Research
Simultaneous brain & spinal cord qMRI to assess focal and remote neurodegeneration after SCI
This project aims to enable the simultaneous analysis of brain and spinal cord MRI data in order to understand the focal and remote neurodegeneration induced by a SCI. We use a new template that incorporates the brain and spinal cord in order to perform voxel-wise statistical analysis within the SPM framework (Blaiotta et al 2018, Neuroimage). The clinical validity of the pipeline has been demonstrated (Azzarito et al 2020, HBM). This approach revealed trauma-induced changes across the sensorimotor system in the cord and brain in SCI patients, comparable to conventional analysis methods. This unique method will also be used to assess the dynamic neurodegenerative processes in the spinal cord and brain post-SCI (Freund et al 2019, Lancet Neurology). Preliminary results indicate that over 5 years atrophy endures both at the level of the spinal cord and brain. It is also envisioned to apply this tool to patients suffering from multiple sclerosis in collaboration with UCSF.
NISCI: Antibodies against Nogo-A to enhance regeneration and functional recovery after acute spinal cord injury, a multicenter European clinical proof of concept trial
This project aims to apply a novel qMRI protocol covering brain and cervical cord down to C4 level as a sub-study within the clinical trial NISCI (www.nisci-2020.eu) to identify iron and myelin-changes in the spinal cord and brain and correlate them to the level of deficit and functional improvement of the patients in the two treatment groups (ATI355 vs. placebo). The NISCI clinical trial is a state-of-the-art placebo-controlled multicentric phase II clinical trial in a consortium of seven leading European SCI centers to assess the efficacy of anti-Nogo-A antibody therapy to significantly improve the neurological recovery and functional outcome of spinal cord injured patients.
The multi-parameter mapping has been optimized for the application on clinical 3T scanners based on product sequences (1 mm isotropic resolution, scanning time <25 min) (Leutritz et al., 2020, HBM). To evaluate the protocol setup for consistency between and within sites (test-retest) we performed a traveling heads study with five healthy subjects across six sites, involving different scanner hard- and software with five healthy subjects across six sites, involving different scanner hard- and software (Leutritz et al., 2020, HBM, 41:42 32– 4247). For processing the data we used the hMRI-toolbox (www.hmri.info) for quantitative MRI data, which is developed by the MPI-CBS and an international consortium (Tabelow et al., 2019, NeuroImage, 194, 191-210). This study is supported by Horizon 2020 Framework Programme, 681094.
In this project, we investigate the metabolic changes above and below the level of injury and in distinctive brain regions of spinal cord injury (SCI) and degenerative cervical myelopathy (DCM) patients. A detailed characterization of these metabolic changes occurring along the whole neuraxis after traumatic and non-traumatic SCI is crucial to acquire information about the underlying alterations driving degeneration and reorganization in patients after injury. The understanding of not only structural but also molecular changes is of high importance when it comes to the diagnostic workup and outcome prediction in these patients. Moreover, we explore the metabolic profile of the uninjured cervical and lumbar cord in longitudinal studies by following these molecular changes over a certain period of time post-injury. We aim to assess the relationship of these biomarkers to lesion severity, clinical impairments, the emergence of neuropathic pain, and neurological recovery. Such sensitive and valid metabolic biomarkers hold the potential to improve outcome prediction and patient stratification in future clinical trials. This project is funded by the International Foundation for Research in Paraplegia (IRP-P158).
Spinal cord and brain at 7T using qMRI
This project aims to assess the reproducibility of ultra-high field qMRI and resting-state fMRI of the cervical spinal cord and brain at 7T scanner in a multi-center study, with Zurich as coordinating center. Ultra-high field MRI is currently an emerging field, with the first clinical 7T MR system in Switzerland installed at the Balgrist Campus. Compared to conventional clinical MR systems, ultra-high field MRI yields higher image resolution and enhanced tissue contrast. Having validated and proven imaging protocols is a necessary first step to adopt ultra-high field MRI for clinical use. We will further compare vital performance indicators between different 7T cervical spine coils, including both custom-built coils and commercial alternatives. A direct comparison of the performance of various coil designs is instrumental to ensure optimal data quality and guide future coil development.
This project aims to apply quantitative MRI (qMRI) techniques, such as intra voxel incoherent motion (IVIM) MRI (estimates blood perfusion in tissue) and quantitative BOLD (qBOLD) (estimates change of (de-) oxyhaemoglobin molecules) allow quantifying in-vivo hemodynamics in the injured spinal cord. SCI and DCM share several phathophysiological processes, including complex hemodynamic impairments at the epicentre of the injury/lesion. Cord hemodynamic impairments contribute to neuronal deficits and consequently clinical impairments after SC. Crucially, experimental evidence suggests that impaired blood flow and hypoxia does not only affect the focal injury site, but also the spinal cord remote to the level of injury. However, how hemodynamics evolves at and beyond the level of lesion and relate to clinical impairments in human SCI is understudied. This qMRI techniques can benefit from ultra-high field (UHF) systems (i.e. 7 Tesla scanner) in patients with no metal implants which enable very high image resolution and contrast. We hypothesise that the impairment of cord perfusion and oxygenation will be variable following SCI and extent beyond the focal lesion area (i.e. above the level of injury). Less hemodynamic impairments (e.g. better tissue oxygenation) will be associated with better clinical outcome and recovery after injury in traumatic and non-traumatic SCI patients. This study is supported by Wing for Life (WFL-CH-19/20)
Tracking sensorimotor impairment after focal CNS lesions
In this project, we explore changes in sensory and motor information flow and processing between the brain and cervical spinal cord in different central nervous system (CNS) pathologies. Usually, CNS disorders like spinal cord injury (SCI), stroke, or multiple sclerosis (MS) lead to an altered flow of incoming (i.e. afferent) and outgoing (i.e. efferent) information and to severe changes of its processing at multiple levels along the neuraxis. To improve treatment of patient population-specific deficits and dysfunctions, we need to better understand the CNS levels involved in and the mechanisms underlying such altered information flow. Here we examine the coupling between brain, spinal cord, and body during impaired dexterous movements and pathological pain processing in SCI, Stroke, or MS patients by means of simultaneous brain and spinal cord fMRI.
By fusing innovative neuroimaging techniques with impairment-related motor tasks or sensory stimulations, we will be measuring the effective connectivity between different neuronal networks in the CNS. Thereby we try to identify the key regions malfunctioning in sensorimotor information processing and integration which are generally affected in prominent disorders and diseases of the CNS such as SCI, stroke, or MS. A more detailed characterization and better understanding of signal transmission deficiency and dysfunctions along the whole neuraxis has the potential to foster the development of specific therapeutic approaches and interventions. This project is funded by the Swiss National Science Foundation (143715).
Brain (re)organisation following major sensory input loss
This project aims to assess how map-like brain representations may change and/or stay remarkably similar following spinal cord injury. This project is led by the Neural Control of Movement lab at ETH Zürich (Department of Health Sciences and Technology), in collaboration with the Neuroimaging group at Balgrist. Following spinal cord injury, the brain is deprived of sensory input from and motor output to the limb(s). Non-human primate studies demonstrated that this leads to extensive reorganisation in brain areas containing detailed map-like body representations (e.g. the primary somatosensory cortex), such that neighbouring body-part representations (e.g. of the face) “invade” the area deprived of input and/or output (e.g. of the hand). The assumption of drastic reorganisation in humans remains highly influential both in the neuroscientific literature and the clinic: reorganisation of affected areas is thought to drive both recovery of function and the formation of maladaptive neuronal circuitry that relate to neuropathic pain. Using a new experimental approach in arm amputees, it was recently demonstrated that functional representations of the missing hand are preserved in the “deprived” area of the somatosensory cortex, a finding that challenges widely held assumptions of brain organisation and reorganisation. However, how can such topographic representations be preserved, even decades after sensory input loss and cortical reorganisation? In this research project, we use functional magnetic resonance imaging (fMRI) in tetraplegic spinal cord injury patients to better understand these processes and examine how they may interact.
In this project, we aim to implement a lumbar fMRI technique to track sensorimotor function in the lumbosacral cord after spinal cord injury (SCI). Functional MRI (fMRI) is a non-invasive technique to probe neuronal activity at a high spatial resolution. fMRI has been routinely applied in the brain and (since more recently) in the cervical spine to investigate motor, sensory, and cognitive function. However, direct adoption of fMRI in the lumbosacral cord is challenging due to the lower size of the cord, lower signal to noise ratio, and higher level of breathing artifacts. The established lumbar fMRI protocol enables us to measure remaining sensorimotor function after incomplete SCI in the lumbar cord at a high spatial specificity. Motor-related activities at L2-S1 are compared to healthy volunteers. Alterations in the activation pattern of the lumbar gray matter will shed light on the trans-synaptic neurodegeneration of the lower motor neurons occurring after SCI.
We started our effort to develop a lumbar fMRI protocol by optimizing the anatomical reference scan. A high-resolution axial reference scan with good gray and white matter contrast is necessary for signal localization and region of interest definition (for example, localizing the ventral horn at L4 neurological level). In particular, we found that a 3D multi-echo gradient-echo sequence provides good time-efficiency, tolerable artifact level, and allows high in-plane resolution in the lumbosacral cord. We performed parameter tuning to find optimal trade-off between gray/white matter contrast, white matter/liquor contrast, and artifact level. The implemented sequence encompasses the whole lumbosacral region (lumbar enlargement plus conus medullaris) by 20 slices of 5 mm
This project aims to implement an advanced quantitative MRI (qMRI) protocol for the brain and spinal cord in traumatic SCI and DCM patients at three international sites (Balgrist University Hospital, Zurich Switzerland, Toronto Western Hospital, Canada; Central MRI center Institute of Neurology, UCL London, UK) on 3 Tesla MRI scanners based on two different vendors. We will assess sensitivity of specific quantitative measurements to spinal cord damage at all centers to confirm the relevance of each technique for clinical assessment, patient management and ultimately clinical outcome. Analysis will provide quantitative measures sensitive to lesion size and location, axonal loss through atrophy and diffusion-derived indices, myelin damage through magnetization transfer properties of tissue, all measured at cervical cord level and distally in the brain. Data will offer great scope for models of progression and further advanced analysis. We setup an acquisition and analysis pipeline with clearly defined standard operating procedures (SOP) that will be the basis for future studies and possible clinical trials, establishing much needed expertise in multi-centre spinal cord imaging. This study is supported by Wings for Life (WFL-CH-007/14)
Pro-CSM
The prospective Pro-CSM study follows patients with degenerative cervical myelopathy (DCM) by morphometric and phase contrast MRI to assess the impact of spinal cord movement as biomarker in DCM. Patients are followed by a standardized clinical (AIS, mJOA, Nurick Score SCIM) and neurophysiological (dermatomal SEPs, contact heat evoked potentials, CHEPs) protocol for 5 years.
The spinal cord is subject to a periodic, cardiac-related movement, which is increased at the level of a cervical stenosis. Increased oscillations may exert mechanical stress on spinal cord tissue causing intramedullary damage. Motion analysis thus holds promise as a biomarker related to disease progression in degenerative cervical myelopathy. Our aim is characterization of the cervical spinal cord motion in patients with degenerative cervical myelopathy.
The Pro-CSM study is a collaboration of the University Spine Center Zurich and is funded by the Balgrist foundation.
Myelination, a proxy for motor skill learning?
This project deals with training-induced brain plasticity. Draganski et al. in their 2004 report in Nature first reported grey matter volume increase in response to acquisition of juggling skill by volumetric MRI. Multiple confirmations of this effect followed, but initial intense interest waned as the limitations of non-quantitative measures were reached and the neural tissue responses underlying skill acquisition remained unproven. In this project, we apply novel microstructural MRI methods at 3T to describe, in unprecedented temporal and spatial detail, the effect of motor learning on the human brain at the tissue level in vivo. In healthy controls we report widespread transient and linear changes in both volumetric and myelin-related signals in both the grey and white matter of the corticospinal and limbic systems in healthy individuals as they learn to master a complex motor task. The dynamic temporal and spatial interactions reveal coherent (i.e., correlated but time-lagged) waves of plasticity during motor learning, with brain areas responding in an elegant, choreographed fashion. Moreover, there is indication of a somatotopy of learning in the corticospinal tract at the level of the capsule interna as patients being trained on the lower limbs exhibited more myelination than controls trained on the upper limb (Azzarito et al., 2021, under review). We next embark on patient studies suffering from non-traumatic SCI at 7T.