Changes in brain perfusion with training-related visuomotor improvement in MS.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. A better understanding of the mechanisms supporting brain plasticity in MS would help to develop targeted interventions to promote recovery. A total of 29 MS patients and 19 healthy volunteers underwent clinical assessment and multi-modal MRI acquisition [fMRI during serial reaction time task (SRT), DWI, T1w structural scans and ASL of resting perfusion] at baseline and after 4-weeks of SRT training. Reduction of functional hyperactivation was observed in MS patients following the training, shown by the stronger reduction of the BOLD response during task execution compared to healthy volunteers. The functional reorganization was accompanied by a positive correlation between improvements in task accuracy and the change in resting perfusion after 4 weeks' training in right angular and supramarginal gyri in MS patients. No longitudinal changes in WM and GM measures and no correlation between task performance improvements and brain structure were observed in MS patients. Our results highlight a potential role for CBF as an early marker of plasticity, in terms of functional (cortical reorganization) and behavioral (performance improvement) changes in MS patients that may help to guide future interventions that exploit preserved plasticity mechanisms.

Hemodynamic timing in resting-state and breathing-task BOLD fMRI.

The blood flow response to a vasoactive stimulus demonstrates regional heterogeneity across both the healthy brain and in cerebrovascular pathology. The timing of a regional hemodynamic response is emerging as an important biomarker of cerebrovascular dysfunction, as well as a confound within fMRI analyses. Previous research demonstrated that hemodynamic timing is more robustly characterized when a larger systemic vascular response is evoked by a breathing challenge, compared to when only spontaneous fluctuations in vascular physiology are present (i.e., in resting-state data). However, it is not clear whether hemodynamic delays in these two conditions are physiologically interchangeable, and how methodological signal-to-noise factors may limit their agreement. To address this, we generated whole-brain maps of hemodynamic delays in nine healthy adults. We assessed the agreement of voxel-wise gray matter (GM) hemodynamic delays between two conditions: resting-state and breath-holding. We found that delay values demonstrated poor agreement when considering all GM voxels, but increasingly greater agreement when limiting analyses to voxels showing strong correlation with the GM mean time-series. Voxels showing the strongest agreement with the GM mean time-series were primarily located near large venous vessels, however these voxels explain some, but not all, of the observed agreement in timing. Increasing the degree of spatial smoothing of the fMRI data enhanced the correlation between individual voxel time-series and the GM mean time-series. These results suggest that signal-to-noise factors may be limiting the accuracy of voxel-wise timing estimates and hence their agreement between the two data segments. In conclusion, caution must be taken when using voxel-wise delay estimates from resting-state and breathing-task data interchangeably, and additional work is needed to evaluate their relative sensitivity and specificity to aspects of vascular physiology and pathology.

Comparing end-tidal CO2, respiration volume per time (RVT), and average gray matter signal for mapping cerebrovascular reactivity amplitude and delay with breath-hold task BOLD fMRI.

Cerebrovascular reactivity (CVR), defined as the cerebral blood flow response to a vasoactive stimulus, is an imaging biomarker with demonstrated utility in a range of diseases and in typical development and aging processes. A robust and widely implemented method to map CVR involves using a breath-hold task during a BOLD fMRI scan. Recording end-tidal CO2 (PETCO2) changes during the breath-hold task is recommended to be used as a reference signal for modeling CVR amplitude in standard units (%BOLD/mmHg) and CVR delay in seconds. However, obtaining reliable PETCO2 recordings requires equipment and task compliance that may not be achievable in all settings. To address this challenge, we investigated two alternative reference signals to map CVR amplitude and delay in a lagged general linear model (lagged-GLM) framework: respiration volume per time (RVT) and average gray matter BOLD response (GM-BOLD). In 8 healthy adults with multiple scan sessions, we compare spatial agreement of CVR maps from RVT and GM-BOLD to those generated with PETCO2. We define a threshold to determine whether a PETCO2 recording has "sufficient" quality for CVR mapping and perform these comparisons in 16 datasets with sufficient PETCO2 and 6 datasets with insufficient PETCO2. When PETCO2 quality is sufficient, both RVT and GM-BOLD produce CVR amplitude maps that are nearly identical to those from PETCO2 (after accounting for differences in scale), with the caveat they are not in standard units to facilitate between-group comparisons. CVR delays are comparable to PETCO2 with an RVT regressor but may be underestimated with the average GM-BOLD regressor. Importantly, when PETCO2 quality is insufficient, RVT and GM-BOLD CVR recover reasonable CVR amplitude and delay maps, provided the participant attempted the breath-hold task. Therefore, our framework offers a solution for achieving high quality CVR maps in both retrospective and prospective studies where sufficient PETCO2 recordings are not available and especially in populations where obtaining reliable measurements is a known challenge (e.g., children). Our results have the potential to improve the accessibility of CVR mapping and to increase the prevalence of this promising metric of vascular health.

Reduced brain oxygen metabolism in patients with multiple sclerosis: Evidence from dual-calibrated functional MRI.

Cerebral energy deficiency is increasingly recognised as an important feature of multiple sclerosis (MS). Until now, we have lacked non-invasive imaging methods to quantify energy utilisation and mitochondrial function in the human brain. Here, we used novel dual-calibrated functional magnetic resonance imaging (dc-fMRI) to map grey-matter (GM) deoxy-haemoglobin sensitive cerebral blood volume (CBVdHb), cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen consumption (CMRO2) in patients with MS (PwMS) and age/sex matched controls. By integrating a flow-diffusion model of oxygen transport, we evaluated the effective oxygen diffusivity of the capillary network (DC) and the partial pressure of oxygen at the mitochondria (PmO2). Significant between-group differences were observed as decreased CBF (p = 0.010), CMRO2 (p < 0.001) and DC (p = 0.002), and increased PmO2 (p = 0.043) in patients compared to controls. No significant differences were observed for CBVdHb (p = 0.389), OEF (p = 0.358), or GM volume (p = 0.302). Regional analysis showed widespread reductions in CMRO2 and DC for PwMS. Our findings may be indicative of reduced oxygen demand or utilisation in the MS brain and mitochondrial dysfunction. Our results suggest changes in brain physiology may precede MRI-detectable GM loss and may contribute to disease progression and neurodegeneration.

Lag-Optimized Blood Oxygenation Level Dependent Cerebrovascular Reactivity Estimates Derived From Breathing Task Data Have a Stronger Relationship With Baseline Cerebral Blood Flow.

Cerebrovascular reactivity (CVR), an important indicator of cerebrovascular health, is commonly studied with the Blood Oxygenation Level Dependent functional MRI (BOLD-fMRI) response to a vasoactive stimulus. Theoretical and empirical evidence suggests that baseline cerebral blood flow (CBF) modulates BOLD signal amplitude and may influence BOLD-CVR estimates. We address how acquisition and modeling choices affect the relationship between baseline cerebral blood flow (bCBF) and BOLD-CVR: whether BOLD-CVR is modeled with the inclusion of a breathing task, and whether BOLD-CVR amplitudes are optimized for hemodynamic lag effects. We assessed between-subject correlations of average GM values and within-subject spatial correlations across cortical regions. Our results suggest that a breathing task addition to a resting-state acquisition, alongside lag-optimization within BOLD-CVR modeling, can improve BOLD-CVR correlations with bCBF, both between- and within-subjects, likely because these CVR estimates are more physiologically accurate. We report positive correlations between bCBF and BOLD-CVR, both between- and within-subjects. The physiological explanation of this positive correlation is unclear; research with larger samples and tightly controlled vasoactive stimuli is needed. Insights into what drives variability in BOLD-CVR measurements and related measurements of cerebrovascular function are particularly relevant when interpreting results in populations with altered vascular and/or metabolic baselines or impaired cerebrovascular reserve.

Verbal fluency difficulties in aphasia: A combination of lexical and executive control deficits.

BACKGROUND: Verbal fluency tasks are routinely used in clinical assessment and research studies of aphasia. People with aphasia produce fewer items in verbal fluency tasks. It remains unclear if their output is limited solely by their lexical difficulties and/or has a basis in their executive control abilities. Recent research has illustrated that detailed characterization of verbal fluency performance using temporal characteristics of words retrieved, clustering and switching, and pause durations, along with separate measures of executive control stands to inform our understanding of the lexical and cognitive underpinnings of verbal fluency in aphasia. AIMS: To determine the locus of the verbal fluency difficulties in aphasia, we compared semantic and letter fluency trials between people with aphasia and healthy control participants using a wide range of variables to capture the performance between the two groups. The groups were also tested on separate measures of executive control to determine the relationship amongst these tasks and fluency performance. METHODS & PROCEDURES: Semantic (animal) and letter (F, A, S) fluency data for 60s trials were collected from 14 people with aphasia (PWA) and 24 healthy adult controls (HC). Variables, such as number of correct responses, clustering and switching analyses, were performed along with temporal measures of the retrieved words (response latencies) and pause durations. Participants performed executive control tasks to measure inhibitory control, mental-set shifting and memory span. OUTCOMES & RESULTS: Compared with HC, PWA produced fewer correct responses, showed greater difficulty with the letter fluency condition, were slower in getting started with the trials, showed slower retrieval times as noted in within- and between-cluster pause durations, and switched less often. Despite these retrieval difficulties, PWA showed a similar decline in the rate of recall to HC, and had similar cluster size. Executive control measures correlated primarily with the letter fluency variables: mostly for PWA and in one instance for HC. CONCLUSIONS & IMPLICATIONS: Poorer performance for PWA is a combination of difficulties in both the lexical and executive components of the verbal fluency task. Our findings highlight the importance of detailed characterization of fluency performance in deciphering the underlying mechanism of retrieval difficulties in aphasia, and illustrate the importance of using letter fluency trials to tap into executive control processes. WHAT THIS PAPER ADDS: What is already known on the subject PWA typically show impaired performance in verbal fluency tasks. It is debated whether this impaired performance is a result of their lexical difficulties or executive control difficulties, or a combination of both. This debate continues because previous studies have mostly used semantic fluency condition without including letter fluency condition; used a limited range of variables (e.g., number of correct responses); and not included separate executive control measures to explain the performance pattern in aphasia. This research addresses these outstanding issues to determine the specific contribution of lexical and executive control processes in verbal fluency in aphasia by including: both semantic and letter fluency conditions; a wide range of variables to identify the relative contribution of lexical and executive control mechanisms; and independent measures of executive control. What this paper adds to existing knowledge Using the multidimensional analysis approach for verbal fluency performance from both semantic and letter fluency conditions, this is the first study to systematically demonstrate that PWA had difficulties in both lexical and executive control components of the task. At the individual level, PWA had greater difficulty on the letter fluency condition compared with semantic fluency. We observed significant correlations between the executive control measures and verbal fluency measures primarily for the letter fluency condition. This research makes a significant contribution to our understanding of lexical and executive control aspects in word production in aphasia. What are the potential or actual clinical implications of this work? From a clinical perspective, this research highlights the importance of using a full range of verbal fluency and executive control measures to tap into the lexical as well as executive control abilities of PWA, and also the utility of using letter fluency to tap into the executive control processes in PWA.

A flow-diffusion model of oxygen transport for quantitative mapping of cerebral metabolic rate of oxygen (CMRO2) with single gas calibrated fMRI.

One promising approach for mapping CMRO2 is dual-calibrated functional MRI (dc-fMRI). This method exploits the Fick Principle to combine estimates of CBF from ASL, and OEF derived from BOLD-ASL measurements during arterial O2 and CO2 modulations. Multiple gas modulations are required to decouple OEF and deoxyhemoglobin-sensitive blood volume. We propose an alternative single gas calibrated fMRI framework, integrating a model of oxygen transport, that links blood volume and CBF to OEF and creates a mapping between the maximum BOLD signal, CBF and OEF (and CMRO2). Simulations demonstrated the method's viability within physiological ranges of mitochondrial oxygen pressure, PmO2, and mean capillary transit time. A dc-fMRI experiment, performed on 20 healthy subjects using O2 and CO2 challenges, was used to validate the approach. The validation conveyed expected estimates of model parameters (e.g., low PmO2), with spatially uniform OEF maps (grey matter, GM, OEF spatial standard deviation ≈ 0.13). GM OEF estimates obtained with hypercapnia calibrated fMRI correlated with dc-fMRI (r = 0.65, p = 2·10-3). For 12 subjects, OEF measured with dc-fMRI and the single gas calibration method were correlated with whole-brain OEF derived from phase measures in the superior sagittal sinus (r = 0.58, p = 0.048; r = 0.64, p = 0.025 respectively). Simplified calibrated fMRI using hypercapnia holds promise for clinical application.

A practical modification to a resting state fMRI protocol for improved characterization of cerebrovascular function.

Cerebrovascular reactivity (CVR), defined here as the Blood Oxygenation Level Dependent (BOLD) response to a CO2 pressure change, is a useful metric of cerebrovascular function. Both the amplitude and the timing (hemodynamic lag) of the CVR response can bring insight into the nature of a cerebrovascular pathology and aid in understanding noise confounds when using functional Magnetic Resonance Imaging (fMRI) to study neural activity. This research assessed a practical modification to a typical resting-state fMRI protocol, to improve the characterization of cerebrovascular function. In 9 healthy subjects, we modelled CVR and lag in three resting-state data segments, and in data segments which added a 2-3 minute breathing task to the start of a resting-state segment. Two different breathing tasks were used to induce fluctuations in arterial CO2 pressure: a breath-hold task to induce hypercapnia (CO2 increase) and a cued deep breathing task to induce hypocapnia (CO2 decrease). Our analysis produced voxel-wise estimates of the amplitude (CVR) and timing (lag) of the BOLD-fMRI response to CO2 by systematically shifting the CO2 regressor in time to optimize the model fit. This optimization inherently increases gray matter CVR values and fit statistics. The inclusion of a simple breathing task, compared to a resting-state scan only, increases the number of voxels in the brain that have a significant relationship between CO2 and BOLD-fMRI signals, and improves our confidence in the plausibility of voxel-wise CVR and hemodynamic lag estimates. We demonstrate the clinical utility and feasibility of this protocol in an incidental finding of Moyamoya disease, and explore the possibilities and challenges of using this protocol in younger populations. This hybrid protocol has direct applications for CVR mapping in both research and clinical settings and wider applications for fMRI denoising and interpretation.

ICA-based denoising strategies in breath-hold induced cerebrovascular reactivity mapping with multi echo BOLD fMRI.

Performing a BOLD functional MRI (fMRI) acquisition during breath-hold (BH) tasks is a non-invasive, robust method to estimate cerebrovascular reactivity (CVR). However, movement and breathing-related artefacts caused by the BH can substantially hinder CVR estimates due to their high temporal collinearity with the effect of interest, and attention has to be paid when choosing which analysis model should be applied to the data. In this study, we evaluate the performance of multiple analysis strategies based on lagged general linear models applied on multi-echo BOLD fMRI data, acquired in ten subjects performing a BH task during ten sessions, to obtain subject-specific CVR and haemodynamic lag estimates. The evaluated approaches range from conventional regression models, i.e. including drifts and motion timecourses as nuisance regressors, applied on single-echo or optimally-combined data, to more complex models including regressors obtained from multi-echo independent component analysis with different grades of orthogonalization in order to preserve the effect of interest, i.e. the CVR. We compare these models in terms of their ability to make signal intensity changes independent from motion, as well as the reliability as measured by voxelwise intraclass correlation coefficients of both CVR and lag maps over time. Our results reveal that a conservative independent component analysis model applied on the optimally-combined multi-echo fMRI signal offers the largest reduction of motion-related effects in the signal, while yielding reliable CVR amplitude and lag estimates, although a conventional regression model applied on the optimally-combined data results in similar estimates. This work demonstrates the usefulness of multi-echo based fMRI acquisitions and independent component analysis denoising for precision mapping of CVR in single subjects based on BH paradigms, fostering its potential as a clinically-viable neuroimaging tool for individual patients. It also proves that the way in which data-driven regressors should be incorporated in the analysis model is not straight-forward due to their complex interaction with the BH-induced BOLD response.

Predictors of training-related improvement in visuomotor performance in patients with multiple sclerosis: A behavioural and MRI study.

BACKGROUND: The development of tailored recovery-oriented strategies in multiple sclerosis requires early identification of an individual's potential for functional recovery. OBJECTIVE: To identify predictors of visuomotor performance improvements, a proxy of functional recovery, using a predictive statistical model that combines demographic, clinical and magnetic resonance imaging (MRI) data. METHODS: Right-handed multiple sclerosis patients underwent baseline disability assessment and MRI of the brain structure, function and vascular health. They subsequently undertook 4 weeks of right upper limb visuomotor practice. Changes in performance with practice were our outcome measure. We identified predictors of improvement in a training set of patients using lasso regression; we calculated the best performing model in a validation set and applied this model to a test set. RESULTS: Patients improved their visuomotor performance with practice. Younger age, better visuomotor abilities, less severe disease burden and concurrent use of preventive treatments predicted improvements. Neuroimaging localised outcome-relevant sensory motor regions, the microstructure and activity of which correlated with performance improvements. CONCLUSION: Initial characteristics, including age, disease duration, visuo-spatial abilities, hand dexterity, self-evaluated disease impact and the presence of disease-modifying treatments, can predict functional recovery in individual patients, potentially improving their clinical management and stratification in clinical trials. MRI is a correlate of outcome, potentially supporting individual prognosis.

Voxelwise optimization of hemodynamic lags to improve regional CVR estimates in breath-hold fMRI.

Cerebrovascular Reactivity (CVR), the responsiveness of blood vessels to a vasodilatory stimulus, is an important indicator of cerebrovascular health. Assessing CVR with fMRI, we can measure the change in the Blood Oxygen Level Dependent (BOLD) response induced by a change in CO2 pressure (%BOLD/mmHg). However, there exists a temporal offset between the recorded CO2 pressure and the local BOLD response, due to both measurement and physiological delays. If this offset is not corrected for, voxel-wise CVR values will not be accurate. In this paper, we propose a framework for mapping hemodynamic lag in breath-hold fMRI data. As breath-hold tasks drive task-correlated head motion artifacts in BOLD fMRI data, our framework for lag estimation fits a model that includes polynomial terms and head motion parameters, as well as a shifted variant of the CO2 regressor (±9 s in 0.3 s increments), and the hemodynamic lag at each voxel is the shift producing the maximum total model R2 within physiological constraints. This approach is evaluated in 8 subjects with multi-echo fMRI data, resulting in robust maps of hemodynamic delay that show consistent regional variation across subjects, and improved contrast-to-noise compared to methods where motion regression is ignored or performed earlier in preprocessing.Clinical Relevance- We map hemodynamic lag using breathhold fMRI, providing insight into vascular transit times and improving the regional accuracy of cerebrovascular reactivity measurements.

Comparing MRI metrics to quantify white matter microstructural damage in multiple sclerosis.

Quantifying white matter damage in vivo is becoming increasingly important for investigating the effects of neuroprotective and repair strategies in multiple sclerosis (MS). While various approaches are available, the relationship between MRI-based metrics of white matter microstructure in the disease, that is, to what extent the metrics provide complementary versus redundant information, remains largely unexplored. We obtained four microstructural metrics from 123 MS patients: fractional anisotropy (FA), radial diffusivity (RD), myelin water fraction (MWF), and magnetisation transfer ratio (MTR). Coregistration of maps of these four indices allowed quantification of microstructural damage through voxel-wise damage scores relative to healthy tissue, as assessed in a group of 27 controls. We considered three white matter tissue-states, which were expected to vary in microstructural damage: normal appearing white matter (NAWM), T2-weighted hyperintense lesional tissue without T1-weighted hypointensity (T2L), and T1-weighted hypointense lesional tissue with corresponding T2-weighted hyperintensity (T1L). All MRI indices suggested significant damage in all three tissue-states, the greatest damage being in T1L. The correlations between indices ranged from r = 0.18 to r = 0.87. MWF was most sensitive when differentiating T2L from NAWM, while MTR was most sensitive when differentiating T1L from NAWM and from T2L. Combining the four metrics into one, through a principal component analysis, did not yield a measure more sensitive to damage than any single measure. Our findings suggest that the metrics are (at least partially) correlated with each other, but sensitive to the different aspects of pathology. Leveraging these differences could be beneficial in clinical trials testing the effects of therapeutic interventions.

Neurovascular Coupling During Visual Stimulation in Multiple Sclerosis: A MEG-fMRI Study.

The process of neurovascular coupling ensures that increases in neuronal activity are fed by increases in cerebral blood flow. Evidence suggests that neurovascular coupling may be impaired in Multiple Sclerosis (MS) due to a combination of brain hypoperfusion, altered cerebrovascular reactivity and oxygen metabolism, and altered levels of vasoactive compounds. Here, we tested the hypothesis that neurovascular coupling is impaired in MS. We characterized neurovascular coupling as the relationship between changes in neuronal oscillatory power within the gamma frequency band (30-80 Hz), as measured by magnetoencephalography (MEG), and associated hemodynamic changes (blood oxygenation level dependent, BOLD, and cerebral blood flow, CBF) as measured by functional MRI. We characterized these responses in the visual cortex in 13 MS patients and in 10 matched healthy controls using a reversing checkerboard stimulus at five visual contrasts. There were no significant group differences in visual acuity, P100 latencies, occipital gray matter (GM) volumes and baseline CBF. However, in the MS patients we found a significant reduction in peak gamma power, BOLD and CBF responses. There were no significant differences in neurovascular coupling between groups, in the visual cortex. Our results suggest that neuronal and vascular responses are altered in MS. Gamma power reduction could be an indicator of GM dysfunction, possibly mediated by GABAergic changes. Altered hemodynamic responses confirm previous reports of a vascular dysfunction in MS. Despite altered neuronal and vascular responses, neurovascular coupling appears to be preserved in MS, at least within the range of damage and disability studied here.