Determining patterns of post-stroke motor recovery through longitudinal multimodal MRI: A step towards patient stratification

Motivated by the need for a better understanding of post-stroke recovery and new biomarkers to improve stroke patient stratification and outcomes, this thesis investigated structure-function coupling and its role in post-stroke recovery. Furthermore, in order to increase data comparability between sessions and centers (a critical challenge in contemporary clinical research), this thesis assessed the reproducibility of microstructure-informed structural connectivity measures in a multi-center dataset.Stroke is one of the major sources of permanent impairment, frequently of motor origin. However the clinical picture is very heterogeneous: patients show divergent courses of recovery and the underlying mechanisms are still unclear. In addition, current treatments still have limited success and are restricted to a 'one-fits-all' approach, not considering the individual patient's phenotype. As efforts to stratify patients based on structural or functional biomarkers are still needed, we chose to investigate the potential of a multimodal biomarker, the Structural Decoupling Index (SDI) (Preti & Van De Ville, 2019b), a new metric assessing the structure-function coupling strength in the brain. The first part (Studies 1 and 2) of this thesis investigates the potential of the SDI as a biomarker. In Study 1, the goals were to evaluate the feasibility of applying the SDI on an individual level in healthy older adults and to investigate the effect of an acute stroke on it. Consistent with the literature, we found a network gradient of SDI in healthy older adults, from high coupling in lower-level sensory areas, to low coupling in higher-level cognitive areas. This confirmed the applicability of SDI on an individual level. Furthermore, we showed that stroke impacts the SDI, with a higher decoupling on the ipsi- compared to the contralesional side, and with network-specific effects in RH stroke patients. In Study 2, the goal was to see whether the SDI evolved over time post-stroke and whether it links to behavior. The longitudinal analysis revealed differential network effects of stroke at T1 and T3. Furthermore, we showed that impairment in cognitive and psychological behavioral domains significantly correlates with variations in SDI in a number of key areas including motor regions (e.g., primary motor cortex) and that the brain pattern associated to behavior changes between T1 and T2. Surprisingly, motor performance did not explain variability in key motor areas (e.g., primary motor cortex). The link between post-stroke behavioral performance and SDI underlines its potential clinical relevance.Driven by the quest for more reproducible analysis pipelines in the context of longitudinal and clinical studies, the second part of this thesis (Study 3) addressed the subject-specific reproducibility and repeatability of microstructure-informed tractography. Through a multi-center study, we demonstrated its high reproducibility and subject-specificity, and we found evidence for increased biological accuracy. My thesis made a contribution by showing that the SDI is sensitive to pathophysiological changes that occur following a stroke and that it links to clinically relevant behavioral measures. In addition, it confirms the reproducibility and subject-specificity of microstructure-informed tractography. Together, my findings pave the way towards patient stratification and more personalized treatments in stroke rehabilitation.

Does one size fit all? - Towards the optimization and personalization of non-invasive brain stimulation paradigms to enhance motor learning

Laurijn Rianne Draaisma

The acquisition and re-acquisition of motor skills is an important aspect of daily life and in the recovery after a stroke. Non-invasive brain stimulation (NIBS) is a technique that is used to improve motor learning and enhance motor recovery in stroke survivors. Although the current results are promising, the outcomes are heterogeneous with responders and non-responders. This thesis aimed to investigate multiple, novel NIBS strategies to enhance stimulation efficacy and to develop approaches for protocol personalization. These alternative strategies include targeting other areas of the motor network than the primary motor cortex (M1), targeting the brain as a network with the use of multifocal stimulation, and using a variety of stimulation techniques (TMS, tACS, tDCS) to study underlying mechanisms. Study 1 explored the methodological implications of TMS for measuring inhibitory and excitatory neurotransmissions. With the use of TMS, short intracortical inhibition (SICI) and intracortical facilitation (ICF) were measured in healthy young adults. SICI and ICF were studied with different stimulators, waveforms, and current directions using a set of interstimulus intervals. Our findings indicated high comparability among the different stimulation paradigms, except for SICI at 3 ms, which enables data sharing across units and facilitates the conduction of multi-center studies.Study 2 measured the effect of 50 Hz tACS applied to the cerebellum on a novel motor learning task in healthy young adults. Targeting the cerebellum with NIBS is a relatively new field of research with open questions that need to be addressed. Therefore, we explored for the first time the effect of CB-tACS on a motor learning task. Our results did not show an improvement of learning with 50 Hz CB-tACS. We argue that this might have been related to the task and/or the selected stimulation frequency. Therefore, this stimulation paradigm requires further optimization to be effective for motor learning.Study 3 compared multifocal sequential stimulation to monofocal tDCS on motor learning in stroke patients. The multifocal paradigm consisted of an orchestrated M1 â CB stimulation setup, the monofocal paradigm targeted the M1. Our results indicated a significant effect of multifocal M1-CB stimulation, mainly driven by CB-tDCS during the early phase of learning. Moreover, baseline performance and neurophysiology were related to stimulation responsiveness that could potentially lead to biomarkers to predict stimulation efficacy in stroke patients.Study 4 measured the effect of personalized bifocal theta tACS applied to the FPN on motor learning in healthy older adults. Sequence learning has a cognitive component related to working memory (WM) capacity, a process mediated by the FPN. We hypothesized that targeting the FPN might be beneficial for motor learning. tACS to the FPN improved performance, when WM load was high, but not when WM-load was low. Therefore, we conclude that the FPN is a promising new target to enhance motor learning which might be most beneficial for individuals with decreased WM capacity due to age or stroke. In conclusion, this thesis demonstrates that targeting alternative motor network areas, and multifocal stimulation is promising. These results expand on the current knowledge of NIBS and identified open questions that require further examination but could ultimately lead towards enhanced efficacy and the personalization of study protocols.

EPFL2022

Gene expression profiling of two distinct neuronal populations in the rodent spinal cord

Jesper Ryge

BACKGROUND: In the field of neuroscience microarray gene expression profiles on anatomically defined brain structures are being used increasingly to study both normal brain functions as well as pathological states. Fluorescent tracing techniques in brain tissue that identifies distinct neuronal populations can in combination with global gene expression profiling potentially increase the resolution and specificity of such studies to shed new light on neuronal functions at the cellular level. METHODOLOGY/PRINCIPAL FINDINGS: We examine the microarray gene expression profiles of two distinct neuronal populations in the spinal cord of the neonatal rat, the principal motor neurons and specific interneurons involved in motor control. The gene expression profiles of the respective cell populations were obtained from amplified mRNA originating from 50-250 fluorescently identified and laser microdissected cells. In the data analysis we combine a new microarray normalization procedure with a conglomerate measure of significant differential gene expression. Using our methodology we find 32 genes to be more expressed in the interneurons compared to the motor neurons that all except one have not previously been associated with this neuronal population. As a validation of our method we find 17 genes to be more expressed in the motor neurons than in the interneurons and of these only one had not previously been described in this population. CONCLUSIONS/SIGNIFICANCE: We provide an optimized experimental protocol that allows isolation of gene transcripts from fluorescent retrogradely labeled cell populations in fresh tissue, which can be used to generate amplified aRNA for microarray hybridization from as few as 50 laser microdissected cells. Using this optimized experimental protocol in combination with our microarray analysis methodology we find 49 differentially expressed genes between the motor neurons and the interneurons that reflect the functional differences between these two cell populations in generating and transmitting the motor output in the rodent spinal cord.

Public Library of Science2008

Mapping of Structure-Function Age-Related Connectivity Changes on Cognition Using Multimodal MRI

Maria Giulia Preti, Dimitri Nestor Alice Van De Ville

The relationship between age-related changes in brain structural connectivity (SC) and functional connectivity (FC) with cognition is not well understood. Furthermore, it is not clear whether cognition is represented via a similar spatial pattern of FC and SC or instead is mapped by distinct sets of distributed connectivity patterns. To this end, we used a longitudinal, within-subject, multimodal approach aiming to combine brain data from diffusion-weighted MRI (DW-MRI), and functional MRI (fMRI) with behavioral evaluation, to better understand how changes in FC and SC correlate with changes in cognition in a sample of older adults. FC and SC measures were derived from the multimodal scans acquired at two time points. Change in FC and SC was correlated with 13 behavioral measures of cognitive function using Partial Least Squares Correlation (PLSC). Two of the measures indicate an age-related change in cognition and the rest indicate baseline cognitive performance. FC and SC-cognition correlations were expressed across several cognitive measures, and numerous structural and functional cortical connections, mainly cingulo-opercular, dorsolateral prefrontal, somatosensory and motor, and temporo-parieto-occipital, contributed both positively and negatively to the brain-behavior relationship. Whole-brain FC and SC captured distinct and independent connections related to the cognitive measures. Overall, we examined age-related function-structure associations of the brain in a comprehensive and integrated manner, using a multimodal approach. We pointed out the behavioral relevance of age-related changes in FC and SC. Taken together, our results highlight that the heterogeneity in distributed FC and SC connectivity patterns provide unique information about the variable nature of healthy cognitive aging.

FRONTIERS MEDIA SA2022