Coherent, time-shifted patterns of microstructural plasticity during motor-skill learning.

Motor skill learning relies on neural plasticity in the motor and limbic systems. However, the spatial and temporal characteristics of these changes-and their microstructural underpinnings-remain unclear. Eighteen healthy males received 1 h of training in a computer-based motion game, 4 times a week, for 4 consecutive weeks, while 14 untrained participants underwent scanning only. Performance improvements were observed in all trained participants. Serial myelin- and iron-sensitive multiparametric mapping at 3T during this period of intensive motor skill acquisition revealed temporally and spatially distributed, performance-related microstructural changes in the grey and white matter across a corticospinal-cerebellar-hippocampal circuit. Analysis of the trajectory of these transient changes suggested time-shifted cascades of plasticity from the dominant sensorimotor system to the contralateral hippocampus. In the cranial corticospinal tracts, changes in myelin-sensitive metrics during training in the posterior limb of the internal capsule were of greater magnitude in those who trained their upper limbs vs. lower limb trainees. Motor skill learning is associated with waves of grey and white matter plasticity, across a broad sensorimotor network.

Quantitative MRI of rostral spinal cord and brain regions is predictive of functional recovery in acute spinal cord injury.

Objective: To reveal the immediate extent of trauma-induced neurodegenerative changes rostral to the level of lesion and determine the predictive clinical value of quantitative MRI (qMRI) following acute spinal cord injury (SCI). Methods: Twenty-four acute SCI patients and 23 healthy controls underwent a high-resolution T1-weighted protocol. Eighteen of those patients and 20 of controls additionally underwent a multi-parameter mapping (MPM) MRI protocol sensitive to the content of tissue structure, including myelin and iron. Patients were examined clinically at baseline, 2, 6, 12, and 24 months post-SCI. We assessed volume and microstructural changes in the spinal cord and brain using T1-weighted MRI, magnetization transfer (MT), longitudinal relaxation rate (R1), and effective transverse relaxation rate (R2*) maps. Regression analysis determined associations between acute qMRI parameters and recovery. Results: At baseline, cord area and its anterior-posterior width were decreased in patients, whereas MT, R1, and R2* parameters remained unchanged in the cord. Within the cerebellum, volume decrease was paralleled by increases of MT and R2* parameters. Early grey matter changes were observed within the primary motor cortex and limbic system. Importantly, early volume and microstructural changes of the cord and cerebellum predicted functional recovery following injury. Conclusions: Neurodegenerative changes rostral to the level of lesion occur early in SCI, with varying temporal and spatial dynamics. Early qMRI markers of spinal cord and cerebellum are predictive of functional recovery. These neuroimaging biomarkers may supplement clinical assessments and provide insights into the potential of therapeutic interventions to enhance neural plasticity.

Progressive neurodegeneration following spinal cord injury: Implications for clinical trials.

OBJECTIVE: To quantify atrophy, demyelination, and iron accumulation over 2 years following acute spinal cord injury and to identify MRI predictors of clinical outcomes and determine their suitability as surrogate markers of therapeutic intervention. METHODS: We assessed 156 quantitative MRI datasets from 15 patients with spinal cord injury and 18 controls at baseline and 2, 6, 12, and 24 months after injury. Clinical recovery (including neuropathic pain) was assessed at each time point. Between-group differences in linear and nonlinear trajectories of volume, myelin, and iron change were estimated. Structural changes by 6 months were used to predict clinical outcomes at 2 years. RESULTS: The majority of patients showed clinical improvement with recovery stabilizing at 2 years. Cord atrophy decelerated, while cortical white and gray matter atrophy progressed over 2 years. Myelin content in the spinal cord and cortex decreased progressively over time, while cerebellar loss decreases decelerated. As atrophy progressed in the thalamus, sustained iron accumulation was evident. Smaller cord and cranial corticospinal tract atrophy, and myelin changes within the sensorimotor cortices, by 6 months predicted recovery in lower extremity motor score at 2 years. Whereas greater cord atrophy and microstructural changes in the cerebellum, anterior cingulate cortex, and secondary sensory cortex by 6 months predicted worse sensory impairment and greater neuropathic pain intensity at 2 years. CONCLUSION: These results draw attention to trauma-induced neuroplastic processes and highlight the intimate relationships among neurodegenerative processes in the cord and brain. These measurable changes are sufficiently large, systematic, and predictive to render them viable outcome measures for clinical trials.

In cervical spondylotic myelopathy spinal cord motion is focally increased at the level of stenosis: a controlled cross-sectional study.

STUDY DESIGN: Level-, age-, and gender-matched controlled cross-sectional cohort study. OBJECTIVES: To investigate alterations of spinal cord (SC) motion within cervical spondylotic myelopathy (CSM) across the cervical spinal segments and its relation to cerebrospinal fluid (CSF)-flow, anatomic conditions, and clinical parameters. SETTING: University Hospital Balgrist, Zurich, Switzerland. METHODS: Overall, 12 patients suffering from CSM at level C5 and 12 controls underwent cardiac-gated 2D phase-contrast-MRI at level C2 and C5 and standard MRI sequences. Parameters of interest: Velocity measurements of SC and CSF (area under the curve = total displacement (normalization for duration of the heart cycle), total displacement ratio (C5/C2; intraindividual normalization for confounders)), spinal canal diameters, clinical motor- and sensory scores, and performance measures. RESULTS: Interrater reliability was excellent for SC motion at both levels and for CSF flow at C2, but not reliable for CSF flow at C5. Within controls, SC motion at C2 positively correlated with SC motion at C5 (p = 0.000); this correlation diminished in patients (p = 0.860). SC total displacement ratio was significantly increased in patients (p = 0.029) and correlated with clinical impairment (p = 0.017). Morphometric measures of the extent of stenosis were not related to SC motion or clinical symptoms. CONCLUSION: The findings revealed physiological interactions of CSF flow and SC motion across the cervical spine in healthy controls while being diminished in CSM patients. Findings of focally increased SC motion at the level of stenosis were related to clinical impairment and might be promising as a diagnostic and prognostic marker in CSM. SPONSORSHIP: CRPP Neurorehab of the University of Zurich, Switzerland.

Relationship between brainstem neurodegeneration and clinical impairment in traumatic spinal cord injury.

BACKGROUND: Brainstem networks are pivotal in sensory and motor function and in recovery following experimental spinal cord injury (SCI). OBJECTIVE: To quantify neurodegeneration and its relation to clinical impairment in major brainstem pathways and nuclei in traumatic SCI. METHODS: Quantitative MRI data of 30 chronic traumatic SCI patients (15 with tetraplegia and 15 with paraplegia) and 23 controls were acquired. Patients underwent a full neurological examination. We calculated quantitative myelin-sensitive (magnetisation transfer saturation (MT) and longitudinal relaxation rate (R1)) and iron-sensitive (effective transverse relaxation rate (R2*)) maps. We constructed brainstem tissue templates using a multivariate Gaussian mixture model and assessed volume loss, myelin reductions, and iron accumulation across the brainstem pathways (e.g. corticospinal tracts (CSTs) and medial lemniscus), and nuclei (e.g. red nucleus and periaqueductal grey (PAG)). The relationship between structural changes and clinical impairment were assessed using regression analysis. RESULTS: Volume loss was detected in the CSTs and in the medial lemniscus. Myelin-sensitive MT and R1 were reduced in the PAG, the CSTs, the dorsal medulla and pons. No iron-sensitive changes in R2* were detected. Lower pinprick score related to more myelin reductions in the PAG, whereas lower functional independence was related to more myelin reductions in the vestibular and pontine nuclei. CONCLUSION: Neurodegeneration, indicated by volume loss and myelin reductions, is evident in major brainstem pathways and nuclei following traumatic SCI; the magnitude of these changes relating to clinical impairment. Thus, quantitative MRI protocols offer new targets, which may be used as neuroimaging biomarkers in treatment trials.

Neurodegeneration in the Spinal Ventral Horn Prior to Motor Impairment in Cervical Spondylotic Myelopathy.

Remote gray matter pathology has been suggested rostral to the compression site in cervical spondylotic myelopathy (CSM). We therefore assessed neurodegeneration in the gray matter ventral and dorsal horns. Twenty patients with CSM and 18 healthy subjects underwent a high-resolution structural and diffusion magnetic resonance imaging protocol at vertebra C2/C3. Patients received comprehensive clinical assessments. T2*-weighted data provided cross-sectional area measurements of gray matter ventral and dorsal horns to identify atrophy. At the identical location, mean diffusivity (MD) and fractional anisotropy (FA) determined the microstructural integrity. Finally, the relationships between neurodegeneration occurring in the gray and white matter and clinical impairment were investigated. Patients suffered from mild-to-moderate CSM with mainly sensory impairment. In the ventral horns, cross-sectional area was not reduced (p = 0.863) but MD was increased (p = 0.045). The magnitude of MD changes within the ventral horn was associated with white matter diffusivity changes (MD: p = 0.013; FA: p = 0.028) within the lateral corticospinal tract. In contrast, dorsal horn cross-sectional area was reduced by 16.0% (p < 0.001) without alterations in diffusivity indices, compared with controls. No associations between the magnitude of ventral and dorsal horn neurodegeneration and clinical impairment were evident. Focal cord gray matter pathology is evident remote to the compression site in vivo in CSM patients. Microstructural changes in the ventral horns (i.e., motoneurons) related to corticospinal tract integrity in the absence of atrophy and marked motor impairment. Dorsal horn atrophy corresponded to main clinical representation of sensory impairment. Thus, neuroimaging biomarkers of cord gray matter integrity reveal focal neurodegeneration prior to marked clinical impairment and thus could serve as predictors of ensuing impairment in CSM patients.

Voxel-based analysis of grey and white matter degeneration in cervical spondylotic myelopathy.

In this prospective study, we made an unbiased voxel-based analysis to investigate above-stenosis spinal degeneration and its relation to impairment in patients with cervical spondylotic myelopathy (CSM). Twenty patients and 18 controls were assessed with high-resolution MRI protocols above the level of stenosis. Cross-sectional areas of grey matter (GM), white matter (WM), and posterior columns (PC) were measured to determine atrophy. Diffusion indices assessed tract-specific integrity of PC and lateral corticospinal tracts (CST). Regression analysis was used to reveal relationships between MRI measures and clinical impairment. Patients showed mainly sensory impairment. Atrophy was prominent within the cervical WM (13.9%, p = 0.004), GM (7.2%, p = 0.043), and PC (16.1%, p = 0.005). Fractional anisotropy (FA) was reduced in the PC (-11.98%, p = 0.006) and lateral CST (-12.96%, p = 0.014). In addition, radial (+28.47%, p = 0.014), axial (+14.72%, p = 0.005), and mean (+16.50%, p = 0.001) diffusivities were increased in the PC. Light-touch score was associated with atrophy (R(2) = 0.3559, p = 0.020) and FA (z score 3.74, p = 0.003) in the PC, as was functional independence and FA in the lateral CST (z score 3.68, p = 0.020). This study demonstrates voxel-based degeneration far above the stenosis at a level not directly affected by the compression and provides unbiased readouts of tract-specific changes that relate to impairment.

Tracking sensory system atrophy and outcome prediction in spinal cord injury.

OBJECTIVE: In patients with subacute spinal cord injury (SCI), the motor system undergoes progressive structural changes rostral to the lesion, which are associated with motor outcome. The extent to which the sensory system is affected and how this relates to sensory outcome are uncertain. METHODS: Changes in the sensory system were prospectively followed by applying a comprehensive magnetic resonance imaging (MRI) protocol to 14 patients with subacute traumatic SCI at baseline, 2 months, 6 months, and 12 months after injury, combined with a full neurological examination and comprehensive pain assessment. Eighteen controls underwent the same MRI protocol. T1-weighted volumes, myelin-sensitive magnetization transfer saturation (MT), and longitudinal relaxation rate (R1) mapping provided data on spinal cord and brain morphometry and microstructure. Regression analysis assessed the relationship between MRI readouts and sensory outcomes. RESULTS: At 12 months from baseline, sensory scores were unchanged and below-level neuropathic pain became prominent. Compared with controls, patients showed progressive degenerative changes in cervical cord and brain morphometry across the sensory system. At 12 months, MT and R1 were reduced in areas of structural decline. Sensory scores at 12 months correlated with rate of change in cord area and brain volume and decreased MT in the spinal cord at 12 months. INTERPRETATION: This study has demonstrated progressive atrophic and microstructural changes across the sensory system with a close relation to sensory outcome. Structural MRI protocols remote from the site of lesion provide new insights into neuronal degeneration underpinning sensory disturbance and have potential as responsive biomarkers of rehabilitation and treatment interventions.

Relationship between structural brainstem and brain plasticity and lower-limb training in spinal cord injury: a longitudinal pilot study.

Rehabilitative training has shown to improve significantly motor outcomes and functional walking capacity in patients with incomplete spinal cord injury (iSCI). However, whether performance improvements during rehabilitation relate to brain plasticity or whether it is based on functional adaptation of movement strategies remain uncertain. This study assessed training improvement-induced structural brain plasticity in chronic iSCI patients using longitudinal MRI. We used tensor-based morphometry (TBM) to analyze longitudinal brain volume changes associated with intensive virtual reality (VR)-augmented lower limb training in nine traumatic iSCI patients. The MRI data was acquired before and after a 4-week training period (16-20 training sessions). Before training, voxel-based morphometry (VBM) and voxel-based cortical thickness (VBCT) assessed baseline morphometric differences in nine iSCI patients compared to 14 healthy controls. The intense VR-augmented training of limb control improved significantly balance, walking speed, ambulation, and muscle strength in patients. Retention of clinical improvements was confirmed by the 3-4 months follow-up. In patients relative to controls, VBM revealed reductions of white matter volume within the brainstem and cerebellum and VBCT showed cortical thinning in the primary motor cortex. Over time, TBM revealed significant improvement-induced volume increases in the left middle temporal and occipital gyrus, left temporal pole and fusiform gyrus, both hippocampi, cerebellum, corpus callosum, and brainstem in iSCI patients. This study demonstrates structural plasticity at the cortical and brainstem level as a consequence of VR-augmented training in iSCI patients. These structural changes may serve as neuroimaging biomarkers of VR-augmented lower limb neurorehabilitation in addition to performance measures to detect improvements in rehabilitative training.

Library-based discovery of DYRK1A/CLK1 inhibitors from natural product extracts.

The dual specificity tyrosine-phosphorylation-regulated kinase DYRK1A possesses diverse roles in neuronal development and adult brain physiology, and increased activity has been linked to neurodegenerative diseases. Very few inhibitors of this kinase have been reported up to now. Screening of a library of > 900 plant and fungal extracts afforded 25 extracts with IC50s < 10 µg/mL against DYRK1A. To identify the active constituents, the extracts were submitted to a process integrating physicochemical data with biological information, referred to as HPLC-based activity profiling. Follow-up investigation of four extracts led to the targeted isolation of harmine (1, IC50 0.022 µM) from Peganum harmala, emodin (3, IC50 4.2 µM) from Cassia nigricans, kaempferol (4, IC50 0.91 µM) from Cuscuta chinensis, and 3,8-di-O-methylherbacetin (11, IC50 8.6 µM), 3,3',4'-tri-O-methylmyricetin (12, IC50 7.1 µM) and ombuin (15, IC50 1.7 µM) from Larrea tridentata as the active constituents. Active extracts and compounds were also tested on the closely related cdc2-like kinase CLK1. Finally, the selectivity profile of compounds was evaluated by including other members of the DYRKs and CLKs families. While the flavonoids and emodin did not show significant differences in the potency of their activities, harmine (1) was most active against DYRK1A, CLK1, and CLK4, and less potent against the other kinases, with selectivity ranging from 2- to 20-fold.