Meso-cortical pathway damage in cognition, apathy and gait in cerebral small vessel disease.

Cerebral small vessel disease (SVD) is known to contribute to cognitive impairment, apathy, and gait dysfunction. Although associations between cognitive impairment and either apathy or gait dysfunction have been shown in SVD, the inter-relations among these three clinical features and their potential common neural basis remains unexplored. The dopaminergic meso-cortical and meso-limbic pathways have been known as the important brain circuits for both cognitive control, emotion regulation and motor function. Here, we investigated the potential inter-relations between cognitive impairment, apathy, and gait dysfunction, with a specific focus on determining whether these clinical features are associated with damage to the meso-cortical and meso-limbic pathways in SVD. In this cross-sectional study, we included 213 participants with SVD in whom MRI scans and comprehensive neurobehavioral assessments were administered. These assessments comprised of six clinical measures: processing speed, executive function, memory, apathy (based on the Apathy Evaluation Scale), and gait function (based on the time and steps in Timed Up and Go test). We reconstructed five tracts connecting ventral tegmental area (VTA) and the dorsolateral prefrontal cortex (dlPFC), ventral lateral PFC (vlPFC), medial orbitofrontal cortex (mOFC), anterior cingulate cortex (ACC) and nucleus accumbens (NAc) within meso-cortical and meso-limbic pathways using diffusion weighted imaging. The damage along the five tracts was quantified using the free water (FW) and FW-corrected mean diffusivity (MD-t) indices. Furthermore, we explored the inter-correlations among the six clinical measures and identified their common components using principal component analysis (PCA). Linear regression analyses showed that higher FW values of tracts within meso-cortical pathways were related to these clinical measures in cognition, apathy, and gait (all P-corrected values < 0.05). PCA showed strong inter-associations among these clinical measures and identified a common component wherein all six clinical measures loaded on. Higher FW values of tracts within meso-cortical pathways were related to the PCA-derived common component (all P-corrected values < 0.05). Moreover, FW values of VTA-ACC tract showed the strongest contribution to the PCA-derived common component over all other neuroimaging features. In conclusion, our study showed that the three clinical features (cognitive impairment, apathy, and gait dysfunction) of SVD are strongly inter-related and that the damage in meso-cortical pathway could be the common neural basis underlying the three features in SVD. These findings advance our understanding of the mechanisms behind these clinical features of SVD and have the potential to inform novel management and intervention strategies for SVD.

Cerebral Small Vessel Disease Progression Increases Risk of Incident Parkinsonism.

OBJECTIVE: Cerebral small vessel disease (SVD) is associated with motor impairments and parkinsonian signs cross-sectionally, however, there are little longitudinal data on whether SVD increases risk of incident parkinsonism itself. We investigated the relation between baseline SVD severity as well as SVD progression, and incident parkinsonism over a follow-up of 14 years. METHODS: This study included 503 participants with SVD, and without parkinsonism at baseline, from the RUN DMC prospective cohort study. Baseline inclusion was performed in 2006 and follow-up took place in 2011, 2015, and 2020, including magnetic resonance imaging (MRI) and motor assessments. Parkinsonism was diagnosed according to the UK Brain Bank criteria, and stratified into vascular parkinsonism (VaP) and idiopathic Parkinson's disease (IPD). Linear mixed-effect models were constructed to estimate individual rate changes of MRI-characteristics. RESULTS: Follow-up for incident parkinsonism was near-complete (99%). In total, 51 (10.2%) participants developed parkinsonism (33 VaP, 17 IPD, and 1 progressive supranuclear palsy). Patients with incident VaP had higher SVD burden compared with patients with IPD. Higher baseline white matter hyperintensities (hazard ratio [HR] = 1.46 per 1-SD increase, 95% confidence interval [CI] = 1.21-1.78), peak width of skeletonized mean diffusivity (HR = 1.66 per 1-SD increase, 95% CI = 1.34-2.05), and presence of lacunes (HR = 1.84, 95% CI = 0.99-3.42) were associated with increased risk of all-cause parkinsonism. Incident lacunes were associated with incident VaP (HR = 4.64, 95% CI = 1.32-16.32). INTERPRETATION: Both baseline SVD severity and SVD progression are independently associated with long-term parkinsonism. Our findings indicate a causal role of SVD in parkinsonism. Future studies are needed to examine the underlying pathophysiology of this relation. ANN NEUROL 2023;93:1130-1141.

Changes in postictal cerebral perfusion are related to the duration of electroconvulsive therapy-induced seizures.

OBJECTIVE: Postictal symptoms may result from cerebral hypoperfusion, which is possibly a consequence of seizure-induced vasoconstriction. Longer seizures have previously been shown to cause more severe postictal hypoperfusion in rats and epilepsy patients. We studied cerebral perfusion after generalized seizures elicited by electroconvulsive therapy (ECT) and its relation to seizure duration. METHODS: Patients with a major depressive episode who underwent ECT were included. During treatment, 21-channel continuous electroencephalogram (EEG) was recorded. Arterial spin labeling magnetic resonance imaging scans were acquired before the ECT course (baseline) and approximately 1 h after an ECT-induced seizure (postictal) to quantify global and regional gray matter cerebral blood flow (CBF). Seizure duration was assessed from the period of epileptiform discharges on the EEG. Healthy controls were scanned twice to assess test-retest variability. We performed hypothesis-driven Bayesian analyses to study the relation between global and regional perfusion changes and seizure duration. RESULTS: Twenty-four patients and 27 healthy controls were included. Changes in postictal global and regional CBF were correlated with seizure duration. In patients with longer seizure durations, global decrease in CBF reached values up to 28 mL/100 g/min. Regional reductions in CBF were most prominent in the inferior frontal gyrus, cingulate gyrus, and insula (up to 35 mL/100 g/min). In patients with shorter seizures, global and regional perfusion increased (up to 20 mL/100 g/min). These perfusion changes were larger than changes observed in healthy controls, with a maximum median global CBF increase of 12 mL/100 g/min and a maximum median global CBF decrease of 20 mL/100 g/min. SIGNIFICANCE: Seizure duration is a key factor determining postictal perfusion changes. In future studies, seizure duration needs to be considered as a confounding factor due to its opposite effect on postictal perfusion.

Regional cortical thinning, demyelination and iron loss in cerebral small vessel disease.

The link between white matter hyperintensities (WMH) and cortical thinning is thought to be an important pathway by which WMH contributes to cognitive deficits in cerebral small vessel disease (SVD). However, the mechanism behind this association and the underlying tissue composition abnormalities are unclear. The objective of this study is to determine the association between WMH and cortical thickness, and the in vivo tissue composition abnormalities in the WMH-connected cortical regions. In this cross-sectional study, we included 213 participants with SVD who underwent standardized protocol including multimodal neuroimaging scans and cognitive assessment (i.e. processing speed, executive function and memory). We identified the cortex connected to WMH using probabilistic tractography starting from the WMH and defined the WMH-connected regions at three connectivity levels (low, medium and high connectivity level). We calculated the cortical thickness, myelin and iron of the cortex based on T1-weighted, quantitative R1, R2* and susceptibility maps. We used diffusion-weighted imaging to estimate the mean diffusivity of the connecting white matter tracts. We found that cortical thickness, R1, R2* and susceptibility values in the WMH-connected regions were significantly lower than in the WMH-unconnected regions (all Pcorrected < 0.001). Linear regression analyses showed that higher mean diffusivity of the connecting white matter tracts were related to lower thickness (ß = -0.30, Pcorrected < 0.001), lower R1 (ß = -0.26, Pcorrected = 0.001), lower R2* (ß = -0.32, Pcorrected < 0.001) and lower susceptibility values (ß = -0.39, Pcorrected < 0.001) of WMH-connected cortical regions at high connectivity level. In addition, lower scores on processing speed were significantly related to lower cortical thickness (ß = 0.20, Pcorrected = 0.030), lower R1 values (ß = 0.20, Pcorrected = 0.006), lower R2* values (ß = 0.29, Pcorrected = 0.006) and lower susceptibility values (ß = 0.19, Pcorrected = 0.024) of the WMH-connected regions at high connectivity level, independent of WMH volumes and the cortical measures of WMH-unconnected regions. Together, our study demonstrated that the microstructural integrity of white matter tracts passing through WMH is related to the regional cortical abnormalities as measured by thickness, R1, R2* and susceptibility values in the connected cortical regions. These findings are indicative of cortical thinning, demyelination and iron loss in the cortex, which is most likely through the disruption of the connecting white matter tracts and may contribute to processing speed impairment in SVD, a key clinical feature of SVD. These findings may have implications for finding intervention targets for the treatment of cognitive impairment in SVD by preventing secondary degeneration.

Relating neural oscillations to laminar fMRI connectivity in visual cortex.

Laminar functional magnetic resonance imaging (fMRI) holds the potential to study connectivity at the laminar level in humans. Here we analyze simultaneously recorded electroencephalography (EEG) and high-resolution fMRI data to investigate how EEG power modulations, induced by a task with an attentional component, relate to changes in fMRI laminar connectivity between and within brain regions in visual cortex. Our results indicate that our task-induced decrease in beta power relates to an increase in deep-to-deep layer coupling between regions and to an increase in deep/middle-to-superficial layer connectivity within brain regions. The attention-related alpha power decrease predominantly relates to reduced connectivity between deep and superficial layers within brain regions, since, unlike beta power, alpha power was found to be positively correlated to connectivity. We observed no strong relation between laminar connectivity and gamma band oscillations. These results indicate that especially beta band, and to a lesser extent, alpha band oscillations relate to laminar-specific fMRI connectivity. The differential effects for alpha and beta bands indicate that they relate to different feedback-related neural processes that are differentially expressed in intra-region laminar fMRI-based connectivity.

Dissociable Contributions of Thalamic-Subregions to Cognitive Impairment in Small Vessel Disease.

BACKGROUND: Structural network damage is a potentially important mechanism by which cerebral small vessel disease (SVD) can cause cognitive impairment. As a central hub of the structural network, the role of thalamus in SVD-related cognitive impairments remains unclear. We aimed to determine the associations between the structural alterations of thalamic subregions and cognitive impairments in SVD. METHODS: In this cross-sectional study, 205 SVD participants without thalamic lacunes from the third follow-up (2020) of the prospective RUN DMC study (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort), which was initiated in 2006, Nijmegen, were included. Cognitive functions included processing speed, executive function, and memory. Probabilistic tractography was performed from thalamus to 6 cortical regions, followed by connectivity-based thalamic segmentation to assess each thalamic subregion volume and connectivity (measured by mean diffusivity [MD] of the connecting white matter tracts) with the cortex. Least absolute shrinkage and selection operator regression analysis was conducted to identify the volumes or connectivity of the total thalamus and 6 thalamic subregions that have the strongest association with cognitive performance. Linear regression and mediation analyses were performed to test the association of least absolute shrinkage and selection operator-selected thalamic subregion volume or MD with cognitive performance, while adjusting for age and education. RESULTS: We found that higher MD of the thalamic-motor tract was associated with worse processing speed (ß=-0.27; P<0.001), higher MD of the thalamic-frontal tract was associated with worse executive function (ß=-0.24; P=0.001), and memory (ß=-0.28; P<0.001), respectively. The mediation analysis showed that MD of thalamocortical tracts mediated the association between corresponding thalamic subregion volumes and the cognitive performances in 3 domains. CONCLUSIONS: Our results suggest that the structural alterations of thalamus are linked to cognitive impairment in SVD, largely depending on the damage pattern of the white matter tracts connecting specific thalamic subregions and cortical regions.

Combining arterial blood contrast with BOLD increases fMRI intracortical contrast.

BOLD fMRI is widely applied in human neuroscience but is limited in its spatial specificity due to a cortical-depth-dependent venous bias. This reduces its localization specificity with respect to neuronal responses, a disadvantage for neuroscientific research. Here, we modified a submillimeter BOLD protocol to selectively reduce venous and tissue signal and increase cerebral blood volume weighting through a pulsed saturation scheme (dubbed Arterial Blood Contrast) at 7 T. Adding Arterial Blood Contrast on top of the existing BOLD contrast modulated the intracortical contrast. Isolating the Arterial Blood Contrast showed a response free of pial-surface bias. The results suggest that Arterial Blood Contrast can modulate the typical fMRI spatial specificity, with important applications in in-vivo neuroscience.

A comparison of multiband and multiband multiecho gradient-echo EPI for task fMRI at 3 T.

A multiband (MB) echo-planar imaging (EPI) sequence is compared to a multiband multiecho (MBME) EPI protocol to investigate differences in sensitivity for task functional magnetic resonance imaging (fMRI) at 3 T. Multiecho sampling improves sensitivity in areas where single-echo-EPI suffers from dropouts. However, It requires in-plane acceleration to reduce the echo train length, limiting the slice acceleration factor and the temporal and spatial resolution Data were acquired for both protocols in two sessions 24 h apart using an adapted color-word interference Stroop task. Besides protocol comparison statistically, we performed test-retest reliability across sessions for different protocols and denoising methods. We evaluated the sensitivity of two different echo-combination strategies for MBME-EPI. We examined the performance of three different data denoising approaches: "Standard," "AROMA," and "FIX" for MB and MBME, and assessed whether a specific method is preferable. We consider using an appropriate autoregressive model order within the general linear model framework to correct TR differences between the protocols. The comparison between protocols and denoising methods showed at group level significantly higher mean z-scores and the number of active voxels for MBME in the motor, subcortical and medial frontal cortices. When comparing different echo combinations, our results suggest that a contrast-to-noise ratio weighted echo combination improves sensitivity in MBME compared to simple echo-summation. This study indicates that MBME can be a preferred protocol in task fMRI at spatial resolution (≥2 mm), primarily in medial prefrontal and subcortical areas.

Role of small acute hyperintense lesions in long-term progression of cerebral small vessel disease and clinical outcome: a 14-year follow-up study.

BACKGROUND: Small hyperintense lesions are found on diffusion-weighted imaging (DWI) in patients with sporadic small vessel disease (SVD). Their exact role in SVD progression remains unclear due to their asymptomatic and transient nature. The main objective is to investigate the role of DWI+lesions in the radiological progression of SVD and their relationship with clinical outcomes. METHODS: Participants with SVD were included from the Radboud University Nijmegen Diffusion tensor MRI Cohort. DWI+lesions were assessed on four time points over 14 years. Outcome measures included neuroimaging markers of SVD, cognitive performance and clinical outcomes, including stroke, all-cause dementia and all-cause mortality. Linear mixed-effect models and Cox regression models were used to examine the outcome measures in participants with a DWI+lesion (DWI+) and those without a DWI+lesion (DWI-). RESULTS: DWI+lesions were present in 45 out of 503 (8.9%) participants (mean age: 66.7 years (SD=8.3)). Participants with DWI+lesions and at least one follow-up (n=33) had higher white matter hyperintensity progression rates (ß=0.36, 95% CI=0.05 to 0.68, p=0.023), more incident lacunes (incidence rate ratio=2.88, 95% CI=1.80 to 4.67, p<0.001) and greater cognitive decline (ß=-0.03, 95% CI=-0.05 to -0.01, p=0.006) during a median follow-up of 13.2 (IQR: 8.8-13.8) years compared with DWI- participants. No differences were found in risk of all-cause mortality, stroke or dementia. CONCLUSION: Presence of a DWI+lesion in patients with SVD is associated with greater radiological progression of SVD and cognitive decline compared with patients without DWI+lesions.

A vision of 14 T MR for fundamental and clinical science.

OBJECTIVE: We outline our vision for a 14 Tesla MR system. This comprises a novel whole-body magnet design utilizing high temperature superconductor; a console and associated electronic equipment; an optimized radiofrequency coil setup for proton measurement in the brain, which also has a local shim capability; and a high-performance gradient set. RESEARCH FIELDS: The 14 Tesla system can be considered a 'mesocope': a device capable of measuring on biologically relevant scales. In neuroscience the increased spatial resolution will anatomically resolve all layers of the cortex, cerebellum, subcortical structures, and inner nuclei. Spectroscopic imaging will simultaneously measure excitatory and inhibitory activity, characterizing the excitation/inhibition balance of neural circuits. In medical research (including brain disorders) we will visualize fine-grained patterns of structural abnormalities and relate these changes to functional and molecular changes. The significantly increased spectral resolution will make it possible to detect (dynamic changes in) individual metabolites associated with pathological pathways including molecular interactions and dynamic disease processes. CONCLUSIONS: The 14 Tesla system will offer new perspectives in neuroscience and fundamental research. We anticipate that this initiative will usher in a new era of ultra-high-field MR.

Spatial Relation Between White Matter Hyperintensities and Incident Lacunes of Presumed Vascular Origin: A 14-Year Follow-Up Study.

BACKGROUND: The underlying mechanisms of incident lacunes regarding their spatial distribution remain largely unknown. We investigated the spatial distribution pattern and MRI predictors of incident lacunes in relation to white matter hyperintensity (WMH) over 14 years follow-up in sporadic small vessel disease. METHODS: Five hundred three participants from the ongoing prospective single-center Radboud University Nijmegen Diffusion Tensor and Magnetic resonance Cohort (RUN DMC) were recruited with baseline assessment in 2006 and follow ups in 2011, 2015, and 2020. Three hundred eighty-two participants who underwent at least 2 available brain MRI scans were included. Incident lacunes were systematically identified, and the spatial relationship between incident lacunes located in subcortical white matter and WMH were determined using a visual rating scale. Adjusted multiple logistic regression and linear mixed-effect regression models were used to assess the association between baseline small vessel disease markers, WMH progression, and incident lacunes. Participants with atrial fibrillation were excluded in multivariable analysis. RESULTS: Eighty incident lacunes were identified in 43 patients (mean age 66.5±8.2 years, 37.2% women) during a mean follow-up time of 11.2±3.3 years (incidence rate 10.0/1000 person-year). Sixty percent of incident lacunes were in the white matter, of which 48.9% showed no contact with preexisting WMH. Baseline WMH volume (odds ratio=2.5 [95% CI, 1.6-4.2]) predicted incident lacunes after adjustment for age, sex, and vascular risk factors. WMH progression was associated with incident lacunes independent of age, sex, baseline WMH volume, and vascular risk factors (odds ratio, 3.2 [95% CI, 1.5-6.9]). Baseline WMH volume and progression rate were higher in participants with incident lacunes in contact with preexisting WMH. No difference in vascular risk factors was observed regarding location or relation with preexisting WMH. CONCLUSIONS: The 2 different distribution patterns of lacunes regarding their relation to WMH may suggest distinct underlying mechanisms, one of which may be more closely linked to a similar pathophysiology as that of WMH. The longitudinal relation between WMH and lacunes further supports plausible shared mechanisms between the 2 key markers.

Determinants and Temporal Dynamics of Cerebral Small Vessel Disease: 14-Year Follow-Up.

BACKGROUND: The aim of this study is to investigate the temporal dynamics of small vessel disease (SVD) and the effect of vascular risk factors and baseline SVD burden on progression of SVD with 4 neuroimaging assessments over 14 years in patients with SVD. METHODS: Five hundred three patients with sporadic SVD (50-85 years) from the ongoing prospective cohort study (RUN DMC [Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort]) underwent baseline assessment in 2006 and follow-up in 2011, 2015, and 2020. Vascular risk factors and magnetic resonance imaging markers of SVD were evaluated. Linear mixed-effects model and negative binomial regression model were used to examine the determinants of temporal dynamics of SVD markers. RESULTS: A total of 382 SVD patients (mean [SD] 64.1 [8.4]; 219 men and 163 women) who underwent at least 2 serial brain magnetic resonance imaging scans were included, with mean (SD) follow-up of 11.15 (3.32) years. We found a highly variable temporal course of SVD. Mean (SD) WMH progression rate was 0.6 (0.74) mL/y (range, 0.02-4.73 mL/y) and 13.6% of patients had incident lacunes (1.03%/y) over the 14-year follow-up. About 4% showed net WMH regression over 14 years, whereas 38 out of 361 (10.5%), 5 out of 296 (2%), and 61 out of 231 (26%) patients showed WMH regression for the intervals 2006 to 2011, 2011 to 2015, and 2015 to 2020, respectively. Of these, 29 (76%), 5 (100%), and 57 (93%) showed overall progression across the 14-year follow-up, and the net overall WMH change between first and last scan considering all participants was a net average WMH progression over the 14-year period. Older age was a strong predictor for faster WMH progression and incident lacunes. Patients with mild baseline WMH rarely progressed to severe WMH. In addition, both baseline burden of SVD lesions and vascular risk factors independently and synergistically predicted WMH progression, whereas only baseline SVD burden predicted incident lacunes over the 14-year follow-up. CONCLUSIONS: SVD shows pronounced progression over time, but mild WMH rarely progresses to clinically severe WMH. WMH regression is noteworthy during some magnetic resonance imaging intervals, although it could be overall compensated by progression over the long follow-up.

Laminar specific fMRI reveals directed interactions in distributed networks during language processing.

Interactions between top-down and bottom-up information streams are integral to brain function but challenging to measure noninvasively. Laminar resolution, functional MRI (lfMRI) is sensitive to depth-dependent properties of the blood oxygen level-dependent (BOLD) response, which can be potentially related to top-down and bottom-up signal contributions. In this work, we used lfMRI to dissociate the top-down and bottom-up signal contributions to the left occipitotemporal sulcus (LOTS) during word reading. We further demonstrate that laminar resolution measurements could be used to identify condition-specific distributed networks on the basis of whole-brain connectivity patterns specific to the depth-dependent BOLD signal. The networks corresponded to top-down and bottom-up signal pathways targeting the LOTS during word reading. We show that reading increased the top-down BOLD signal observed in the deep layers of the LOTS and that this signal uniquely related to the BOLD response in other language-critical regions. These results demonstrate that lfMRI can reveal important patterns of activation that are obscured at standard resolution. In addition to differences in activation strength as a function of depth, we also show meaningful differences in the interaction between signals originating from different depths both within a region and with the rest of the brain. We thus show that lfMRI allows the noninvasive measurement of directed interaction between brain regions and is capable of resolving different connectivity patterns at submillimeter resolution, something previously considered to be exclusively in the domain of invasive recordings.

Single-subject Single-session Temporally-Independent Functional Modes of Brain Activity.

Temporally independent functional modes (TFMs) are functional brain networks identified based on their temporal independence. The rationale behind identifying TFMs is that different functional networks may share a common anatomical infrastructure yet display distinct temporal dynamics. Extracting TFMs usually require a larger number of samples than acquired in standard fMRI experiments, and thus have therefore previously only been performed at the group level. Here, using an ultra-fast fMRI sequence, MESH-EPI, with a volume repetition time of 158 â€‹ms, we conducted an exploratory study with n â€‹= â€‹6 subjects and computed TFMs at the single subject level on both task and resting-state datasets. We identified 6 common temporal modes of activity in our participants, including a temporal default mode showing patterns of anti-correlation between the default mode and the task-positive networks, a lateralised motor mode and a visual mode integrating the visual cortex and the visual streams. In alignment with other findings reported recently, we also showed that independent time-series are largely free from confound contamination. In particular for ultra-fast fMRI, TFMs can separate the cardiac signal from other fluctuations. Using a non-linear dimensionality reduction technique, UMAP, we obtained preliminary evidence that combinations of spatial networks as described by the TFM model are highly individual. Our results show that it is feasible to measure reproducible TFMs at the single-subject level, opening new possibilities for investigating functional networks and their integration. Finally, we provide a python toolbox for generating TFMs and comment on possible applications of the technique and avenues for further investigation.

Alterations and test-retest reliability of functional connectivity network measures in cerebral small vessel disease.

While structural network analysis consolidated the hypothesis of cerebral small vessel disease (SVD) being a disconnection syndrome, little is known about functional changes on the level of brain networks. In patients with genetically defined SVD (CADASIL, n = 41) and sporadic SVD (n = 46), we independently tested the hypothesis that functional networks change with SVD burden and mediate the effect of disease burden on cognitive performance, in particular slowing of processing speed. We further determined test-retest reliability of functional network measures in sporadic SVD patients participating in a high-frequency (monthly) serial imaging study (RUN DMC-InTENse, median: 8 MRIs per participant). Functional networks for the whole brain and major subsystems (i.e., default mode network, DMN; fronto-parietal task control network, FPCN; visual network, VN; hand somatosensory-motor network, HSMN) were constructed based on resting-state multi-band functional MRI. In CADASIL, global efficiency (a graph metric capturing network integration) of the DMN was lower in patients with high disease burden (standardized beta = -.44; p [corrected] = .035) and mediated the negative effect of disease burden on processing speed (indirect path: std. beta = -.20, p = .047; direct path: std. beta = -.19, p = .25; total effect: std. beta = -.39, p = .02). The corresponding analyses in sporadic SVD showed no effect. Intraclass correlations in the high-frequency serial MRI dataset of the sporadic SVD patients revealed poor test-retest reliability and analysis of individual variability suggested an influence of age, but not disease burden, on global efficiency. In conclusion, our results suggest that changes in functional connectivity networks mediate the effect of SVD-related brain damage on cognitive deficits. However, limited reliability of functional network measures, possibly due to age-related comorbidities, impedes the analysis in elderly SVD patients.

Contribution of acute infarcts to cerebral small vessel disease progression.

OBJECTIVE: To determine the contribution of acute infarcts, evidenced by diffusion-weighted imaging positive (DWI+) lesions, to progression of white matter hyperintensities (WMH) and other cerebral small vessel disease (SVD) markers. METHODS: We performed monthly 3T magnetic resonance imaging (MRI) for 10 consecutive months in 54 elderly individuals with SVD. MRI included high-resolution multishell DWI, and 3-dimensional fluid-attenuated inversion recovery, T1, and susceptibility-weighted imaging. We determined DWI+ lesion evolution, WMH progression rate (ml/mo), and number of incident lacunes and microbleeds, and calculated for each marker the proportion of progression explained by DWI+ lesions. RESULTS: We identified 39 DWI+ lesions on 21 of 472 DWI scans in 9 of 54 subjects. Of the 36 DWI+ lesions with follow-up MRI, 2 evolved into WMH, 4 evolved into a lacune (3 with cavity <3mm), 3 evolved into a microbleed, and 27 were not detectable on follow-up. WMH volume increased at a median rate of 0.027 ml/mo (interquartile range = 0.005-0.073), but was not significantly higher in subjects with DWI+ lesions compared to those without (p = 0.195). Of the 2 DWI+ lesions evolving into WMH on follow-up, one explained 23% of the total WMH volume increase in one subject, whereas the WMH regressed in the other subject. DWI+ lesions preceded 4 of 5 incident lacunes and 3 of 10 incident microbleeds. INTERPRETATION: DWI+ lesions explain only a small proportion of the total WMH progression. Hence, WMH progression seems to be mostly driven by factors other than acute infarcts. DWI+ lesions explain the majority of incident lacunes and small cavities, and almost one-third of incident microbleeds, confirming that WMH, lacunes, and microbleeds, although heterogeneous on MRI, can have a common initial appearance on MRI. ANN NEUROL 2019;86:582-592.

Memory decline in elderly with cerebral small vessel disease explained by temporal interactions between white matter hyperintensities and hippocampal atrophy.

White matter hyperintensities (WMH) constitute the visible spectrum of cerebral small vessel disease (SVD) markers and are associated with cognitive decline, although they do not fully account for memory decline observed in individuals with SVD. We hypothesize that WMH might exert their effect on memory decline indirectly by affecting remote brain structures such as the hippocampus. We investigated the temporal interactions between WMH, hippocampal atrophy and memory decline in older adults with SVD. Five hundred and three participants of the RUNDMC study underwent neuroimaging and cognitive assessments up to 3 times over 8.7 years. We assessed WMH volumes semi-automatically and calculated hippocampal volumes (HV) using FreeSurfer. We used linear mixed effects models and causal mediation analyses to assess both interaction and mediation effects of hippocampal atrophy in the associations between WMH and memory decline, separately for working memory (WM) and episodic memory (EM). Linear mixed effect models revealed that the interaction between WMH and hippocampal volumes explained memory decline (WM: ß = .067; 95%CI[.024-0.111]; p < .01; EM: ß = .061; 95%CI[.025-.098]; p < .01), with better model fit when the WMH*HV interaction term was added to the model, for both WM (likelihood ratio test, χ2 [1] = 9.3, p < .01) and for EM (likelihood ratio test, χ2 [1] = 10.7, p < .01). Mediation models showed that both baseline WMH volume (ß = -.170; p = .001) and hippocampal atrophy (ß = 0.126; p = .009) were independently related to EM decline, but the effect of baseline WMH on EM decline was not mediated by hippocampal atrophy (p value indirect effect: 0.572). Memory decline in elderly with SVD was best explained by the interaction of WMH and hippocampal volumes. The relationship between WMH and memory was not causally mediated by hippocampal atrophy, suggesting that memory decline during aging is a heterogeneous condition in which different pathologies contribute to the memory decline observed in elderly with SVD.

Higher GABA concentration in the medial prefrontal cortex of Type 2 diabetes patients is associated with episodic memory dysfunction.

Type 2 diabetes (T2D) is associated with an accelerated episodic memory decline, but the underlying pathophysiological mechanisms are not well understood. Hallmarks of T2D comprise impairment of insulin secretion and insulin sensitivity. Insulin signaling modulates cerebral neurotransmitter activity, including the excitatory glutamate and inhibitory gamma-aminobutyric acid (GABA) systems. Here we tested the hypothesis that the glutamate and GABA systems are altered in T2D patients and this relates to memory decline and insulin resistance. Using 1 H-magnetic resonance spectroscopy (MRS), we examined glutamate and GABA concentrations in episodic memory relevant brain regions (medial prefrontal cortex and precuneus) of T2D patients and matched controls. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamps and memory performance was assessed using a face-profession associations test. T2D patients exhibited peripheral insulin resistance and had a decreased memory for face-profession associations as well as elevated GABA concentration in the medial prefrontal cortex but not precuneus. In addition, medial prefrontal cortex GABA concentration was negatively associated with memory performance suggesting that abnormal GABA levels in the medial prefrontal cortex are linked to the episodic memory decline that occurs in T2D patients.

Fast model-based T2 mapping using SAR-reduced simultaneous multislice excitation.

PURPOSE: To obtain whole-brain high-resolution T2 maps in 2 minutes by combining simultaneous multislice excitation and low-power PINS (power independent of number of slices) refocusing pulses with undersampling and a model-based reconstruction. METHODS: A multi-echo spin-echo sequence was modified to acquire multiple slices simultaneously, ensuring low specific absorption rate requirements. In addition, the acquisition was undersampled to achieve further acceleration. Data were reconstructed by subsequently applying parallel imaging to separate signals from different slices, and a model-based reconstruction to estimate quantitative T2 from the undersampled data. The signal model used is based on extended phase graph simulations that also account for nonideal slice profiles and B1 inhomogeneity. In vivo experiments with 3 healthy subjects were performed to compare accelerated T2 maps to fully sampled single-slice acquisitions. The accuracy of the T2 values was assessed with phantom experiments by comparing the T2 values to single-echo spin-echo measurements. RESULTS: In vivo results showed that conventional multi-echo spin-echo, simultaneous multislice, and undersampling result in similar mean T2 values within regions of interest. However, combining simultaneous multislice and undersampling results in higher SDs (about 7 ms) in comparison to a conventional sequence (about 3 ms). The T2 values were reproducible between scan and rescan (SD < 1.2 ms) within subjects and were in similar ranges across subjects (SD < 4.5 ms). CONCLUSION: The proposed method is a fast T2 mapping technique that enables whole-brain acquisitions at 0.7-mm in-plane resolution, 3-mm slice thickness, and low specific absorption rate in 2 minutes.

Porcupine: A visual pipeline tool for neuroimaging analysis.

The field of neuroimaging is rapidly adopting a more reproducible approach to data acquisition and analysis. Data structures and formats are being standardised and data analyses are getting more automated. However, as data analysis becomes more complicated, researchers often have to write longer analysis scripts, spanning different tools across multiple programming languages. This makes it more difficult to share or recreate code, reducing the reproducibility of the analysis. We present a tool, Porcupine, that constructs one's analysis visually and automatically produces analysis code. The graphical representation improves understanding of the performed analysis, while retaining the flexibility of modifying the produced code manually to custom needs. Not only does Porcupine produce the analysis code, it also creates a shareable environment for running the code in the form of a Docker image. Together, this forms a reproducible way of constructing, visualising and sharing one's analysis. Currently, Porcupine links to Nipype functionalities, which in turn accesses most standard neuroimaging analysis tools. Our goal is to release researchers from the constraints of specific implementation details, thereby freeing them to think about novel and creative ways to solve a given problem. Porcupine improves the overview researchers have of their processing pipelines, and facilitates both the development and communication of their work. This will reduce the threshold at which less expert users can generate reusable pipelines. With Porcupine, we bridge the gap between a conceptual and an implementational level of analysis and make it easier for researchers to create reproducible and shareable science. We provide a wide range of examples and documentation, as well as installer files for all platforms on our website: https://timvanmourik.github.io/Porcupine. Porcupine is free, open source, and released under the GNU General Public License v3.0.