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Active+finger+extension:+a+simple+movement+predicting+recovery+of+arm+function+in+patients+with+acute+stroke.">Active finger extension: a simple movement predicting recovery of arm function in patients with acute stroke.</a> Stroke. 38 (3), 1088-1090 (2007).</li><li>Nijland, R. H., van Wegen, E. 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The authors have nothing to disclose.

CST function evaluated with MEP status is a key prognostic biomarker for UL recovery and outcome after stroke. A total of 95% of patients with a functional CST at 1 week poststroke achieve an Action Research Arm Test (ARAT) score of at least 34 out of 57 by 3 months poststroke17. Conversely, 100% of patients without a functional CST at 1 week poststroke achieve an ARAT score of less than 34 by 3 months poststroke17. Evaluating CST function within a week poststroke may impro...

Upper limb function is commonly impaired after stroke, and recovery of UL function is important for regaining independence in daily living activities1. Stroke rehabilitation trials are often aimed at improving UL recovery and outcomes after stroke. The majority of stroke rehabilitation research is conducted with patients at the chronic stage (&#62;6 months poststroke), yet most rehabilitation occurs early after stroke2,3. More research needs to be conducted with patients soon after a stroke to build an evidence base for rehabilitation practice.
One of the greatest challenges when conducting research soon after the stroke is detecting the effects of the intervention against the background of recovery occurring during the initial weeks and months after the stroke. High intersubject variability in clinical presentation and recovery creates noise that can obscure the beneficial effects of interventions. Intervention and control groups are typically balanced on clinical measures of initial neurological impairment. However, these measures are often poor predictors of the patient&#39;s potential for subsequent recovery, particularly those with severe initial impairment4,5. This means that groups can be matched for baseline clinical measures and not matched for their recovery potential, which makes it more difficult to ascertain the intervention&#39;s effects. Biomarkers can address this challenge by identifying an individual patient&#39;s potential for motor recovery, so that groups can be accurately matched and stratified6,7,8. Biomarkers can also be used to select patients who are most likely to respond to the intervention&#39;s known or hypothesized mechanisms of action6.
The functional integrity of the corticospinal tract (CST) is a key biomarker that predicts recovery of UL function after stroke5,8,9,10,11,12. The CST conveys descending motor output from the primary motor cortex to the spinal cord and is essential for coordination and fine motor control. Patients with a functional CST after stroke are more likely to regain strength, coordination, and dexterity than patients without. A clinical assessment can be sufficient to confirm that the CST is functional in mildly impaired patients13,14,15. However, patients with more severe initial impairment may or may not have a functional CST, and a neurophysiological assessment using transcranial magnetic stimulation (TMS) is needed9,10,11,16,17.
TMS is a noninvasive and painless technique that can be used to test CST function18. The TMS coil delivers a magnetic stimulus over the primary motor cortex that generates a descending volley in the CST, eliciting a motor-evoked potential (MEP) in the muscles of the contralateral limb19. The presence of a MEP in the paretic arm or hand (MEP+) indicates a functional CST and is associated with greater potential for recovery of UL function. Patients who are MEP- are most likely to have worse UL recovery, with no return of coordinated and dexterous hand function4,6,9,12,16.
Testing all patients with TMS is impractical and unnecessary, as those with mild initial impairment most likely have a functional CST17. Therefore, a hierarchical approach is needed so that TMS is only used for patients with more severe initial impairment. The PREP2 algorithm was developed using a combination of clinical measures and TMS to evaluate CST function and predict likely UL outcome at 3 months poststroke (Figure 1)17. PREP2 starts at day 3 poststroke by testing the strength of shoulder abduction and finger extension in the paretic arm (SAFE score), using Medical Research Council grades. If the sum of these grades is 5 or more out of 10, it is &#34;safe&#34; to assume the patient is MEP+. These patients are expected to have a good or excellent UL outcome by 3 months poststroke, depending on their age17. These patients do not need TMS to determine MEP status, minimizing cost and unnecessary testing for the patient.
Patients with a SAFE score of less than 5 on day 3 poststroke require TMS to determine the functional integrity of their CST. If a MEP can be elicited from the paretic extensor carpi radialis (ECR) or first dorsal interosseus (FDI) muscles, the patient is MEP+ and is expected to recover fine motor control of the hand by 3 months poststroke. Approximately half of patients with a SAFE score less than 5 on day 3 poststroke are MEP+. Importantly, patients can have a SAFE score as low as zero and be MEP+. This illustrates the need for TMS in this subgroup of patients, as clinical assessment alone cannot distinguish between patients with and without a functional CST. Patients who are MEP- have significant CST damage. These patients are expected to have a limited or poor UL functional outcome depending on their overall stroke severity, measured with the National Institute of Health Stroke Scale (NIHSS) (Figure 1)17. These MEP- patients are not expected to regain coordinated and dexterous finger control and can be grouped together for research purposes.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/60665/60665fig01.jpg" /> 
Figure 1: The PREP2 algorithm. SAFE = Shoulder Abduction, Finger Extension score, which is the sum of the Medical Research Council grades for each of these movements out of 5, for a total SAFE score out of 10. MEP+ = Motor Evoked Potentials can be elicited from the paretic extensor carpi radialis (ECR) and/or first dorsal interosseous (FDI) muscles of the paretic UL using transcranial magnetic stimulation. NIHSS = National Institutes of Health Stroke Scale. The algorithm predicts one of four possible UL functional outcomes at 3 months poststroke. Each prediction category is associated with a rehabilitation focus that can be used to tailor UL therapy2. The colored dots represent, proportionally, PREP2 algorithm accuracy. The dots are color-coded based on the outcome category actually achieved 3 months poststroke (Green = Excellent; Blue = Good; Orange = Limited; Red = Poor). Figure reproduced from Stinear et al.17. <a href="https://www.jove.com/files/ftp_upload/60665/60665fig01large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
In clinical practice, PREP2 predicts one of four outcome categories that can be used to tailor rehabilitation for individual patients and help patients and families to understand what they can expect for their UL recovery. To date, PREP2 is the only externally validated UL prediction tool that combines clinical assessment and biomarker information in a decision tree17. It is also the only UL prediction tool with research on the effects of implementation in clinical practice20,21. PREP2 predictions are accurate for about 75% of patients, too optimistic for 17% and too pessimistic for 8% of patients at 3 months poststroke17. Accuracy is highest for MEP- patients (accurate for 90% of MEP- patients), highlighting the value of using TMS to identify these patients with severe damage to the descending motor pathways17. PREP2 remains correct for around 80% of patients at 2 years poststroke22. This supports the use of PREP2 to predict UL functional motor outcomes at 3 months and longer term. Information about delivering PREP2 predictions and using them in clinical practice is outside the scope of this methods paper, but detailed resources are available online23.
PREP2 provides researchers with a tool to select and stratify patients for clinical trials. This allows patients to be grouped not only according to baseline clinical characteristics, but also their neurobiological potential for UL recovery. Despite the mounting evidence for the use of TMS as a prognostic biomarker for UL recovery, lack of familiarity with TMS protocols in hospital settings with subacute stroke patients may be a barrier to its use in research. Therefore, this protocol aims to demonstrate how to use the SAFE score and TMS to evaluate CST function in patients in a hospital setting early after stroke.

<table><tbody><tr><td>alcohol/skin cleansing wipes</td><td>Reynard</td><td></td><td>alcohol prep pads</td></tr><tr><td>electromyography electrodes</td><td>3M</td><td></td><td>red dot electrodes</td></tr><tr><td>Magstim TMS coil</td><td>Magstim</td><td></td><td>flat figure-8 coil</td></tr><tr><td>razors</td><td>any</td><td></td><td></td></tr><tr><td>skin prep tape</td><td>3M</td><td></td><td>red dot skin prep tape</td></tr><tr><td>TMS stimulator</td><td>Magstim</td><td></td><td>Magstim 200 single pulse stimulator</td></tr></tbody></table>

determining the functional status of the corticospinal tract within one week of stroke

High interindividual variability in the recovery of upper limb (UL) function after stroke means it is difficult to predict an individual&#39;s potential for recovery based on clinical assessments alone. The functional integrity of the corticospinal tract is an important prognostic biomarker for recovery of UL function, particularly for those with severe initial UL impairment. This article presents a protocol for evaluating corticospinal tract function within 1 week of stroke. This protocol can be used to select and stratify patients in trials of interventions designed to improve UL motor recovery and outcomes after stroke. The protocol also forms part of the PREP2 algorithm, which predicts UL function for individual patients 3 months poststroke. The algorithm sequentially combines a UL strength assessment, age, transcranial magnetic stimulation, and stroke severity, within a few days of the stroke. The benefits of using PREP2 in clinical practice are described elsewhere. This article focuses on the use of a UL strength assessment and transcranial magnetic stimulation to evaluate corticospinal tract function.

The SAFE score and TMS can be used to ascertain the functional status of the CST within one week of stroke. Patients who have a SAFE score of at least 5 on day 3, or are MEP+ when tested with TMS, have a functional CST and are expected to regain at least some coordination and dexterity. Patients who are MEP- do not have a functional CST and therefore are likely to be limited to improvements in proximal arm movements and gross movements of the hand. The functional status of the CST can therefore be used to select patients...

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Determining the Functional Status of the Corticospinal Tract Within One Week of Stroke

This protocol is for evaluating corticospinal tract function within 1 week of stroke. It can be used to select and stratify patients in trials of interventions designed to improve upper limb motor recovery and outcomes and in clinical practice for predicting upper limb functional outcomes 3 months after stroke.

High interindividual variability in the recovery of upper limb (UL) function after stroke means it is difficult to predict an individual&#39;s potential ...

determining-functional-status-corticospinal-tract-within-one-week

Research

JoVE Journal

Neuroscience

8.5K Views.  University of Auckland. This protocol is for evaluating corticospinal tract function within 1 week of stroke. It can be used to select and stratify patients in trials of interventions designed to improve upper limb motor recovery and outcomes and in clinical practice for predicting upper limb functional outcomes 3 months after stroke.

Video: Determining the Functional Status of the Corticospinal Tract Within One Week of Stroke

Methods to Quantify Pharmacologically Induced Alterations in Motor Function in Human Incomplete SCI

Spinal cord injury (SCI) is a debilitating disorder, which produces profound deficits in volitional motor control. Following medical stabilization, recovery from SCI typically involves long term rehabilitation. While recovery of walking ability is a primary goal in many patients early after injury, those with a motor incomplete SCI, indicating partial preservation of volitional control, may have the sufficient residual descending pathways necessary to attain this goal. However, despite physical interventions, motor impairments including weakness, and the manifestation of abnormal involuntary reflex activity, called spasticity or spasms, are thought to contribute to reduced walking recovery. Doctrinaire thought suggests that remediation of this abnormal motor reflexes associated with SCI will produce functional benefits to the patient. For example, physicians and therapists will provide specific pharmacological or physical interventions directed towards reducing spasticity or spasms, although there continues to be little empirical data suggesting that these strategies improve walking ability.
In the past few decades, accumulating data has suggested that specific neuromodulatory agents, including agents which mimic or facilitate the actions of the monoamines, including serotonin (5HT) and norepinephrine (NE), can initiate or augment walking behaviors in animal models of SCI. Interestingly, many of these agents, particularly 5HTergic agonists, can markedly increase spinal excitability, which in turn also increases reflex activity in these animals. Counterintuitive to traditional theories of recovery following human SCI, the empirical evidence from basic science experiments suggest that this reflex hyper excitability and generation of locomotor behaviors are driven in parallel by neuromodulatory inputs (5HT) and may be necessary for functional recovery following SCI. 
The application of this novel concept derived from basic scientific studies to promote recovery following human SCI would appear to be seamless, although the direct translation of the findings can be extremely challenging. Specifically, in the animal models, an implanted catheter facilitates delivery of very specific 5HT agonist compounds directly onto the spinal circuitry. The translation of this technique to humans is hindered by the lack of specific surgical techniques or available pharmacological agents directed towards 5HT receptor subtypes that are safe and effective for human clinical trials. However, oral administration of commonly available 5HTergic agents, such as selective serotonin reuptake inhibitors (SSRIs), may be a viable option to increase central 5HT concentrations in order to facilitate walking recovery in humans. Systematic quantification of how these SSRIs modulate human motor behaviors following SCI, with a specific focus on strength, reflexes, and the recovery of walking ability, are missing.
This video demonstration is a progressive attempt to systematically and quantitatively assess the modulation of reflex activity, volitional strength and ambulation following the acute oral administration of an SSRI in human SCI. Agents are applied on single days to assess the immediate effects on motor function in this patient population, with long-term studies involving repeated drug administration combined with intensive physical interventions.

This video demonstrates modulation of reflex activity, volitional strength and ambulation through clinical and quantitative assessments in individuals with motor incomplete SCI as a result of acute oral administration of a serotonin reuptake inhibitor (SSRI).

Spinal cord injury (SCI) is a debilitating disorder, which produces profound deficits in volitional motor control. Following medical stabilization, ...

Medicine

Assessing Forelimb Function after Unilateral Cervical SCI using Novel Tasks: Limb Step-alternation, Postural Instability and Pasta Handling

Cervical spinal cord injury (cSCI) can cause devastating neurological deficits, including impairment or loss of upper limb and hand function. A majority of the spinal cord injuries in humans occur at the cervical levels. Therefore, developing cervical injury models and developing relevant and sensitive behavioral tests is of great importance. Here we describe the use of a newly developed forelimb step-alternation test after cervical spinal cord injury in rats. In addition, we describe two behavioral tests that have not been used after spinal cord injury: a postural instability test (PIT), and a pasta-handling test. All three behavioral tests are highly sensitive to injury and are easy to use. Therefore, we feel that these behavioral tests can be instrumental in investigating therapeutic strategies after cSCI.

Three new behavioral tests (forelimb step-alternation, postural instability test, pasta handling test) for evaluating forelimb function after cervical spinal cord injury in rodents are described.

Cervical spinal cord injury (cSCI) can cause devastating neurological deficits, including impairment or loss of upper limb and hand function. A majority ...

Behavior

Compensatory Limb Use and Behavioral Assessment of Motor Skill Learning Following Sensorimotor Cortex Injury in a Mouse Model of Ischemic Stroke

Mouse models have become increasingly popular in the field of behavioral neuroscience, and specifically in studies of experimental stroke. As models advance, it is important to develop sensitive behavioral measures specific to the mouse. The present protocol describes a skilled motor task for use in mouse models of stroke. The Pasta Matrix Reaching Task functions as a versatile and sensitive behavioral assay that permits experimenters to collect accurate outcome data and manipulate limb use to mimic human clinical phenomena including compensatory strategies (i.e., learned non-use) and focused rehabilitative training. When combined with neuroanatomical tools, this task also permits researchers to explore the mechanisms that support behavioral recovery of function (or lack thereof) following stroke. The task is both simple and affordable to set up and conduct, offering a variety of training and testing options for numerous research questions concerning functional outcome following injury. Though the task has been applied to mouse models of stroke, it may also be beneficial in studies of functional outcome in other upper extremity injury models.

Mouse models have become increasingly popular in studies of behavioral neuroscience. As models advance, it is important to develop sensitive behavioral measures specific to the mouse. This protocol describes the Pasta Matrix Reaching Task, which is a skilled motor task for use in mouse models of stroke.

Mouse models have become increasingly popular in the field of behavioral neuroscience, and specifically in studies of experimental stroke. As models ...

Asymmetric Walkway: A Novel Behavioral Assay for Studying Asymmetric Locomotion

Behavioral assays are commonly used for the assessment of sensorimotor impairment in the central nervous system (CNS). The most sophisticated methods for quantifying locomotor deficits in rodents is to measure minute disturbances of unconstrained gait overground (e.g., manual BBB score or automated CatWalk). However, cortical inputs are not required for the generation of basic locomotion produced by the spinal central pattern generator (CPG). Thus, unconstrained walking tasks test locomotor deficits due to motor cortical impairment only indirectly. In this study, we propose a novel, precise foot-placement locomotor task that evaluates cortical inputs to the spinal CPG. An instrumented peg-way was used to impose symmetrical and asymmetrical locomotor tasks mimicking lateralized movement deficits. We demonstrate that shifts from equidistant inter-stride lengths of 20% produce changes in the forelimb stance phase characteristics during locomotion with preferred stride length. Furthermore, we propose that the asymmetric walkway allows for measurements of behavioral outcomes produced by cortical control signals. These measures are relevant for the assessment of impairment after cortical damage.

Here, we present a protocol to quantify precise stepping in rodents. Cortical and the spinal central pattern generator signals are required for precise foot-placement during obstructed locomotion. We report here the novel constrained walking task that directly examines precise stepping behavior.

Behavioral assays are commonly used for the assessment of sensorimotor impairment in the central nervous system (CNS). The most sophisticated methods for ...

Standing Neurophysiological Assessment of Lower Extremity Muscles Post-Stroke

Transcranial magnetic stimulation (TMS) is a common tool used to measure the behavior of motor circuits in healthy and neurologically impaired populations. TMS is used extensively to study motor control and the response to neurorehabilitation of the upper extremities. However, TMS has been less utilized in the study of lower extremity postural and walking-specific motor control. The limited use and the additional methodological challenges of lower extremity TMS assessments have contributed to the lack of consistency in lower extremity TMS procedures within the literature. Inspired by the decreased ability to record lower extremity TMS motor evoked potentials (MEP), this methodological report details steps to enable post-stroke TMS assessments in a standing posture. The standing posture allows for the activation of the neuromuscular system, reflecting a state more akin to the system's state during postural and walking tasks. Using dual-top force plates, we instructed participants to equally distribute their weight between their paretic and non-paretic legs. Visual feedback of the participants' weight distribution was provided. Using image guidance software, we delivered single TMS pulses via a double-cone coil to the participants' lesioned and non-lesioned hemispheres and measured the corticomotor response of the paretic and non-paretic tibialis anterior and soleus muscles. Performing assessments in the standing position increased the TMS response rate and allowed for the use of the lower stimulation intensities compared to the standard sitting/resting position. Utilization of this TMS protocol can provide a common approach to assess the lower extremity corticomotor response post-stroke when the neurorehabilitation of postural and gait impairments are of interest.

This protocol describes the process for performing a neurophysiological assessment of the lower extremity muscles, tibialis anterior and soleus, in a standing position using TMS in people post-stroke. This position provides a greater probability of eliciting a post-stroke TMS response and allows for the use of reduced stimulator power during neurophysiological assessments.

Transcranial magnetic stimulation (TMS) is a common tool used to measure the behavior of motor circuits in healthy and neurologically impaired ...

Unilateral Pyramidotomy of the Corticospinal Tract in Rats for Assessment of Neuroplasticity-inducing Therapies

The corticospinal tract (CST) can be completely severed unilaterally in the medullary pyramids of the rodent brainstem. The CST is a motor tract that has great importance for distal muscle control in humans and, to a lesser extent, in rodents. A unilateral cut of one pyramid results in loss of CST innervation of the spinal cord mainly on the contralateral side of the spinal cord leading to transient motor disability in the forelimbs and sustained loss of dexterity. Ipsilateral projections of the corticospinal tract are minor. We have refined our surgical method to increase the chances of lesion completeness. We describe postsurgical care. Deficits on the Montoya staircase pellet reaching test and the horizontal ladder test shown here are detected up to 8 weeks postinjury. Deficits on the cylinder rearing test are only detected transiently. Therefore, the cylinder test may only be suitable for detection of short term recovery. We show how, electrophysiologically and anatomically, one may assess lesions and plastic changes. We also describe how to analyse fibers from the uninjured CST sprouting across the midline into the deprived areas. It is challenging to obtain &#62;90% complete lesions consistently due to the proximity to the basilar artery in the medulla oblongata and survival rates can be low. Alternative surgical approaches and behavioural testing are described in this protocol. The pyramidotomy model is a good tool for assessing neuroplasticity-inducing treatments, which increase sprouting of intact fibers after injury.

The corticospinal tract, one of the major sensorimotor tracts, can be lesioned unilaterally in the rodent brainstem in order to test neuroplasticity-inducing therapies for the central nervous system. This surgical procedure (&#8220;pyramidotomy&#8221;) and postoperative assessments are described in this protocol.

The corticospinal tract (CST) can be completely severed unilaterally in the medullary pyramids of the rodent brainstem. The CST is a motor tract that has ...

Bilateral Assessment of the Corticospinal Pathways of the Ankle Muscles Using Navigated Transcranial Magnetic Stimulation

Distal leg muscles receive neural input from motor cortical areas via the corticospinal tract, which is one of the main motor descending pathway in humans and can be assessed using transcranial magnetic stimulation (TMS). Given the role of distal leg muscles in upright postural and dynamic tasks, such as walking, a growing research interest in the assessment and modulation of the corticospinal tracts relative to the function of these muscles has emerged in the last decade. However, methodological parameters used in previous work have varied across studies making the interpretation of results from cross-sectional and longitudinal studies less robust. Therefore, use of a standardized TMS protocol specific to the assessment of leg muscles&#39; corticomotor response (CMR) will allow for direct comparison of results across studies and cohorts. The objective of this paper is to present a protocol that provides the flexibility to simultaneously assess the bilateral CMR of two main ankle antagonistic muscles, the tibialis anterior and soleus, using single pulse TMS with a neuronavigation system. The present protocol is applicable while the examined muscle is either fully relaxed or isometrically contracted at a defined percentage of maximum isometric voluntary contraction. Using each subject&#39;s structural MRI with the neuronavigation system ensures accurate and precise positioning of the coil over the leg cortical representations during assessment. Given the inconsistency in CMR derived measures, this protocol also describes a standardized calculation of these measures using automated algorithms. Though this protocol is not conducted during upright postural or dynamic tasks, it&#160;can be used to assess bilaterally any pair of leg muscles, either antagonistic or synergistic, in both neurologically intact and impaired subjects.

The present protocol describes the simultaneous, bilateral assessment of the corticomotor response of the tibialis anterior and soleus during rest and tonic voluntary activation using a single pulse transcranial magnetic stimulation and neuronavigation system.

Distal leg muscles receive neural input from motor cortical areas via the corticospinal tract, which is one of the main motor descending pathway in humans ...

Structured Motor Rehabilitation After Selective Nerve Transfers

After severe nerve injuries, selective nerve transfers provide an opportunity to restore motor and sensory function. Functional recovery depends both on the successful re-innervation of the targets in the periphery and on the motor re-learning process entailing cortical plasticity. While there is an increasing number of methods to improve rehabilitation, their routine implementation in a clinical setting remains a challenge due to their complexity and long duration. Therefore, recommendations for rehabilitation strategies are presented with the aim of guiding medical doctors and therapists through the long-lasting rehabilitation process and providing step-by-step instructions for supporting motor re-learning.
Directly after nerve transfer surgery, no motor function is present, and therapy should focus on promoting activity in the sensory-motor cortex areas of the paralyzed body part. After about two to six months (depending on the severity and modality of injury, the distance of nerve regeneration and many other factors), the first motor activity can be detected via electromyography (EMG). Within this phase of rehabilitation, multimodal feedback is used to re-learn the motor function. This is especially critical after nerve transfers, as muscle activation patterns change due to the altered neural connection. Finally, muscle strength should be sufficient to overcome gravity/resistance of antagonistic muscles and joint stiffness, and more functional tasks can be implemented in rehabilitation.

Here, we present a protocol for the motor rehabilitation of patients with severe nerve injuries and selective nerve transfer surgery. It aims at restoring the motor function proposing several stages in patient education, early-stage therapy after surgery and interventions for rehabilitation after successful re-innervation of the nerve&#8217;s target.

After severe nerve injuries, selective nerve transfers provide an opportunity to restore motor and sensory function. Functional recovery depends both on ...

A Mouse Model of Direct Anastomosis via the Prespinal Route for Crossing Nerve Transfer Surgery

Crossing nerve transfer surgery has been a powerful approach for repairing injured upper extremities in patients with brachial plexus avulsion injuries. Recently, this surgery was creatively applied in the clinical treatment of brain injury and achieved substantial rehabilitation of the paralyzed arm. This functional recovery after the surgery suggests that peripheral sensorimotor intervention induces profound neuroplasticity to compensate for the loss of function after brain damage; however, the underlying neural mechanism is poorly understood. Therefore, an emergent clinical animal model is required. Here, we simulated clinical surgery to establish a protocol of direct anastomosis of bilateral brachial plexus nerves via the prespinal route in mice. Neuroanatomical, electrophysiological, and behavioral experiments helped identify that the transferred nerves of these mice successfully reinnervated the impaired forelimb and contributed to accelerating motor recovery after brain injury. Therefore, the mouse model revealed the neural mechanisms underlying rehabilitation upon crossing nerve transfer after central and peripheral nervous system injuries.

We simulated clinical surgery to establish a protocol of direct anastomosis of bilateral brachial plexus nerves via the prespinal route in mice, contributing to the study of the neural mechanisms underlying rehabilitation upon crossing nerve transfer after central and peripheral nervous system injuries.

Crossing nerve transfer surgery has been a powerful approach for repairing injured upper extremities in patients with brachial plexus avulsion injuries. ...

Enhancing Stroke Rehabilitation with Virtual Reality-Based Occupational Training

Cognitive Function and Upper Limb Rehabilitation Training Post-Stroke Using a Digital Occupational Training System

Stroke rehabilitation often requires frequent and intensive therapy to improve functional recovery. Virtual reality (VR) technology has shown the potential to meet these demands by providing engaging and motivating therapy options. The digital occupational training system is a VR application that utilizes cutting-edge technologies, including multi-touch screens, virtual reality, and human-computer interaction, to offer diverse training techniques for advanced cognitive capacity and hand-eye coordination abilities. The objective of this study was to assess the effectiveness of this program in enhancing cognitive function and upper extremity rehabilitation in stroke patients. The training and assessment consist of five cognitive modules covering perception, attention, memory, logical reasoning, and calculation, along with hand-eye coordination training. This research indicates that after eight weeks of training, the digital occupational training system can significantly improve cognitive function, daily living skills, attention, and self-care abilities in stroke patients. This software can be employed as a time-saving and clinically effective rehabilitation aid to complement traditional one-on-one occupational therapy sessions. In summary, the digital occupational training system shows promise and offers potential financial benefits as a tool to support the functional recovery of stroke patients.

Author Spotlight: Rehabilitation of Stroke Patients With a Digital Occupational Training System

The current protocol outlines how the VR-based digital occupational training system enhances the rehabilitation of patients with cognitive impairment and upper limb dysfunction following a stroke.