Advances in Spinal Cord Neuromodulation: The Integration of Neuroengineering, Computational Approaches, and Innovative Conceptual Frameworks.

Spinal cord stimulation (SCS) is an approved treatment for intractable pain and has recently emerged as a promising area of research for restoring function after spinal cord lesion. This review will focus on the historical evolution of this transition and the path that remains to be taken for these methods to be rigorously evaluated for application in clinical practice. New developments in SCS are being driven by advances in the understanding of spinal cord lesions at the molecular, cellular, and neuronal levels, as well as the understanding of compensatory mechanisms. Advances in neuroengineering and the computational neurosciences have enabled the development of new conceptual SCS strategies, such as spatiotemporal neuromodulation, which allows spatially selective stimulation at precise time points during anticipated movement. It has also become increasingly clear that these methods are only effective when combined with intensive rehabilitation techniques, such as new task-oriented methods and robotic aids. The emergence of innovative approaches to spinal cord neuromodulation has sparked significant enthusiasm among patients and in the media. Non-invasive methods are perceived to offer improved safety, patient acceptance, and cost-effectiveness. There is an immediate need for well-designed clinical trials involving consumer or advocacy groups to evaluate and compare the effectiveness of various treatment modalities, assess safety considerations, and establish outcome priorities.

Development of new outcome measures for adult SMA type III and IV: a multimodal longitudinal study.

OBJECTIVE: The aim of this study was the comprehensive characterisation of longitudinal clinical, electrophysiological and neuroimaging measures in type III and IV adult spinal muscular atrophy (SMA) with a view to propose objective monitoring markers for future clinical trials. METHODS: Fourteen type III or IV SMA patients underwent standardised assessments including muscle strength testing, functional evaluation (SMAFRS and MFM), MUNIX (abductor pollicis brevis, APB; abductor digiti minimi, ADM; deltoid; tibialis anterior, TA; trapezius) and quantitative cervical spinal cord MRI to appraise segmental grey and white matter atrophy. Patients underwent a follow-up assessment with the same protocol 24 months later. Longitudinal comparisons were conducted using the Wilcoxon-test for matched data. Responsiveness was estimated using standardized response means (SRM) and a composite score was generated based on the three most significant variables. RESULTS: Significant functional decline was observed based on SMAFRS (p = 0.019), pinch and knee flexion strength (p = 0.030 and 0.027), MUNIX and MUSIX value in the ADM (p = 0.0006 and 0.043) and in TA muscle (p = 0.025). No significant differences were observed based on cervical MRI measures. A significant reduction was detected in the composite score (p = 0.0005, SRM = -1.52), which was the most responsive variable and required a smaller number of patients than single variables in the estimation of sample size for clinical trials. CONCLUSIONS: Quantitative strength testing, SMAFRS and MUNIX readily capture disease progression in adult SMA patients. Composite multimodal scores increase predictive value and may reduce sample size requirements in clinical trials.

Efficacy of Psychoeducation and Cognitive Rehabilitation After Mild Traumatic Brain Injury for Preventing Post-concussional Syndrome in Individuals With High Risk of Poor Prognosis: A Randomized Clinical Trial.

Unfavorable outcomes (UO) occur in 15-20% of patients with mild traumatic brain injury (mTBI). Early identification of patients at risk of UO is crucial for suitable management to be initiated, increasing the chances of full recovery. We previously developed a prognostic tool for early identification (8-21 days after the injury) of patients likely to develop UO. Patients whose initial risk factors indicate UO are at risk of developing post-concussion syndrome (PCS). In the present study, we examined the beneficial effects of early multidimensional management (MM) on prognosis. We used our prognostic tool to classify 221 mTBI patients into a UO (97) group or a favorable outcome (FO) group (124). We randomized the UO patients into two subgroups: a group that underwent MM (involving psychoeducation and cognitive rehabilitation) (34) and a control group with no specific treatment other than psychoeducation (46). At 6 months, these two groups were compared to assess the impact of MM. Among the followed-up patients initially classified as having FO (101), 95% had FO at 6 months and only five had PCS [as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV classification]. Among the followed-up MM patients, 94% did not have PCS 6 months after injury, whereas 52% of the control patients had PCS. The effect of MM on the recovery of patients at 6 months, once adjusted for the main confounding factors, was significant (p < 0.001). These results show that the initiation of MM after early identification of at-risk mTBI patients can considerably improve their outcomes. Clinical Trials Registration: The study was registered at ClinicalTrials.gov (NCT03811626).

The spinal and cerebral profile of adult spinal-muscular atrophy: A multimodal imaging study.

Spinal muscular atrophy (SMA) type III and IV are autosomal recessive, slowly progressive lower motor neuron syndromes. Nevertheless, wider cerebral involvement has been consistently reported in mouse models. The objective of this study is the characterisation of spinal and cerebral pathology in adult forms of SMA using multimodal quantitative imaging. METHODS: Twenty-five type III and IV adult SMA patients and 25 age-matched healthy controls were enrolled in a spinal cord and brain imaging study. Structural measures of grey and white matter involvement and diffusion parameters of white matter integrity were evaluated at each cervical spinal level. Whole-brain and region-of-interest analyses were also conducted in the brain to explore cortical thickness, grey matter density and tract-based white matter alterations. RESULTS: In the spinal cord, considerable grey matter atrophy was detected between C2-C6 vertebral levels. In the brain, increased grey matter density was detected in motor and extra-motor regions of SMA patients. No white matter pathology was identified neither at brain and spinal level. CONCLUSIONS: Adult forms of SMA are associated with selective grey matter degeneration in the spinal cord with preserved white matter integrity. The observed increased grey matter density in the motor cortex may represent adaptive reorganisation.

The motor unit number index (MUNIX) profile of patients with adult spinal muscular atrophy.

OBJECTIVE: Objective of this study is the comprehensive characterisation of motor unit (MU) loss in type III and IV Spinal Muscular Atrophy (SMA) using motor unit number index (MUNIX), and evaluation of compensatory mechanisms based on MU size indices (MUSIX). METHODS: Nineteen type III and IV SMA patients and 16 gender- and age-matched healthy controls were recruited. Neuromuscular performance was evaluated by muscle strength testing and functional scales. Compound motor action potential (CMAP), MUNIX and MUSIX were studied in the abductor pollicis brevis (APB), abductor digiti minimi (ADM), deltoid, tibialis anterior and trapezius muscles. A composite MUNIX score was also calculated. RESULTS: SMA patients exhibited significantly reduced MUNIX values (p < 0.05) in all muscles, while MUSIX was increased, suggesting active re-innervation. Significant correlations were identified between MUNIX/MUSIX and muscle strength. Similarly, composite MUNIX scores correlated with disability scores. Interestingly, in SMA patients MUNIX was much lower in the ADM than in the ABP, a pattern which is distinctly different from that observed in Amyotrophic Lateral Sclerosis. CONCLUSIONS: MUNIX is a sensitive measure of MU loss in adult forms of SMA and correlates with disability. SIGNIFICANCE: MUNIX evaluation is a promising candidate biomarker for longitudinal studies and pharmacological trials in adult SMA patients.

Early Detection of Poor Outcome after Mild Traumatic Brain Injury: Predictive Factors Using a Multidimensional Approach a Pilot Study.

Mild traumatic brain injury (MTBI) is a common condition within the general population, usually with good clinical outcome. However, in 10-25% of cases, a post-concussive syndrome (PCS) occurs. Identifying early prognostic factors for the development of PCS can ensure widespread clinical and economic benefits. The aim of this study was to demonstrate the potential value of a comprehensive neuropsychological evaluation to identify early prognostic factors following MTBI. We performed a multi-center open, prospective, longitudinal study that included 72 MTBI patients and 42 healthy volunteers matched for age, gender, and socioeconomic status. MTBI patients were evaluated 8-21 days after injury, and 6 months thereafter, with a full neurological and psychological examination and brain MRI. At 6 months follow-up, MTBI patients were categorized into two subgroups according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) as having either favorable or unfavorable evolution (UE), corresponding to the presence of major or mild neurocognitive disorder due to traumatic brain injury. Univariate and multivariate logistical regression analysis demonstrated the importance of patient complaints, quality of life, and cognition in the outcome of MTBI patients, but only 6/23 UE patients were detected early via the multivariate logistic regression model. Using several variables from each of these three categories of variables, we built a model that assigns a score to each patient presuming the possibility of UE. Statistical analyses showed this last model to be reliable and sensitive, allowing early identification of patients at risk of developing PCS with 95.7% sensitivity and 77.6% specificity.

An Attempt of Early Detection of Poor Outcome after Whiplash.

The main concern with whiplash is that a large proportion of whiplash patients experience disabling symptoms or whiplash-associated disorders (WAD) for months if not years following the accident. Therefore, identifying early prognostic factors of WAD development is important as WAD have widespread clinical and economic consequences. In order to tackle that question, our study was specifically aimed at combining several methods of investigation in the same WAD patients at the acute stage and 6 months later. Our longitudinal, open, prospective, multi-center study included 38 whiplash patients, and 13 healthy volunteers matched for age, gender, and socio-economic status with the whiplash group. Whiplash patients were evaluated 15-21 days after road accident, and 6 months later. At each appointment, patients underwent a neuropsychological evaluation, a full clinical neurological examination, neurophysiological and postural tests, oto-neurological tests, cervical spine cord magnetic resonance imaging (MRI) with tractography (DTI). At 6 months, whiplash patients were categorized into two subgroups based on the results of the Diagnostic and Statistical Manual of Mental Disorders as having either favorable or unfavorable progression [an unfavorable classification corresponding to the presence of post-concussion symptom (PCS)] and we searched retrospectively for early prognostic factors of WAD predicting the passage to chronicity. We found that patients displaying high level of catastrophizing at the acute stage and/or post-traumatic stress disorder associated with either abnormalities in head or trunk kinematics, abnormal test of the otolithic function and at the Equitest or a combination of these syndromes, turned to chronicity. This study suggests that low-grade whiplash patients should be submitted as early as possible after the trauma to neuropsychological and motor control tests in a specialized consultation. In addition, they should be evaluated by a neuro-otologist for a detailed examination of vestibular functions, which should include cervical vestibular evoked myogenic potential. Then, if diagnosed at risk of WAD, these patients should be subjected to an intensive preventive rehabilitation program, including vestibular rehabilitation if required.

Specific and evolving resting-state network alterations in post-concussion syndrome following mild traumatic brain injury.

Post-concussion syndrome has been related to axonal damage in patients with mild traumatic brain injury, but little is known about the consequences of injury on brain networks. In the present study, our aim was to characterize changes in functional brain networks following mild traumatic brain injury in patients with post-concussion syndrome using resting-state functional magnetic resonance imaging data. We investigated 17 injured patients with persistent post-concussion syndrome (under the DSM-IV criteria) at 6 months post-injury compared with 38 mild traumatic brain injury patients with no post-concussion syndrome and 34 healthy controls. All patients underwent magnetic resonance imaging examinations at the subacute (1-3 weeks) and late (6 months) phases after injury. Group-wise differences in functional brain networks were analyzed using graph theory measures. Patterns of long-range functional networks alterations were found in all mild traumatic brain injury patients. Mild traumatic brain injury patients with post-concussion syndrome had greater alterations than patients without post-concussion syndrome. In patients with post-concussion syndrome, changes specifically affected temporal and thalamic regions predominantly at the subacute stage and frontal regions at the late phase. Our results suggest that the post-concussion syndrome is associated with specific abnormalities in functional brain network that may contribute to explain deficits typically observed in PCS patients.

Involvement of spinal sensory pathway in ALS and specificity of cord atrophy to lower motor neuron degeneration.

Our objective was to demonstrate that ALS patients have sensory pathway involvement and that local cord atrophy reflects segmental lower motor neuron involvement. Twenty-nine ALS patients with spinal onset and twenty-one healthy controls were recruited. Diffusion tensor imaging (DTI), magnetization transfer and atrophy index were measured in the spinal cord, complemented with transcranial magnetic stimulations. Metrics were quantified within the lateral corticospinal and the dorsal segments of the cervical cord. Significant differences were detected between patients and controls for DTI and magnetization transfer metrics in the lateral and dorsal segments of the spinal cord. Fractional anisotropy correlated with ALSFRS-R (p = 0.04) and motor threshold (p = 0.02). Stepwise linear regression detected local spinal cord atrophy associated with weakness in the corresponding muscle territory, i.e. C4 level for deltoid and C7 level for hand muscles. In conclusion, impairment of spinal sensory pathways was detected at an early stage of the disease. Our data also demonstrate an association between muscle deficits and local spinal cord atrophy, suggesting that atrophy is a sensitive biomarker for lower motor neurons degeneration.

Correction: Specific and Evolving Resting-State Network Alterations in Post-Concussion Syndrome Following Mild Traumatic Brain Injury.

[This corrects the article DOI: 10.1371/journal.pone.0065470.].

Structural integrity and postconcussion syndrome in mild traumatic brain injury patients.

The presence of a postconcussion syndrome (PCS) induces substantial socio-professional troubles in mild traumatic brain injury (mTBI) patients. Although the exact origin of these disorders is not known, they may be the consequence of diffuse axonal injury (DAI) impacting structural integrity. In the present study, we compared structural integrity at the subacute and late stages after mTBI and in case of PCS, using diffusion-weighted imaging (DWI). Fifty-three mTBI patients were investigated and compared with 40 healthy controls. All patients underwent a DWI examination at the subacute (8-21 days) and late (6 months) phases after injury. MTBI patients with PCS were detected at the subacute phase using the ICD-10 classification. Groupwise differences in structural integrity were investigated using Tract-Based Spatial Statistics (TBSS). A loss of structural integrity was found in mTBI patients at the subacute phase but partially resolved over time. Moreover, we observed that mTBI patients with PCS had greater and wider structural impairment than patients without PCS. These damages persisted over time for PCS patients, while mTBI patients without PCS partly recovered. In conclusion, our results strengthen the relationship between structural integrity and PCS.