CADASIL Affects Multiple Aspects of Cerebral Small Vessel Function on 7T-MRI

International audienceObjective: Cerebral small vessel diseases (cSVDs) are a major cause of stroke and dementia. We used cutting-edge 7T-MRI techniques in patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), to establish which aspects of cerebral small vessel function are affected by this monogenic form of cSVD. Methods: We recruited 23 CADASIL patients (age 51.1 AE 10.1 years, 52% women) and 13 age-and sex-matched controls (46.1 AE 12.6, 46% women). Small vessel function measures included: basal ganglia and centrum semiovale perforating artery blood flow velocity and pulsatility, vascular reactivity to a visual stimulus in the occipital cortex and reactivity to hypercapnia in the cortex, subcortical gray matter, white matter, and white matter hyperintensities. Results: Compared with controls, CADASIL patients showed lower blood flow velocity and higher pulsatility index within perforating arteries of the centrum semiovale (mean difference À 0.09 cm/s, p = 0.03 and 0.20, p = 0.009) and basal ganglia (mean difference À 0.98 cm/s, p = 0.003 and 0.17, p = 0.06). Small vessel reactivity to a short visual stimulus was decreased (blood-oxygen-level dependent [BOLD] mean difference À0.21%, p = 0.04) in patients, while reactivity to hypercapnia was preserved in the cortex, subcortical gray matter, and normal appearing white matter. Among patients, reactivity to hypercapnia was decreased in white matter hyperintensities compared to normal appearing white matter (BOLD mean difference À0.29%, p = 0.02). Interpretation: Multiple aspects of cerebral small vessel function on 7T-MRI were abnormal in CADASIL patients, indicative of increased arteriolar stiffness and regional abnormalities in reactivity, locally also in relation to white matter injury. These observations provide novel markers of cSVD for mechanistic and intervention studies

Zooming in on cerebral small vessel function in small vessel diseases with 7T MRI: Rationale and design of the “ZOOM@SVDs” study

Background: Cerebral small vessel diseases (SVDs) are a major cause of stroke and dementia. Yet, specific treatment strategies are lacking in part because of a limited understanding of the underlying disease processes. There is therefore an urgent need to study SVDs at their core, the small vessels themselves. Objective: This paper presents the rationale and design of the ZOOM@SVDs study, which aims to establish measures of cerebral small vessel dysfunction on 7T MRI as novel disease markers of SVDs. Methods: ZOOM@SVDs is a prospective observational cohort study with two years follow-up. ZOOM@SVDs recruits participants with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL, N = 20), sporadic SVDs (N = 60), and healthy controls (N = 40). Participants undergo 7T brain MRI to assess different aspects of small vessel function including small vessel reactivity, cerebral perforating artery flow, and pulsatility. Extensive work-up at baseline and follow-up further includes clinical and neuropsychological assessment as well as 3T brain MRI to assess conventional SVD imaging markers. Measures of small vessel dysfunction are compared between patients and controls, and related to the severity of clinical and conventional MRI manifestations of SVDs. Discussion: ZOOM@SVDs will deliver novel markers of cerebral small vessel function in patients with monogenic and sporadic forms of SVDs, and establish their relation with disease burden and progression. These small vessel markers can support etiological studies in SVDs and may serve as surrogate outcome measures in future clinical trials to show target engagement of drugs directed at the small vessels

Neuronal Models for EEG–fMRI Integration

Human brain activity can be measured in many ways, providing different views into its functions. Common measurements of human brain function, such as functional MRI (fMRI) and electroencephalography (EEG), are often integrated to get the best spatial and temporal resolution, but these measurements frequently show differences. This chapter therefore considers how the pooling of signals across populations of neurons affects these measurements. We consider a modeling framework in which fMRI and field potential signals integrate across transmembrane currents in a population of neurons, because synaptic activity is thought to be the largest drive of the fMRI signal and transmembrane potentials are the biggest source of field potentials. We formulate computations that provide simplified abstractions that inform how levels of synaptic activity or synchrony across neurons contribute to fMRI or electrophysiological signals and how to interpret deviations or similarities between measurements. The modeling framework and computations highlight that the level of activity in a neuronal population influences each measurement, but synchrony only has a large effect on field potentials and not on the fMRI signal. An application to data from human visual cortex explains why certain signals correlate and others do not. Advancing the fundamental understanding of how different measurements integrate neuronal activity will be important to combine fMRI and EEG measurements to better understand human brain function

Effect sizes of BOLD CVR, resting-state signal fluctuations and time delay measures for the assessment of hemodynamic impairment in carotid occlusion patients

Background and purpose: The BOLD signal amplitude as a response to a hypercapnia stimulus is commonly used to assess cerebrovascular reserve. Despite recent advances, the implementation remains cumbersome and alternative ways to assess hemodynamic impairment are desirable. Resting-state BOLD signal fluctuations (rsBOLD) have been proposed however data on its sensitivity and dependence on baseline venous cerebral blood volume (vCBV) is limited. The primary aim of this study was to compare the effect sizes of resting-state and hypercapnia induced BOLD signal changes in the detection of hemodynamic impairment. The second aim of the study was to assess the dependence of BOLD signal variability on vCBV. Materials and methods: Fifteen patients with internal carotid artery occlusive disease and 15 matched healthy controls were included in this study. The BOLD signal was derived from a dual-echo gradient-echo echo-planar sequence during hypercapnia (HC) and hyperoxia (HO) gas modulations. BOLD (fractional) amplitude of low frequency fluctuations ((f)ALFF) was compared to HC-BOLD, BOLD response delays derived from time delay analysis and ΔBOLD in response to progressively increasing HC. Effect sizes (i.e. the standard mean difference between patients and controls) were calculated. HO-BOLD was used to estimate vCBV, and its contribution to the variability in rsBOLD signal was evaluated. Results: The effect sizes of ALFF and fALFF (0.61 and 0.72) were lower than the effect sizes related to hypercapnia-based hemodynamic assessment analysis; 1.62, 1.56 and 0.90 for HC-BOLD, BOLD response delays and ΔBOLD in response to progressively increasing HC. A moderate relation was found between (f)ALFF and HC-BOLD in controls (R2 of 0.61 and 0.42), but this relation decreased in patients (R2 of 0.33 and 0.15). (f)ALFF did not differ between patients and controls whereas HC-BOLD did (p < 0.005). The ΔBOLD response to progressively increasing HC was significantly different in between patients and controls for ΔEtCO2 values ≥ 2 mmHg (at +2 mmHg F(1, 18) = 5.85, p = 0.026). Up to 31% and 53% of the variance in the ALFF and HC-BOLD spatial distribution could be explained by HO-BOLD. Conclusion: ALFF and fALFF demonstrated a moderate effect size to detect hemodynamic impairment whereas the effect size was large for methods employing a hypercapnia-based vascular stress stimulus. Based on our analysis of BOLD signal change as a response to a progressively increasing hypercapnia stimulus we can argue that a hypercapnia stimulus of at least 2 mmHg above baseline EtCO2 is necessary to evaluate hemodynamic impairment. We also demonstrated that a substantial amount of information imbedded in the rsBOLD and HC-BOLD was explained by HO-BOLD. HO-BOLD can serve as a proxy for vCBV and this thus indicates that one should be careful when adopting these techniques in disease cases with compromised CBV

Effect sizes of BOLD CVR, resting-state signal fluctuations and time delay measures for the assessment of hemodynamic impairment in carotid occlusion patients

Background and purpose: The BOLD signal amplitude as a response to a hypercapnia stimulus is commonly used to assess cerebrovascular reserve. Despite recent advances, the implementation remains cumbersome and alternative ways to assess hemodynamic impairment are desirable. Resting-state BOLD signal fluctuations (rsBOLD) have been proposed however data on its sensitivity and dependence on baseline venous cerebral blood volume (vCBV) is limited. The primary aim of this study was to compare the effect sizes of resting-state and hypercapnia induced BOLD signal changes in the detection of hemodynamic impairment. The second aim of the study was to assess the dependence of BOLD signal variability on vCBV. Materials and methods: Fifteen patients with internal carotid artery occlusive disease and 15 matched healthy controls were included in this study. The BOLD signal was derived from a dual-echo gradient-echo echo-planar sequence during hypercapnia (HC) and hyperoxia (HO) gas modulations. BOLD (fractional) amplitude of low frequency fluctuations ((f)ALFF) was compared to HC-BOLD, BOLD response delays derived from time delay analysis and ΔBOLD in response to progressively increasing HC. Effect sizes (i.e. the standard mean difference between patients and controls) were calculated. HO-BOLD was used to estimate vCBV, and its contribution to the variability in rsBOLD signal was evaluated. Results: The effect sizes of ALFF and fALFF (0.61 and 0.72) were lower than the effect sizes related to hypercapnia-based hemodynamic assessment analysis; 1.62, 1.56 and 0.90 for HC-BOLD, BOLD response delays and ΔBOLD in response to progressively increasing HC. A moderate relation was found between (f)ALFF and HC-BOLD in controls (R2 of 0.61 and 0.42), but this relation decreased in patients (R2 of 0.33 and 0.15). (f)ALFF did not differ between patients and controls whereas HC-BOLD did (p < 0.005). The ΔBOLD response to progressively increasing HC was significantly different in between patients and controls for ΔEtCO2 values ≥ 2 mmHg (at +2 mmHg F(1, 18) = 5.85, p = 0.026). Up to 31% and 53% of the variance in the ALFF and HC-BOLD spatial distribution could be explained by HO-BOLD. Conclusion: ALFF and fALFF demonstrated a moderate effect size to detect hemodynamic impairment whereas the effect size was large for methods employing a hypercapnia-based vascular stress stimulus. Based on our analysis of BOLD signal change as a response to a progressively increasing hypercapnia stimulus we can argue that a hypercapnia stimulus of at least 2 mmHg above baseline EtCO2 is necessary to evaluate hemodynamic impairment. We also demonstrated that a substantial amount of information imbedded in the rsBOLD and HC-BOLD was explained by HO-BOLD. HO-BOLD can serve as a proxy for vCBV and this thus indicates that one should be careful when adopting these techniques in disease cases with compromised CBV

On the sensitivity of the diffusion MRI signal to brain activity in response to a motor cortex paradigm

Diffusion functional magnetic resonance imaging (dfMRI) is a promising technique to map functional activations by acquiring diffusion-weighed spin-echo images. In previous studies, dfMRI showed higher spatial accuracy at activation mapping compared to classic functional MRI approaches. However, it remains unclear whether dfMRI measures result from changes in the intracellular/extracellular environment, perfusion, and/or T2 values. We designed an acquisition/quantification scheme to disentangle such effects in the motor cortex during a finger-tapping paradigm. dfMRI was acquired at specific diffusion weightings to selectively suppress perfusion and free-water diffusion, then time series of the apparent diffusion coefficient (ADC-fMRI) and of intravoxel incoherent motion (IVIM) effects were derived. ADC-fMRI provided ADC estimates sensitive to changes in perfusion and free-water volume, but not to T2/T2* values. With IVIM modeling, we isolated the perfusion contribution to ADC, while suppressing T2 effects. Compared to conventional gradient-echo blood oxygenation level-dependent fMRI, activation maps obtained with dfMRI and ADC-fMRI had smaller clusters, and the spatial overlap between the three techniques was below 50%. Increases of perfusion fractions were observed during task in both dfMRI and ADC-fMRI activations. Perfusion effects were more prominent with ADC-fMRI than with dfMRI but were significant in less than 25% of activation regions. IVIM modeling suggests that the sensitivity to task of dfMRI derives from a decrease of intracellular/extracellular diffusion and an increase of the pseudo-diffusion signal fraction, leading to different, more confined spatial activation patterns compared to classic functional MRI

Can 7T MPRAGE match MP2RAGE for gray-white matter contrast?

Ultra-High Field (UHF) MRI provides a significant increase in Signal-to-Noise Ratio (SNR) and gains in contrast weighting in several functional and structural acquisitions. Unfortunately, an increase in field strength also induces non-uniformities in the transmit field (B1+) that can compromise image contrast non-uniformly. The MPRAGE is one of the most common T1 weighted (T1w) image acquisitions for structural imaging. It provides excellent contrast between gray and white matter and is widely used for brain segmentation. At 7T, the signal non-uniformities tend to complicate this and therefore, the self-bias-field corrected MP2RAGE is often used there. In both MPRAGE and MP2RAGE, more homogeneous image contrast can be achieved with adiabatic pulses, like the TR-FOCI inversion pulse, or special pulse design on parallel transmission systems, like Universal Pulses (UP). In the present study, we investigate different strategies to improve the bias-field for MPRAGE at 7T, comparing the contrast and GM/WM segmentability against MP2RAGE. The higher temporal efficiency of MPRAGE combined with the potential of the user-friendly UPs was the primary motivation for this MPRAGE-MP2RAGE comparison. We acquired MPRAGE data in six volunteers, adding a k-space shutter to reduce scan time, a kt-point UP approach for homogeneous signal excitation, and a TR-FOCI pulse for homogeneous inversion. Our results show remarkable signal contrast improvement throughout the brain, including regions of low B1+ such as the cerebellum. The improvements in the MPRAGE were largest following the introduction of the UPs. In addition to the CNR, both SNR and GM/WM segmentability were also assessed. Among the MPRAGEs, the combined strategy (UP + TR-FOCI) yielded highest SNR and showed highest spatial similarity between GM segments to the MP2RAGE. Interestingly, the distance between gray and white matter peaks in the intensity histograms did not increase, as better pulses and higher SNR especially benefitted the (cerebellar) gray matter. Overall, the gray-white matter contrast from MP2RAGE is higher, with higher CNR and higher intensity peak distances, even when scaled to scan time. Hence, the extra acquisition time for MP2RAGE is justified by the improved segmentability

Ultra-high field MRI:Advancing systems neuroscience towards mesoscopic human brain function

Human MRI scanners at ultra-high magnetic field strengths of 7 T and higher are increasingly available to the neuroscience community. A key advantage brought by ultra-high field MRI is the possibility to increase the spatial resolution at which data is acquired, with little reduction in image quality. This opens a new set of opportunities for neuroscience, allowing investigators to map the human cortex at an unprecedented level of detail. In this review, we present recent work that capitalizes on the increased signal-to-noise ratio available at ultra-high field and discuss the theoretical advances with a focus on sensory and motor systems neuroscience. Further, we review research performed at sub-millimeter spatial resolution and discuss the limits and the potential of ultra-high field imaging for structural and functional imaging in human cortex. The increased spatial resolution achievable at ultra-high field has the potential to unveil the fundamental computations performed within a given cortical area, ultimately allowing the visualization of the mesoscopic organization of human cortex at the functional and structural level

Comparing hand movement rate dependence of cerebral blood volume and BOLD responses at 7T

Functional magnetic resonance imaging (fMRI) based on the Blood Oxygenation Level Dependent (BOLD) contrast takes advantage of the coupling between neuronal activity and the hemodynamics to allow a non-invasive localisation of the neuronal activity. In general, fMRI experiments assume a linear relationship between neuronal activation and the observed hemodynamics. However, the relationship between BOLD responses, neuronal activity, and behaviour are often nonlinear. In addition, the nonlinearity between BOLD responses and behaviour may be related to neuronal process rather than a neurovascular uncoupling. Further, part of the nonlinearity may be driven by vascular nonlinearity effects in particular from large vessel contributions. fMRI based on cerebral blood volume (CBV), promises a higher microvascular specificity, potentially without vascular nonlinearity effects and reduced contamination of the large draining vessels compared to BOLD. In this study, we aimed to investigate differences in BOLD and VASO-CBV signal changes during a hand movement task over a broad range of movement rates. We used a double readout 3D-EPI sequence at 7T to simultaneously measure VASO-CBV and BOLD responses in the sensorimotor cortex. The measured BOLD and VASO-CBV responses increased very similarly in a nonlinear fashion, plateauing for movement rates larger than 1 Hz. Our findings show a tight relationship between BOLD and VASO-CBV responses, indicating that the overall interplay of CBV and BOLD responses are similar for the assessed range of movement rates. These results suggest that the observed nonlinearity of neuronal origin is already present in VASO-CBV measurements, and consequently shows relatively unchanged BOLD responses