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•EEG-MRS imaging combination unravels further modulating factors of catecholamine effects.•Baseline GABA+ has a predictive role in brain regions influencing responsiveness to MPH stimulation and cognitive control.•The predictive impact of GABA+ levels in key brain areas varies based on the required cognitive effort.•GABA+ baseline levels in the ACC are particularly important in high-effort situations. Catecholamines and amino acid transmitter systems are known to interact, the exact links and their impact on cognitive control functions have however remained unclear. Using a multi-modal imaging approach combining EEG and proton-magnetic resonance spectroscopy (1H-MRS), we investigated the effect of different degrees of pharmacological catecholaminergic enhancement onto theta band activity (TBA) as a measure of interference control during response inhibition and execution. It was central to our study to evaluate the predictive impact of in-vivo baseline GABA+ concentrations in the striatum, the anterior cingulate cortex (ACC) and the supplemental motor area (SMA) of healthy adults under varying degrees of methylphenidate (MPH) stimulation. We provide evidence for a predictive interrelation of baseline GABA+ concentrations in cognitive control relevant brain areas onto task-induced TBA during response control stimulated with MPH. Baseline GABA+ concentrations in the ACC, the striatum, and the SMA had a differential impact on predicting interference control-related TBA in response execution trials. GABA+ concentrations in the ACC appeared to be specifically important for TBA modulations when the cognitive effort needed for interference control was high – that is when no prior task experience exists, or in the absence of catecholaminergic enhancement with MPH. The study highlights the predictive role of baseline GABA+ concentrations in key brain areas influencing cognitive control and responsiveness to catecholaminergic enhancement, particularly in high-effort scenarios.

Behavioral flexibility and goal-directed behavior heavily depend on fronto-striatal networks. Within these circuits, gamma-aminobutyric acid (GABA) and glutamate play an important role in (motor) response inhibition, but it has remained largely unclear whether they are also relevant for cognitive inhibition. We hence investigated the functional role of these transmitters for cognitive inhibition during cognitive flexibility. Healthy young adults performed two paradigms assessing different aspects of cognitive flexibility. Magnetic resonance spectroscopy (MRS) was used to quantify GABA+ and total glutamate/glutamine (Glx) levels in the striatum and anterior cingulate cortex (ACC) referenced to N-acetylaspartate (NAA). We observed typical task switching and backward inhibition effects, but striatal and ACC concentrations of GABA+/NAA and Glx/NAA were not associated with cognitive flexibility in a functionally relevant manner. The assumption of null effects was underpinned by Bayesian testing. These findings suggest that behavioral and cognitive inhibition are functionally distinct faculties, that depend on (at least partly) different brain structures and neurotransmitter systems. While previous studies consistently demonstrated that motor response inhibition is modulated by ACC and striatal GABA levels, our results suggest that the functionally distinct cognitive inhibition required for successful switching is not, or at least to a much lesser degree, modulated by these factors.

Cognitive control, which is critical for goal‐directed behavior, involves resolving conflicts between competing stimuli and is influenced by neurotransmitter interactions within cortico‐subcortical areas. This study investigated the relationship between baseline amino acid transmitter levels and interference control, focusing on the effects of experimentally enhancing catecholaminergic signaling. Using a double‐blind, placebo‐controlled crossover design with two dosage groups, n = 71 healthy human adults underwent proton magnetic resonance spectroscopy once to assess baseline GABA+ and Glx levels in the anterior cingulate cortex (ACC), striatum, and supplementary motor area (SMA). Participants then performed a subliminally primed flanker task inducing different scales of conflict twice while EEG was recorded: once after receiving a placebo (lactase) and once more under either low (0.25 mg/kg) or medium (0.50 mg/kg) doses of methylphenidate (MPH), which modulates the catecholaminergic and amino acid transmitter systems driving cognitive and interference control. Medium MPH doses were more effective than low doses at reducing subliminal interference effects, highlighting dose‐specific behavioral improvements. Higher striatal GABA+ levels led to better interference control at low doses, while lower ACC GABA+ and GABA+/Glx levels were associated with better interference control at medium doses, suggesting a dose‐dependent shift from striatal to ACC dominance in conflict resolution. Neurophysiological (EEG data) analyses revealed increased theta‐band (TBA) and alpha‐band activity (ABA) overlapping in the mid‐superior‐frontal and inferior‐frontal clusters under conditions of heightened cognitive control demands. The findings highlight that whether and how amino acid transmitter levels in cognitive control‐relevant regions modulate interference conflicts depends on the degree of catecholaminergic signaling. We found medium methylphenidate doses (0.5 mg/kg) to be more effective than low doses (0.25 mg/kg) at reducing subliminal interference effects, with higher striatal GABA+ levels leading to better interference control at low doses, while lower ACC GABA+ and GABA+/Glx levels led to better interference control at medium doses.

Catecholamines and amino acid transmitter systems are known to interact, the exact links and their impact on cognitive control functions have however remained unclear. Using a multi-modal imaging approach combining EEG and proton-magnetic resonance spectroscopy ( H-MRS), we investigated the effect of different degrees of pharmacological catecholaminergic enhancement onto theta band activity (TBA) as a measure of interference control during response inhibition and execution. It was central to our study to evaluate the predictive impact of in-vivo baseline GABA+ concentrations in the striatum, the anterior cingulate cortex (ACC) and the supplemental motor area (SMA) of healthy adults under varying degrees of methylphenidate (MPH) stimulation. We provide evidence for a predictive interrelation of baseline GABA+ concentrations in cognitive control relevant brain areas onto task-induced TBA during response control stimulated with MPH. Baseline GABA+ concentrations in the ACC, the striatum, and the SMA had a differential impact on predicting interference control-related TBA in response execution trials. GABA+ concentrations in the ACC appeared to be specifically important for TBA modulations when the cognitive effort needed for interference control was high - that is when no prior task experience exists, or in the absence of catecholaminergic enhancement with MPH. The study highlights the predictive role of baseline GABA+ concentrations in key brain areas influencing cognitive control and responsiveness to catecholaminergic enhancement, particularly in high-effort scenarios.

Pelizaeus‐Merzbacher disease (PMD) is a rare childhood hypomyelinating leukodystrophy. Quantification of the pronounced myelin deficit and delineation of subtle myelination processes are of high clinical interest. Quantitative magnetic resonance imaging (qMRI) techniques can provide in vivo insights into myelination status, its spatial distribution, and dynamics during brain maturation. They may serve as potential biomarkers to assess the efficacy of myelin‐modulating therapies. However, registration techniques for image quantification and statistical comparison of affected pediatric brains, especially those of low or deviant image tissue contrast, with healthy controls are not yet established. This study aimed first to develop and compare postprocessing pipelines for atlas‐based quantification of qMRI data in pediatric patients with PMD and evaluate their registration accuracy. Second, to apply an optimized pipeline to investigate spatial myelin deficiency using myelin water imaging (MWI) data from patients with PMD and healthy controls. This retrospective single‐center study included five patients with PMD (mean age, 6 years ± 3.8) who underwent conventional brain MRI and diffusion tensor imaging (DTI), with MWI data available for a subset of patients. Three methods of registering PMD images to a pediatric template were investigated. These were based on (a) T1‐weighted (T1w) images, (b) fractional anisotropy (FA) maps, and (c) a combination of T1w, T2‐weighted, and FA images in a multimodal approach. Registration accuracy was determined by visual inspection and calculated using the structural similarity index method (SSIM). SSIM values for the registration approaches were compared using a t test. Myelin water fraction (MWF) was quantified from MWI data as an assessment of relative myelination. Mean MWF was obtained from two PMDs (mean age, 3.1 years ± 0.3) within four major white matter (WM) pathways of a pediatric atlas and compared to seven healthy controls (mean age, 3 years ± 0.2) using a Mann–Whitney U test. Our results show that visual registration accuracy estimation and computed SSIM were highest for FA‐based registration, followed by multimodal, and T1w‐based registration (SSIMFA = 0.67 ± 0.04 vs. SSIMmultimodal = 0.60 ± 0.03 vs. SSIMT1 = 0.40 ± 0.14). Mean MWF of patients with PMD within the WM pathways was significantly lower than in healthy controls MWFPMD = 0.0267 ± 0.021 vs. MWFcontrols = 0.1299 ± 0.039. Specifically, MWF was measurable in brain structures known to be myelinated at birth (brainstem) or postnatally (projection fibers) but was scarcely detectable in other brain regions (commissural and association fibers). Taken together, our results indicate that registration accuracy was highest with an FA‐based registration pipeline, providing an alternative to conventional T1w‐based registration approaches in the case of hypomyelinating leukodystrophies missing normative intrinsic tissue contrasts. The applied atlas‐based analysis of MWF data revealed that the extent of spatial myelin deficiency in patients with PMD was most pronounced in commissural and association and to a lesser degree in brainstem and projection pathways. FA‐based template registration is superior to conventional T1w registration in patients with hypomyelinating Pelizaeus‐Merzbacher disease (PMD) and provides an alternative approach that enables atlas‐based assessment of myelination using quantitative magnetic resonance imaging in hypomyelinating disorders.

Hintergrund: Multiple Sklerose (MS) ist eine Erkrankung, die mit Demyelinisierung und axonaler Degeneration einhergeht. Diese konnen mittels Diffusionstensorbildgebung (DTI) und Myelin-Wasser-Bildgebung (MWI) quantifiziert werden, indem der Einfluss der MS-Lasionen (T2L) auf das umgebende Traktgewebe (\"normal appearing tract tissue\", NATT) bestimmt wird. Methoden: Bei 28 MS-Patienten sowie 26 gesunde Probanden wurden Myelin-Wasser-Fraktion (MWF; [1]) sowie die DTI-Messwerte (FA, RD, MD, AD) in T2L und NATT bestimmt. Atlasbasiert [2] wurden Fasertrakte selektiert und die relative Lasionsbelastung (rLB) der Trakte berechnet, um die Lasionslast unabhangig vom Traktvolumen zu vergleichen. Ergebnisse: Es wurde ein signifikanter Unterschied von MWF und FA zwischen Kontrollen und Patienten gefunden (MWF; p < 0,001; FA: p = 0,0018). Des Weiteren zeigte sich eine moderate Korrelation zwischen [MWF.sub.Lesion] u. [MW.sub.FNATT] (r=0,62) und [FA.sub.Lesion und] [F.sub.ANATT] (r=0,60; Abb. 1). Es bestand demgegenuber keine Korrelation zwischen [MWF.sub.Lesion] und [FA.sub.Lesion] (r=0,18) und eine schwache, aber nahezu moderate Korrelation zwischen [MW.sub.FNATT] und [F.sub.ANATT] (r=0,48). Diskussion: Die moderate Korrelation zwischen der Schadigung des Lasionsgewebes und der NATT zeigt, dass Lasionen bei MS einen Einfluss auf das sie umgebende Traktgewebe haben. Dieser Effekt verstarkt sich in Abhangigkeit vom Grad der Schadigung der Lasionen. Fazit: Unsere Ergebnisse stutzen die Hypothese, dass die Waller-Degeneration von Axonen vom Ausmass der inflammatorischen Schadigung der fokalen Lasion abhangt. Unsere Ergebnisse weisen darauf hin, dass der axonale Verlust innerhalb der Lasionen nicht parallel mit der inflammatorischen Demyelinisierung entsteht, was hypothetisch auf teilweise axonal schutzende Remyelinisierung zuruckzufuhren ist. Gleichzeitig verlaufen aber Demyelinisierung und axonaler Verlust ausserhalb der Lasionen im NATT parallel, hinweisend auf einen moglicherweise langsam progredienten, homogenen degenerativen Prozess.

In a companion paper by Cohen-Adad et al . we introduce the spine generic quantitative MRI protocol that provides valuable metrics for assessing spinal cord macrostructural and microstructural integrity. This protocol was used to acquire a single subject dataset across 19 centers and a multi-subject dataset across 42 centers (for a total of 260 participants), spanning the three main MRI manufacturers: GE, Philips and Siemens. Both datasets are publicly available via git-annex. Data were analysed using the Spinal Cord Toolbox to produce normative values as well as inter/intra-site and inter/intra-manufacturer statistics. Reproducibility for the spine generic protocol was high across sites and manufacturers, with an average inter-site coefficient of variation of less than 5% for all the metrics. Full documentation and results can be found at https://spine-generic.rtfd.io/ . The datasets and analysis pipeline will help pave the way towards accessible and reproducible quantitative MRI in the spinal cord. Measurement(s) spinal cord Technology Type(s) magnetic resonance imaging Factor Type(s) manufacturer • site Sample Characteristic - Organism Homo sapiens Sample Characteristic - Location Canada • Switzerland • Australia • United States of America • United Kingdom • Germany • French Republic • Czech Republic • Italy • Japan • Kingdom of Spain • China Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.14052269

Background: Neural functional connectivity (FC) dynamics at rest may be linked to cognitive and behavioural deficits in multiple sclerosis (MS) [1]. However, it is still unclear how FC network dynamics can be differentially characterized for MS versus healthy controls (HC) and during the cause of the disease. Here, we investigate properties of two mutually exclusive dynamic FC brain states: functional segregation (I) and integration (II). Methods: Results: Dynamic functional connectivity (DFC) analyses. Statistical analyses: There was no significant linear time effect on the parameters. We observed an increasing trend of the effect on DMT of state I (F-value: 0.352, p-value: 0.071; Fig. 5). In the group comparisons, we observed significant group differences in the MDT of state I (p-value: 0.002) and prevalence of state I (p-value: 0.0002). Discussion: 1) The two patterns in the HC confirm that functional segregation versus integration is a useful organizational principle of brain function [2]. 2) We found no linear effect of time on our dynamic FC parameters over a time scale of 3 years in MS. 3) Altered MDT and prevalence of the states may help to explain cognitive impairments in MS [1]. Conclusion: Our analyses show that dynamic FC parameters may show differences in MS as compared to HC but are not sensitive enough to track longitudinal decline. Additional analysis to investigate correlations with clinical severity and other imaging measures are in progress.

Background: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by demyelinated lesions. Conventional magnetic resonance imaging (MRI) detects various pathological changes in the tissue but is non-specific for myelin. The in vivo MRI technique Multi-Component Driven Equalibrium Single Pulse Observation of T1 and T2 (mcDESPOT) [1], which allows the determination of relative myelination by measuring the myelin water fraction (MWF) [2], can enable the quantification of demyelination in lesions. The aim of this study was to assess the intra- and interindividual variability of MWF in lesions to analyze differences in focal myelin loss in an RRMS cohort. Methoden: FLAIR images and mcDESPOT data were measured from n = 112 relapsing remitting patients. A 1.5T MR scanner and an 8-channel head coil was used to obtain the multi-component T1 and T2 information from sets of Fast Low Angle SHot (FLASH) and True Fast Imaging with Steady State Precession (TrueFISP) sequences over a range of flip angles measured at constant TR [1]. The co-registration of the MR data was done with Statistical Parametric Mapping (SPM) [3]. The MWF maps were calculated according to the established method from the mcDESPOT sequences [1]. The lesions were segmented into binary masks. An algorithm was developed to automate the reading of the MWF of individual lesions for analysis of myelination differences. To compare two groups, the two-sided Wilcoxon rank sum test was used (significance level 5%). Results: The median MWF in the white matter (WM) of healthy controls showed a significant difference (p = 0.0011) to RRMS patients. 2787 WM FLAIR lesions were examined. The median MWF loss within the lesions varies from 6% to 70% for different patients compared to control white matter MWF levels. In a group comparison it could be shown that patients with a higher degree of disability of EDSS [greater than or equal to] 4 significantly (p = 0.00026) have lower MWF values than patients with EDSS [less than or equal to] 2. Discussion: Significant reduction and heterogeneity of MWF in NAWM and MS lesions has been identified, reflecting varying degrees of demyelination. Conclusion: This technique may be helpful to differentiate patients with early onset of strong myelin loss from those with low myelin loss.

Background: Selective neurodegeneration in Amyotrophic Lateral Sclerosis (ALS) affects the primary motor system. We aimed to understand the relationship between cortical degeneration and the desintegration of the related motor corticospinal tract (CST) by applying both Diffusion Tensor Imaging (DTI) and the multi-component driven equilibrium single pulse observation of T1 and T2 (mcDESPOT). Methods: ALS patients (n = 27) were recruited for the NiSALS (Neuroimaging Society in Amyotrophic Lateral Sclerosis) registry and underwent cerebral neuroimaging and quantitative MRI. Age/range matched healthy control subjects (n = 21) provided a comparative dataset. Data was acquired on a SIEMENS Verio 3T scanner. DTI: EPI sequence, diffusion scheme with two b/values (0/100), 64 diffusion directions and a resolution of 2 mm[and]3. Mean diffusivity (MD), axial (AD) and radial diffusivity (RD) and fractional anisotropy (FA) measures were calculated. mcDESPOT: isotropic 1.7 mm[and]3 whole-brain data; FLASH (TR: 5.9 ms, FA = [4, 5.3, 6.6, 8, 9.3, 12, 17.3, 24][degrees]), trueFISP (TR 5.6 ms; FA = [9.8, 13.1, 16.4, 19.7, 22.9, 29.5, 42.6, 59][degrees]) and inversion prepared FLASH (TR 5.7 ms, FA = 5[degrees], TI [450, 700] ms, PE 72). The relaxation measures T1 time and T2 time, myelin water fraction (MWF) and residence time (MRT) were retrieved. The corticospinal tract (CST) was generated as region-of-interest (ROI) by tractographic reconstruction (DSIstudio) and diffusion measures were acquired. The multicomponent relaxation characteristics and myelin water measures were retrieved (Deoni et al.) including T1/T2 time, MWF and MRT of individual tracts. Results: Higher MD (p < 0.01) and lower FA (p < 0.01) were found in ALS CST. Notably, RD revealed highly significant lower values in ALS CST (p 0.0013). Whereas the CST MWF in ALS patients was non-significantly lower than in controls we found significantly higher values in CST MRT in ALS (p < 0.01). Discussion: Motor system degeneration in ALS effects CST integrity reflected by changes MD, RD and FA. Whereas significant differences in MRT also reveals early alteration of myelin integrity, the relative myelin content measured by MWF was assumably not significantly different in ALS given the early observation at the time of disease diagnosis. Conclusion: Secondary WM tract degeneration occurs early in disease. Besides the loss of structural integrity early alterations of the myelin characteristics indicate changes of its composition.