Cassandra Sampaio-Baptista

Background Corticospinal tract (CST) integrity, assessed using diffusion weighted MR imaging, has frequently been associated with motor impairment following stroke. However, which specific biological features contribute to this relationship remains unknown. In the current paper we used quantitative multimodal imaging to shed light on the biophysical properties underlying this relationship in the CST and explore additional whole brain relationships with motor impairment. Methods Twenty-seven chronic stroke survivors underwent MRI scanning, including multi-shell diffusion weighted imaging and quantitative Multi-Parameter Mapping, from which we derived ten metrics, sensitive to different microstructure properties. We tested the relationship between these MRI metrics and stroke survivors’ impairment scores on the Upper-Extremity Fugl Meyer (UE-FM), using multimodal and unimodal statistical inference, in both the CST and across the whole brain. Results Using an ROI approach to replicate and extend on previous findings, a joint multimodal analysis revealed that greater CST microstructure asymmetry was associated with worse motor impairment. The strongest relationships were found between impairment and several modalities sensitive to free water and myelination. This result was further confirmed using a voxel-wise approach. Beyond the CST, modalities sensitive to free water, myelination and the Neurite Density Index, were also found to be related to motor impairment, particularly in the superior longitudinal fasciculus, corpus callosum and thalamic radiations, with magnetisation transfer saturation showing the strongest relationship in these areas. Conclusion Modalities that are sensitive to myelin and free water exhibited the most significant correlation with motor impairment. This suggests that these specific biological features may account for the previously identified relationships between diffusion metrics and motor impairments. Myelin metrics in particular were also highly correlated with motor impairment in other brain regions. This study illustrates the advantages of using multimodal data to identify more specific biological factors that contribute to motor impairment in stroke patients.

Oligodendrocytes continue to differentiate from their precursor cells even in adulthood, a process that can be modulated by neuronal activity and experience. Previous work has indicated that conditional ablation of oligodendrogenesis in adult mice leads to learning and memory deficits in a range of behavioral tasks. The current study replicated and re‐evaluated evidence for a role of oligodendrogenesis in motor learning, using a complex running wheel task. Further, we found that ablating oligodendrogenesis alters brain microstructure (ex vivo MRI) and brain activity (in vivo EEG) independent of experience with the task. This suggests a role for adult oligodendrocyte formation in the maintenance of brain function and indicates that task‐independent changes due to oligodendrogenesis ablation need to be considered when interpreting learning and memory deficits in this model.

Previous work has shown that motor skill learning stimulates and requires generation of myelinating oligodendrocytes (OLs) from their precursor cells (OLPs) in the brains of adult mice. In the present study we ask whether OL production is also required for non-motor learning and cognition, using T-maze and radial-arm-maze tasks that tax spatial working memory. We find that maze training stimulates OLP proliferation and OL production in the medial prefrontal cortex (mPFC), anterior corpus callosum (genu), dorsal thalamus and hippocampal formation of adult male mice; myelin sheath formation is also stimulated in the genu. Genetic blockade of OL differentiation and neo-myelination inMyrfconditional-knockout mice strongly impairs training-induced improvements in maze performance. We find a strong positive correlation between the performance of individual wild type mice and the scale of OLP proliferation and OL generation during training, but not with the number or intensity of c-Fos⁺neurons in their mPFC, underscoring the important role played by OL lineage cells in cognitive processing.

Oligodendrocytes continue to differentiate from their precursor cells even in adulthood, a process that can be modulated by neuronal activity and experience. Yet, our understanding of the functional role of adult oligodendrogenesis remains limited. Previous work has indicated that conditional ablation of oligodendrogenesis in adult mice can lead to learning and memory deficits in a range of behavioural tasks. Our results, reported here, have replicated a key finding that learning to run on a complex wheel with unevenly spaced rungs is disrupted by ablation of oligodendrogenesis. However, using ex vivo MRI (MTR and DTI), we also found that ablating oligodendrogenesis by itself alters brain microstructure, independent of behavioural experience. Furthermore, in vivo EEG recording in behaviourally naïve mice with ablated oligodendrogenesis revealed altered brain activity in the form of increased EEG power density across a broad frequency range. Together, our data indicate that disrupting the formation of new oligodendrocytes directly alters brain microstructure and activity. This suggests a role for adult oligodendrogenesis in the maintenance of brain function and indicates that task-independent changes to brain structure and function might contribute to the learning and memory deficits associated with oligodendrogenesis ablation.

Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows for comparisons with data modalities collected under invasive or terminal procedures. Currently, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. Here we introduce StandardRat, a consensus rat functional magnetic resonance imaging acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired from rats across 46 centers. We developed a reproducible pipeline for analyzing rat data acquired with diverse protocols and determined experimental and processing parameters associated with the robust detection of functional connectivity across centers. We show that the standardized protocol enhances biologically plausible functional connectivity patterns relative to previous acquisitions. The protocol and processing pipeline described here is openly shared with the neuroimaging community to promote interoperability and cooperation toward tackling the most important challenges in neuroscience.

Real-time functional MRI neurofeedback allows individuals to self-modulate their ongoing brain activity. This may be a useful tool in clinical disorders that are associated with altered brain activity patterns. Motor impairment after stroke has previously been associated with decreased laterality of motor cortex activity. Here we examined whether chronic stroke survivors were able to use real-time fMRI neurofeedback to increase laterality of motor cortex activity and assessed effects on motor performance and on brain structure and function. We carried out a randomized, double-blind, sham-controlled trial (ClinicalTrials.gov: NCT03775915) in which 24 chronic stroke survivors with mild to moderate upper limb impairment experienced three training days of either Real (n = 12) or Sham (n = 12) neurofeedback. Assessments of brain structure, brain function and measures of upper-limb function were carried out before and 1 week after neurofeedback training. Additionally, measures of upper-limb function were repeated 1 month after neurofeedback training. Primary outcome measures were (i) changes in lateralization of motor cortex activity during movements of the stroke-affected hand throughout neurofeedback training days; and (ii) changes in motor performance of the affected limb on the Jebsen Taylor Test (JTT). Stroke survivors were able to use Real neurofeedback to increase laterality of motor cortex activity within (P = 0.019), but not across, training days. There was no group effect on the primary behavioural outcome measure, which was average JTT performance across all subtasks (P = 0.116). Secondary analysis found improvements in the performance of the gross motor subtasks of the JTT in the Real neurofeedback group compared to Sham (P = 0.010). However, there were no improvements on the Action Research Arm Test or the Upper Extremity Fugl–Meyer score (both P > 0.5). Additionally, decreased white-matter asymmetry of the corticospinal tracts was detected 1 week after neurofeedback training (P = 0.008), indicating that the tracts become more similar with Real neurofeedback. Changes in the affected corticospinal tract were positively correlated with participants neurofeedback performance (P = 0.002). Therefore, here we demonstrate that chronic stroke survivors are able to use functional MRI neurofeedback to self-modulate motor cortex activity in comparison to a Sham control, and that training is associated with improvements in gross hand motor performance and with white matter structural changes.

Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows comparison with invasive or terminal procedures. To date, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. We introduce StandardRat , a consensus rat functional MRI acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired in rats from 46 centers. We developed a reproducible pipeline for the analysis of rat data acquired with diverse protocols and determined experimental and processing parameters associated with a more robust functional connectivity detection. We show that the standardized protocol enhances biologically plausible functional connectivity patterns, relative to pre-existing acquisitions. The protocol and processing pipeline described here are openly shared with the neuroimaging community to promote interoperability and cooperation towards tackling the most important challenges in neuroscience.

Real-time functional magnetic resonance imaging (fMRI) neurofeedback allows individuals to self-modulate their ongoing brain activity. This may be a useful tool in clinical disorders which are associated with altered brain activity patterns. Motor impairment after stroke has previously been associated with decreased laterality of motor cortex activity. Here we examined whether chronic stroke survivors were able to use real-time fMRI neurofeedback to increase laterality of motor cortex activity and assessed effects on motor performance and on brain structure and function. We carried out a randomized, double-blind, sham-controlled trial in which 24 chronic stroke survivors with mild to moderate upper limb impairment experienced three training days of either Real (n=12) or Sham (n=12) neurofeedback. Stroke survivors were able to use Real neurofeedback to increase laterality of motor cortex activity within, but not across, training days. Improvement in gross hand motor performance assessed by the Jebsen Taylor Test (JTT) was observed in the Real neurofeedback group compared to Sham. However, there were no improvements on the Action Research Arm Test (ARAT) or the Upper Extremity Fugl-Meyer (UE-FM) score. Additionally, decreased white-matter asymmetry of the corticospinal tracts was detected 1-week after neurofeedback training, indicating that the tracts become more similar with Real neurofeedback. Changes in the affected corticospinal tract was positively correlated with neurofeedback performance. Therefore, here we demonstrate that chronic stroke survivors are able to use fMRI neurofeedback to self-modulate motor cortex activity, and that training is associated with improvements in hand motor performance and with white matter structural changes.