Breath-hold BOLD fMRI without CO2 sampling enables estimation of venous cerebral blood volume: potential use in normalization of stimulus-evoked BOLD fMRI data.

BOLD fMRI signal has been used in conjunction with vasodilatory stimulation as a marker of cerebrovascular reactivity (CVR): the relative change in cerebral blood flow (CBF) arising from a unit change in the vasodilatory stimulus. Using numerical simulations, we demonstrate that the variability in the relative BOLD signal change induced by vasodilation is strongly influenced by the variability in deoxyhemoglobin-containing cerebral blood volume (CBV), as this source of variability is likely to be more prominent than that of CVR. It may, therefore, be more appropriate to describe the relative BOLD signal change induced by an isometabolic vasodilation as a proxy of deoxygenated CBV (CBVdHb) rather than CVR. With this in mind, a new method was implemented to map a marker of CBVdHb, termed BOLD-CBV, based on the normalization of voxel-wise BOLD signal variation by an estimate of the intravascular venous BOLD signal from voxels filled with venous blood. The intravascular venous BOLD signal variation, recorded during repeated breath-holding, was extracted from the superior sagittal sinus in a cohort of 27 healthy volunteers and used as a regressor across the whole brain, yielding maps of BOLD-CBV. In the same cohort, we demonstrated the potential use of BOLD-CBV for the normalization of stimulus-evoked BOLD fMRI by comparing group-level BOLD fMRI responses to a visuomotor learning task with and without the inclusion of voxel-wise vascular covariates of BOLD-CBV and the BOLD signal change per mmHg variation in end-tidal carbon dioxide (BOLD-CVR). The empirical measure of BOLD-CBV accounted for more between-subject variability in the motor task-induced BOLD responses than BOLD-CVR estimated from end-tidal carbon dioxide recordings. The new method can potentially increase the power of group fMRI studies by including a measure of vascular characteristics and has the strong practical advantage of not requiring experimental measurement of end-tidal carbon dioxide, unlike traditional methods to estimate BOLD-CVR. It also more closely represents a specific physiological characteristic of brain vasculature than BOLD-CVR, namely blood volume.

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.

Pathophysiology of multiple sclerosis damage and repair: Linking cerebral hypoperfusion to the development of irreversible tissue loss in multiple sclerosis using magnetic resonance imaging.

BACKGROUND AND PURPOSE: Reduced cerebral perfusion has been observed in multiple sclerosis (MS) and may contribute to tissue loss both acutely and chronically. Here, we test the hypothesis that hypoperfusion occurs in MS and relates to the presence of irreversible tissue damage. METHODS: In 91 patients with relapsing MS and 26 healthy controls (HC), gray matter (GM) cerebral blood flow (CBF) was assessed using pulsed arterial spin labeling. GM volume, T1 hypointense and T2 hyperintense lesion volumes (T1LV and T2LV, respectively), and the proportion of T2-hyperintense lesion volume that appears hypointense on T1-weighted magnetic resonance imaging (T1LV/T2LV) were quantified. GM CBF and GM volume were evaluated globally, as well as regionally, using an atlas-based approach. RESULTS: Global GM CBF was lower in patients (56.9 ± 12.3 mL/100 g/min) than in HC (67.7 ± 10.0 mL/100 g/min; p < 0.001), a difference that was widespread across brain regions. Although total GM volume was comparable between groups, significant reductions were observed in a subset of subcortical structures. GM CBF negatively correlated with T1LV (r = -0.43, p = 0.0002) and T1LV/T2LV (r = -0.37, p = 0.0004), but not with T2LV. CONCLUSIONS: GM hypoperfusion occurs in MS and is associated with irreversible white matter damage, thus suggesting that cerebral hypoperfusion may actively contribute and possibly precede neurodegeneration by hampering tissue repair abilities in MS.

Cerebral blood flow patterns in preterm and term neonates assessed with pseudo-continuous arterial spin labeling perfusion MRI.

In preterm (PT) infants, regional cerebral blood flow (CBF) disturbances may predispose to abnormal brain maturation even without overt brain injury. Therefore, it would be informative to determine the spatial distribution of grey matter (GM) CBF in PT and full-term (FT) newborns at term-equivalent age (TEA) and to assess the relationship between the features of the CBF pattern and both prematurity and prematurity-related brain lesions. In this prospective study, we obtained measures of CBF in 66 PT (51 without and 15 with prematurity-related brain lesions) and 38 FT newborns through pseudo-continuous arterial spin labeling (pCASL) MRI acquired at TEA. The pattern of GM CBF was characterized by combining an atlas-based automated segmentation of structural MRI with spatial normalization and hierarchical clustering. The effects of gestational age (GA) at birth and brain injury on the CBF pattern were investigated. We identified 4 physiologically-derived clusters of brain regions that were labeled Fronto-Temporal, Parieto-Occipital, Insular-Deep GM (DGM) and Sensorimotor, from the least to the most perfused. We demonstrated that GM perfusion was associated with GA at birth in the Fronto-Temporal and Sensorimotor clusters, positively and negatively, respectively. Moreover, the presence of periventricular leukomalacia was associated with significantly increased Fronto-Temporal GM perfusion and decreased Insular-DGM perfusion, while the presence of germinal matrix hemorrhage appeared to mildly decrease the Insular-DGM perfusion. Prematurity and prematurity-related brain injury heterogeneously affect brain perfusion. ASL MRI may, therefore, have strong potential as a noninvasive tool for the accurate stratification of individuals at risk of domain-specific impairment.

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.

Cerebrovascular reactivity in multiple sclerosis is restored with reduced inflammation during immunomodulation.

Cerebrovascular reactivity (CVR) reflects the capacity of the brain's vasculature to increase blood flow following a vasodilatory stimulus. Reactivity is an essential property of the brain's blood vessels that maintains nutrient supplies in the face of changing demand. In Multiple Sclerosis (MS), CVR may be diminished with brain inflammation and this may contribute to neurodegeneration. We test the hypothesis that CVR is altered with MS neuroinflammation and that it is restored when inflammation is reduced. Using a breath-hold task during functional Magnetic Resonance Imaging (MRI), we mapped grey matter and white matter CVRs (CVRGM and CVRWM, respectively) in 23 young MS patients, eligible for disease modifying therapy, before and during Interferon beta treatment. Inflammatory activity was inferred from the presence of Gadolinium enhancing lesions at MRI. Eighteen age and gender-matched healthy controls (HC) were also assessed. Enhancing lesions were observed in 12 patients at the start of the study and in 3 patients during treatment. Patients had lower pre-treatment CVRGM (p = 0.04) and CVRWM (p = 0.02) compared to HC. In patients, a lower pre-treatment CVRGM was associated with a lower GM volume (r = 0.60, p = 0.003). On-treatment, there was an increase in CVRGM (p = 0.02) and CVRWM (p = 0.03) that negatively correlated with pre-treatment CVR (GM: r = - 0.58, p = 0.005; WM: r = - 0.60, p = 0.003). CVR increased when enhancing lesions reduced in number (GM: r = - 0.48, p = 0.02, WM: r = - 0.62, p = 0.003). Resolution of inflammation may restore altered cerebrovascular function limiting neurodegeneration in MS. Imaging of cerebrovascular function may thereby inform tissue physiology and improve treatment monitoring.

Cerebrovascular Variants and the Role of the Selfish Brain in Young-Onset Hypertension.

BACKGROUND: Variants in the posterior anatomy of the cerebral circulation are associated with hypertension and lower cerebral blood flow in midlife (age ≈55 years); however, whether these variants are a result of aging or long-term exposure to high blood pressure is unclear. Additionally, the role these variants play in early onset of hypertension (<40 years) and poor cerebral perfusion in this population is unknown. METHODS: We retrospectively examined whether specific cerebrovascular variants (vertebral artery hypoplasia and absent/hypoplastic posterior communicating arteries (an incomplete posterior circle of Willis) measured via magnetic resonance angiography) were associated with a diagnosis of hypertension in 220 young adults (<40 years; n=164 primary hypertensive [mean age±SD, 32±6 years] and n=56 [30±6 years] normotensive adults). Whether cerebrovascular variants were associated with lower cerebral blood flow (phase-contrast angiography) was measured in the hypertensive group only (n=146). RESULTS: Binary logistic regression (adjusted for age, sex, and body mass index) showed that vertebral artery hypoplasia with an incomplete posterior circle of Willis was associated with hypertension diagnosis (P<0.001, odds ratio; 11.79 [95% CI, 3.34-41.58]). Vertebral artery hypoplasia plus an incomplete circle of Willis was associated with lower cerebral blood flow in young adults with hypertension (P=0.0172). CONCLUSIONS: Vertebral artery hypoplasia plus an incomplete posterior circle of Willis independently predicts hypertension in young adults suggesting that this variant is not acquired with aging into midlife. Importantly this variant combination was associated with lower cerebral perfusion, which may have long-term consequences on cerebrovascular health in young adults with hypertension.

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 comparison of GABA-ergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation on visual and motor cortical oscillations, using magnetoencephalography.

Studying changes in cortical oscillations can help elucidate the mechanistic link between receptor physiology and the clinical effects of anaesthetic drugs. Propofol, a GABA-ergic drug produces divergent effects on visual cortical activity: increasing induced gamma-band responses (GBR) while decreasing evoked responses. Dexmedetomidine, an α2- adrenergic agonist, differs from GABA-ergic sedatives both mechanistically and clinically as it allows easy arousability from deep sedation with less cognitive side-effects. Here we use magnetoencephalography (MEG) to characterize and compare the effects of GABA-ergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation, on visual and motor cortical oscillations. Sixteen male participants received target-controlled infusions of propofol and dexmedetomidine, producing mild-sedation, in a placebo-controlled, cross-over study. MEG data was collected during a combined visuomotor task. The key findings were that propofol significantly enhanced visual stimulus induced GBR (44% increase in amplitude) while dexmedetomidine decreased it (40%). Propofol also decreased the amplitudes of the Mv100 (visual M100) (27%) and Mv150 (52%) visual evoked fields (VEF), whilst dexmedetomidine had no effect on these. During the motor task, neither drug had any significant effect on movement related gamma synchrony (MRGS), movement related beta de-synchronisation (MRBD) or Mm100 (movement-related M100) movement-related evoked fields (MEF), although dexmedetomidine slowed the Mm300. Dexmedetomidine increased (92%) post-movement beta synchronisation/rebound (PMBR) power while propofol reduced it (70%, statistically non- significant). Overall, dexmedetomidine and propofol, at equi-sedative doses, produce contrasting effects on visual induced GBR, VEF, PMBR and MEF. These findings provide a mechanistic link between the known receptor physiology of these sedative drugs with their known clinical effects and may be used to explore mechanisms of other anaesthetic drugs on human consciousness.

Contribution of Metabolomics to Multiple Sclerosis Diagnosis, Prognosis and Treatment.

Metabolomics-based technologies map in vivo biochemical changes that may be used as early indicators of pathological abnormalities prior to the development of clinical symptoms in neurological conditions. Metabolomics may also reveal biochemical pathways implicated in tissue dysfunction and damage and thus assist in the development of novel targeted therapeutics for neuroinflammation and neurodegeneration. Metabolomics holds promise as a non-invasive, high-throughput and cost-effective tool for early diagnosis, follow-up and monitoring of treatment response in multiple sclerosis (MS), in combination with clinical and imaging measures. In this review, we offer evidence in support of the potential of metabolomics as a biomarker and drug discovery tool in MS. We also use pathway analysis of metabolites that are described as potential biomarkers in the literature of MS biofluids to identify the most promising molecules and upstream regulators, and show novel, still unexplored metabolic pathways, whose investigation may open novel avenues of research.

Corrigendum: A Frequency-Domain Machine Learning Method for Dual-Calibrated fMRI Mapping of Oxygen Extraction Fraction (OEF) and Cerebral Metabolic Rate of Oxygen Consumption (CMRO2).

[This corrects the article DOI: 10.3389/frai.2020.00012.].

Distinct effects of prematurity on MRI metrics of brain functional connectivity, activity, and structure: Univariate and multivariate analyses.

Premature birth affects the developmental trajectory of the brain during a period of intense maturation with possible lifelong consequences. To better understand the effect of prematurity on brain structure and function, we performed blood-oxygen-level dependent (BOLD) and anatomical magnetic resonance imaging (MRI) at 40 weeks of postmenstrual age on 88 newborns with variable gestational age (GA) at birth and no evident radiological alterations. We extracted measures of resting-state functional connectivity and activity in a set of 90 cortical and subcortical brain regions through the evaluation of BOLD correlations between regions and of fractional amplitude of low-frequency fluctuation (fALFF) within regions, respectively. Anatomical information was acquired through the assessment of regional volumes. We performed univariate analyses on each metric to examine the association with GA at birth, the spatial distribution of the effects, and the consistency across metrics. Moreover, a data-driven multivariate analysis (i.e., Machine Learning) framework exploited the high dimensionality of the data to assess the sensitivity of each metric to the effect of premature birth. Prematurity was associated with bidirectional alterations of functional connectivity and regional volume and, to a lesser extent, of fALFF. Notably, the effects of prematurity on functional connectivity were spatially diffuse, mainly within cortical regions, whereas effects on regional volume and fALFF were more focal, involving subcortical structures. While the two analytical approaches delivered consistent results, the multivariate analysis was more sensitive in capturing the complex pattern of prematurity effects. Future studies might apply multivariate frameworks to identify premature infants at risk of a negative neurodevelopmental outcome.

Evaluation of denoising strategies for task-based functional connectivity: Equalizing residual motion artifacts between rest and cognitively demanding tasks.

In-scanner head motion represents a major confounding factor in functional connectivity studies and it raises particular concerns when motion correlates with the effect of interest. One such instance regards research focused on functional connectivity modulations induced by sustained cognitively demanding tasks. Indeed, cognitive engagement is generally associated with substantially lower in-scanner movement compared with unconstrained, or minimally constrained, conditions. Consequently, the reliability of condition-dependent changes in functional connectivity relies on effective denoising strategies. In this study, we evaluated the ability of common denoising pipelines to minimize and balance residual motion-related artifacts between resting-state and task conditions. Denoising pipelines-including realignment/tissue-based regression, PCA/ICA-based methods (aCompCor and ICA-AROMA, respectively), global signal regression, and censoring of motion-contaminated volumes-were evaluated according to a set of benchmarks designed to assess either residual artifacts or network identifiability. We found a marked heterogeneity in pipeline performance, with many approaches showing a differential efficacy between rest and task conditions. The most effective approaches included aCompCor, optimized to increase the noise prediction power of the extracted confounding signals, and global signal regression, although both strategies performed poorly in mitigating the spurious distance-dependent association between motion and connectivity. Censoring was the only approach that substantially reduced distance-dependent artifacts, yet this came at the great cost of reduced network identifiability. The implications of these findings for best practice in denoising task-based functional connectivity data, and more generally for resting-state data, are discussed.

Extended-amygdala intrinsic functional connectivity networks: A population study.

Pre-clinical and human neuroimaging research implicates the extended-amygdala (ExtA) (including the bed nucleus of the stria terminalis [BST] and central nucleus of the amygdala [CeA]) in networks mediating negative emotional states associated with stress and substance-use behaviours. The extent to which individual ExtA structures form a functionally integrated unit is controversial. We utilised a large sample (n > 1,000 healthy young adult humans) to compare the intrinsic functional connectivity networks (ICNs) of the BST and CeA using task-free functional magnetic resonance imaging (fMRI) data from the Human Connectome Project. We assessed whether inter-individual differences within these ICNs were related to two principal components representing negative disposition and alcohol use. Building on recent primate evidence, we tested whether within BST-CeA intrinsic functional connectivity (iFC) was heritable and further examined co-heritability with our principal components. We demonstrate the BST and CeA to have discrete, but largely overlapping ICNs similar to previous findings. We found no evidence that within BST-CeA iFC was heritable; however, post hoc analyses found significant BST iFC heritability with the broader superficial and centromedial amygdala regions. There were no significant correlations or co-heritability associations with our principal components either across the ICNs or for specific BST-Amygdala iFC. Possible differences in phenotype associations across task-free, task-based, and clinical fMRI are discussed, along with suggestions for more causal investigative paradigms that make use of the now well-established ExtA ICNs.

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.

Multi-centre, multi-vendor reproducibility of 7T QSM and R2* in the human brain: Results from the UK7T study.

INTRODUCTION: We present the reliability of ultra-high field T2* MRI at 7T, as part of the UK7T Network's "Travelling Heads" study. T2*-weighted MRI images can be processed to produce quantitative susceptibility maps (QSM) and R2* maps. These reflect iron and myelin concentrations, which are altered in many pathophysiological processes. The relaxation parameters of human brain tissue are such that R2* mapping and QSM show particularly strong gains in contrast-to-noise ratio at ultra-high field (7T) vs clinical field strengths (1.5-3T). We aimed to determine the inter-subject and inter-site reproducibility of QSM and R2* mapping at 7T, in readiness for future multi-site clinical studies. METHODS: Ten healthy volunteers were scanned with harmonised single- and multi-echo T2*-weighted gradient echo pulse sequences. Participants were scanned five times at each "home" site and once at each of four other sites. The five sites had 1× Philips, 2× Siemens Magnetom, and 2× Siemens Terra scanners. QSM and R2* maps were computed with the Multi-Scale Dipole Inversion (MSDI) algorithm (https://github.com/fil-physics/Publication-Code). Results were assessed in relevant subcortical and cortical regions of interest (ROIs) defined manually or by the MNI152 standard space. RESULTS AND DISCUSSION: Mean susceptibility (χ) and R2* values agreed broadly with literature values in all ROIs. The inter-site within-subject standard deviation was 0.001-0.005 ppm (χ) and 0.0005-0.001 ms-1 (R2*). For χ this is 2.1-4.8 fold better than 3T reports, and 1.1-3.4 fold better for R2*. The median ICC from within- and cross-site R2* data was 0.98 and 0.91, respectively. Multi-echo QSM had greater variability vs single-echo QSM especially in areas with large B0 inhomogeneity such as the inferior frontal cortex. Across sites, R2* values were more consistent than QSM in subcortical structures due to differences in B0-shimming. On a between-subject level, our measured χ and R2* cross-site variance is comparable to within-site variance in the literature, suggesting that it is reasonable to pool data across sites using our harmonised protocol. CONCLUSION: The harmonized UK7T protocol and pipeline delivers on average a 3-fold improvement in the coefficient of reproducibility for QSM and R2* at 7T compared to previous reports of multi-site reproducibility at 3T. These protocols are ready for use in multi-site clinical studies at 7T.

Graded fMRI Neurofeedback Training of Motor Imagery in Middle Cerebral Artery Stroke Patients: A Preregistered Proof-of-Concept Study.

Ischemic stroke of the middle cerebral artery (MCA), a major brain vessel that supplies the primary motor and premotor cortex, is one of the most common causes for severe upper limb impairment. Currently available motor rehabilitation training largely lacks satisfying efficacy with over 70% of stroke survivors showing residual upper limb dysfunction. Motor imagery-based functional magnetic resonance imaging neurofeedback (fMRI-NF) has been suggested as a potential therapeutic technique to improve motor impairment in stroke survivors. In this preregistered proof-of-concept study (https://osf.io/y69jc/), we translated graded fMRI-NF training, a new paradigm that we have previously studied in healthy participants, to first-time MCA stroke survivors with residual mild to severe impairment of upper limb motor function. Neurofeedback was provided from the supplementary motor area (SMA) targeting two different neurofeedback target levels (low and high). We hypothesized that MCA stroke survivors will show (1) sustained SMA-region of interest (ROI) activation and (2) a difference in SMA-ROI activation between low and high neurofeedback conditions during graded fMRI-NF training. At the group level, we found only anecdotal evidence for these preregistered hypotheses. At the individual level, we found anecdotal to moderate evidence for the absence of the hypothesized graded effect for most subjects. These null findings are relevant for future attempts to employ fMRI-NF training in stroke survivors. The study introduces a Bayesian sequential sampling plan, which incorporates prior knowledge, yielding higher sensitivity. The sampling plan was preregistered together with a priori hypotheses and all planned analysis before data collection to address potential publication/researcher biases. Unforeseen difficulties in the translation of our paradigm to a clinical setting required some deviations from the preregistered protocol. We explicitly detail these changes, discuss the accompanied additional challenges that can arise in clinical neurofeedback studies, and formulate recommendations for how these can be addressed. Taken together, this work provides new insights about the feasibility of motor imagery-based graded fMRI-NF training in MCA stroke survivors and serves as a first example for comprehensive study preregistration of an (fMRI) neurofeedback experiment.

Altered cerebrovascular response to acute exercise in patients with Huntington's disease.

The objective of this study was to determine whether a single session of exercise was sufficient to induce cerebral adaptations in individuals with Huntington's disease and to explore the time dynamics of any acute cerebrovascular response. In this case-control study, we employed arterial-spin labelling MRI in 19 Huntington's disease gene-positive participants (32-65 years, 13 males) and 19 controls (29-63 years, 10 males) matched for age, gender, body mass index and self-reported activity levels, to measure global and regional perfusion in response to 20 min of moderate-intensity cycling. Cerebral perfusion was measured at baseline and 15, 40 and 60 min after exercise cessation. Relative to baseline, we found that cerebral perfusion increased in patients with Huntington's disease yet was unchanged in control participants in the precentral gyrus (P = 0.016), middle frontal gyrus (P = 0.046) and hippocampus (P = 0.048) 40 min after exercise cessation (+15 to +32.5% change in Huntington's disease participants, -7.7 to 0.8% change in controls). The length of the disease-causing trinucleotide repeat expansion in the huntingtin gene predicted the change in the precentral gyrus (P = 0.03) and the intensity of the exercise intervention predicted hippocampal perfusion change in Huntington's disease participants (P < 0.001). In both groups, exercise increased hippocampal blood flow 60 min after exercise cessation (P = 0.039). These findings demonstrate the utility of acute exercise as a clinically sensitive experimental paradigm to modulate the cerebrovasculature. Twenty minutes of aerobic exercise induced transient cerebrovascular adaptations in the hippocampus and cortex selectively in Huntington's disease participants and likely represents latent neuropathology not evident at rest.

Most Small Cerebral Cortical Veins Demonstrate Significant Flow Pulsatility: A Human Phase Contrast MRI Study at 7T.

Phase contrast MRI (pcMRI) has been used to investigate flow pulsatility in cerebral arteries, larger cerebral veins, and the cerebrospinal fluid (CSF). Such measurements of intracranial pulsatility and compliance are beginning to inform understanding of the pathophysiology of conditions including normal pressure hydrocephalus, multiple sclerosis, and dementias. We demonstrate the presence of flow pulsatility in small cerebral cortical veins, for the first time using pcMRI at 7 T, with the aim of improving our understanding of the hemodynamics of this little-studied vascular compartment. A method for establishing where venous flow is pulsatile is introduced, revealing significant pulsatility in 116 out of 146 veins, across eight healthy participants, assessed in parietal and frontal regions. Distributions of pulsatility index (PI) and pulse waveform delay were characterized, indicating a small, but statistically significant (p < 0.05), delay of 59 ± 41 ms in cortical veins with respect to the superior sagittal sinus, but no differences between veins draining different arterial supply territories. Measurements of pulsatility in smaller cortical veins, a hitherto unstudied compartment closer to the capillary bed, could lead to a better understanding of intracranial compliance and cerebrovascular (patho)physiology.

Assessment of the Effects of Aerobic Fitness on Cerebrovascular Function in Young Adults Using Multiple Inversion Time Arterial Spin Labeling MRI.

This cross-sectional study investigated the effects of aerobic fitness on cerebrovascular function in the healthy brain. Gray matter cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) were quantified in a sample of young adults within a normal fitness range. Based on existing Transcranial Doppler ultrasound and fMRI evidence, we predicted a positive relationship between fitness and resting gray matter CBF and CVR. Exploratory hypotheses that higher V . O2peak would be associated with higher GM volume and cognitive performance were also investigated. 20 adults underwent a V . O2peak test and a battery of cognitive tests. All subjects also underwent an MRI scan where multiple inversion time (MTI) pulsed arterial spin labeling (PASL) was used to quantify resting CBF and CVR to 5% CO2. Region of interest analysis showed a non-significant inverse correlation between whole-brain gray matter CBF and V . O2peak; r = -0.4, p = 0.08, corrected p (p') = 0.16 and a significant positive correlation between V . O2peak and whole-brain averaged gray matter CVR; r = 0.62, p = 0.003, p' = 0.006. Voxel-wise analysis revealed a significant inverse association between V . O2peak and resting CBF in the left and right thalamus, brainstem, right lateral occipital cortex, left intra-calcarine cortex and cerebellum. The results of this study suggest that aerobic fitness is associated with lower baseline CBF and greater CVR in young adults.