Segmental analysis in cervical spinal cord injury reveals the recovery potential of hand muscles with preserved corticospinal tract: Insights beyond impairment scales

Cervical spinal cord injury (SCI) severely impacts widespread bodily functions with extensive impairments for individuals, who prioritize regaining hand function. Although prior work has focused on the recovery at the person- level, the factors determining the recovery potential of individual muscles are poorly understood. There is a need for changing this paradigm in the field by moving beyond person-level classification of residual strength and sacral sparing to a muscle-specific analysis with a focus on the role of corticospinal tract (CST) sparing. The most striking part of human evolution involved the development of dextrous hand use with a respective expansion of the sensorimotor cortex controlling hand movements, which, because of the extensive CST projections, may constitute a drawback after SCI. Here, we investigated the muscle-specific natural recovery after cervical SCI in 748 patients from the European Multicenter Study about SCI (EMSCI), one of the largest datasets analysed to date. All participants were assessed within the first 4 weeks after SCI and re-assessed at 12, 24, and 48 weeks. Subsets of individuals underwent electrophysiological multimodal evaluations to discern CST and lower motor neuron (LMN) integrity [motor evoked potentials (MEP): N = 203; somatosensory evoked potentials (SSEP): N = 313; nerve conduction studies (NCS): N = 280]. We show the first evidence of the importance of CST sparing for proportional recovery in SCI, which is known in stroke survivors to represent the biological limits of structural and functional plasticity. In AIS D, baseline strength is a good predictor of segmental muscle strength recovery, while the proportionality in relation to baseline strength is lower for AIS B/C and breaks for AIS A. More severely impaired individuals showed non-linear and more variable recovery profiles, especially for hand muscles, while measures of CST sparing (by means of MEP) improved the prediction of hand muscle strength recovery. Therefore, assessment strategies for muscle-specific motor recovery in acute SCI improve by accounting for CST sparing and complement gross person-level predictions. The latter is of paramount importance for clinical trial outcomes and to target neurorehabilitation of upper limb function, where any single muscle function impacts the outcome of independence in cervical SCI. ![Figure][1] Graphical abstract Segmental analysis in cervical spinal cord injury reveals the recovery potential of hand muscles with preserved corticospinal tract: Insights beyond impairment scales. (A, upper panels) Cervical SCI (yellow) may cause impairment of motor function below the level of lesion depending on the completeness of the injury. Individuals with a sensorimotor complete lesion (AIS A), as defined by the absence of sacral sparing, show a non-proportional strength recovery as related to the baseline strength, in contrast to less severely affected patients (AIS B-D) - reflecting the limitations on structural and functional plasticity in this group. (A, lower panel) The area of spinal cord damage typically extents across several segments below the level of lesion with variable preservation of muscle innervation and is described as zone of partial preservation (ZPP). (B) The recovery of hand muscle strength is more challenged compared to more proximal muscles when accounting for the distance from the level of lesion. (C, upper panel) The strength recovery of proximal muscles is proportional to the baseline strength in AIS D (great R[2][2] values) but limited in AIS A, likely indicating the limits of recovery in severe SCI. (C, lower panel) Also, additional clinical baseline variables [e.g., distance from the motor level of injury (DST); pin prick (PP) and light touch (LT) sensation] primarily increased the prediction of strength recovery for proximal muscles, becoming less effective in more distal muscles, such as the intrinsic hand muscles. (D) Overall, the proportional prediction of strength recovery in distal hand muscles is less strong while failing in AIS A (inversion of proportionality). (D, lower panel) The addition of neurophysiological baseline measures related to CST integrity (by means of MEP) increased the prediction of strength recovery of hand muscles, indicating the importance of residual CST projections to spinal motoneurons for hand strength recovery. Clinical studies aiming at restitution of hand function after SCI may benefit from the addition of MEP assessments early after the SCI, to unveil hand muscles with a potential for recovery. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Wings for Life Spinal Cord Research Foundation (Project #210) and the Nogo Inhibition in Spinal Cord Injury project (NISCI - HZ2020). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study is based on the European Multicenter Study about SCI (EMSCI; ClinicalTrials.gov Identifier: [NCT01571531][3]) investigating the natural recovery after SCI. (...) Seven hundred and ninety-nine participants with cervical SCI were enrolled in dedicated SCI centres: the Hohe Warte Bayreuth (Bayreuth, Germany), BG-Trauma Center (Murnau, Germany), RKU Universitats- und Rehabilitationskliniken Ulm (Ulm, Germany), Spinal Cord Injury Center of Heidelberg University Hospital (Heidelberg, Germany), and Spinal Cord Injury Center - Balgrist University Hospital (Zurich, Switzerland). The research followed the Declaration of Helsinki and was approved by the Institutional Review Board of the abovementioned institutions: Bayrische Landesarztekammer, Ethik-Kommission (REB #188/2003; Bayreuth, Germany), Ethik-Kommission der Bayerischen Landesarztekammer (REB approval was waived because the project was treated as a data registry, but informed consent was obtained from all participants; Murnau, Germany), Universitat Ulm Ethikkommission (REB #71/2005; Ulm, Germany), Universitat Heidelberg Ethikkommission der Med. Fakultat (REB #S-188/2003; Heidelberg, Germany), Kanton Zurich Kantonale Ethikkommission (REB #EK-03/2004/PB_2016-00293; Zurich, Switzerland). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. [1]: pending:yes [2]: #ref-2 [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01571531&atom=%2Fmedrxiv%2Fearly%2F2021%2F11%2F30%2F2021.11.30.21265051.atom