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We aimed to compare the ability of diffusion tensor imaging and multi‐compartment spherical mean technique to detect focal tissue damage and in distinguishing between different connectivity patterns associated with varying clinical outcomes in multiple sclerosis (MS). Seventy‐six people diagnosed with MS were scanned using a SIEMENS Prisma Fit 3T magnetic resonance imaging (MRI), employing both conventional (T1w and fluid‐attenuated inversion recovery) and advanced diffusion MRI sequences from which fractional anisotropy (FA) and microscopic FA (μFA) maps were generated. Using automated fiber quantification (AFQ), we assessed diffusion profiles across multiple white matter (WM) pathways to measure the sensitivity of anisotropy diffusion metrics in detecting localized tissue damage. In parallel, we analyzed structural brain connectivity in a specific patient cohort to fully grasp its relationships with cognitive and physical clinical outcomes. This evaluation comprehensively considered different patient categories, including cognitively preserved (CP), mild cognitive deficits (MCD), and cognitively impaired (CI) for cognitive assessment, as well as groups distinguished by physical impact: those with mild disability (Expanded Disability Status Scale [EDSS] <=3) and those with moderate–severe disability (EDSS >3). In our initial objective, we employed Ridge regression to forecast the presence of focal MS lesions, comparing the performance of μFA and FA. μFA exhibited a stronger association with tissue damage and a higher predictive precision for focal MS lesions across the tracts, achieving an R‐squared value of.57, significantly outperforming the R‐squared value of.24 for FA (p‐value <.001). In structural connectivity, μFA exhibited more pronounced differences than FA in response to alteration in both cognitive and physical clinical scores in terms of effect size and number of connections. Regarding cognitive groups, FA differences between CP and MCD groups were limited to 0.5% of connections, mainly around the thalamus, while μFA revealed changes in 2.5% of connections. In the CP and CI group comparison, which have noticeable cognitive differences, the disparity was 5.6% for FA values and 32.5% for μFA. Similarly, μFA outperformed FA in detecting WM changes between the MCD and CI groups, with 5% versus 0.3% of connections, respectively. When analyzing structural connectivity between physical disability groups, μFA still demonstrated superior performance over FA, disclosing a 2.1% difference in connectivity between regions closely associated with physical disability in MS. In contrast, FA spotted a few regions, comprising only 0.6% of total connections. In summary, μFA emerged as a more effective tool than FA in predicting MS lesions and identifying structural changes across patients with different degrees of cognitive and global disability, offering deeper insights into the complexities of MS‐related impairments. [ABSTRACT FROM AUTHOR]

The relationship between brain diffusion microstructural changes and disability in multiple sclerosis (MS) remains poorly understood. We aimed to explore the predictive value of microstructural properties in white (WM) and grey matter (GM), and identify areas associated with mid-term disability in MS patients. We studied 185 patients (71% female; 86% RRMS) with the Expanded Disability Status Scale (EDSS), timed 25-foot walk (T25FW), nine-hole peg test (9HPT), and Symbol Digit Modalities Test (SDMT) at two time-points. We used Lasso regression to analyse the predictive value of baseline WM fractional anisotropy and GM mean diffusivity, and to identify areas related to each outcome at 4.1 years follow-up. Motor performance was associated with WM (T25FW: RMSE = 0.524, R2 = 0.304; 9HPT dominant hand: RMSE = 0.662, R2 = 0.062; 9HPT non-dominant hand: RMSE = 0.649, R2 = 0.139), and SDMT with GM diffusion metrics (RMSE = 0.772, R2 = 0.186). Cingulum, longitudinal fasciculus, optic radiation, forceps minor and frontal aslant were the WM tracts most closely linked to motor dysfunction, and temporal and frontal cortex were relevant for cognition. Regional specificity related to clinical outcomes provide valuable information that can be used to develop more accurate predictive models that could improve therapeutic strategies. [ABSTRACT FROM AUTHOR]

The Default-Mode Network (DMN) is compromised in healthy aging and in several neurodegenerative diseases. Glutamate and GABA are the main excitatory and inhibitory human neurotransmitters respectively, and are highly implicated in neuroplasticity and brain activation, where N-acetyl-aspartate (NAA) seems also to be involved. The aim of the present investigation was to determine if metabolite concentrations of these neurochemicals can be modulated in core regions of the DMN in healthy elderly. For this purpose we used a plasticity inducing TMS protocol, intermittent theta-burst stimulation (iTBS). Twenty-one cognitively healthy elderly (mean age: 67.29, SD: 4.88) were included. Individually-guided neuronavigated iTBS was applied over the left inferior parietal lobe (IPL) in the middle of two Magnetic Resonance Spectroscopy (MRS) acquisitions measuring GABA, Glx (Glutamate + Glutamine) and total NAA (tNAA) concentrations. The MRS voxel was centered over the parietal cingulate cortex (PCC). Subjects were randomly assigned to receive real ( N = 11) or sham ( N = 10) iTBS. A resting-state functional Magnetic Resonance Imaging (rs-fMRI) acquisition and a high-resolution 3D sequence were also acquired. TNAA decreased significantly within the PCC after iTBS application ( F = 5.271, p = 0.035; Fig. 1). Greater neurochemical response to iTBS in posteromedial areas was related to (1) lower baseline rs-fMRI connectivity between the stimulated area and the PCC region ( r = −0.649, p = 0.031; Stim-to-PCC in Fig. 2), (2) reduced brain atrophy in different cortical regions (i.e. paracentral lobe: r = 0.751, p = 0.008), and (3) better scores in a phonetic fluency task ( r = 0.663, p = 0.026). Our findings show that a TMS intervention is able to modulate tNAA concentrations from the stimulation site to a distal DMN core area. Further, the magnitude of the observed neurochemical modulation was related to baseline connectivity between these two areas, as with greater structural brain integrity and better cognitive performance. Demonstration of experimentally-controlled neurochemical modulation in key cortical areas opens the possibility of TMS to be used as a tool to interrogate brain neurochemical changes in aging and in early neurodegenerative conditions. [ABSTRACT FROM AUTHOR]

Introduction The capacity of repetitive TMS to transiently interfere with cognitive processes in humans may offer an experimental platform for pharmacological studies. Developing compounds could then be tested to reverse artificially generated cognitive dysfunction, providing first hints of efficacy. In the FP7-IMI European ’Pharmacog’ Project, an rTMS protocol previously published in the literature, was adapted and validated as a ’cognitive challenge model’ to mimic episodic memory dysfunction occurring in early Alzheimer’s disease. However, it would be desirable to test whether the effects of TMS are comparable and reproducible across different centres and time-point assessments. Objectives Our main aims were, (1) to find out if visual memory interference through rTMS administration could be replicated using our specific experimental settings and task adaptations (Fig. 1), (2) to test if results are comparable in two centres and (3) to investigate if the effects obtained are reproducible when subjects are re-tested 15 days later. Methods 68 healthy young male subjects were included. Neuronavigated (Fig. 1) repetitive TMS was applied over the left dorsolateral prefrontal cortex (LDLPFC) or the Vertex area (control condition) during encoding of pictures, for latter memory recognition. Subjects attended one of two research centres in three main occasions: On visit 1, rTMS was applied using a sham coil and served as a baseline measure. On visit 2, real rTMS was administered. On visit 3, 15 days later, a subsample ( N = 21) performed the same protocol to test for reproducibility of effects. Results A time (visit 1 vs visit 2) × TMS type (LDLPFC vs Vertex) ANOVA and posterior pairwise comparisons revealed that only rTMS delivered over the LDLPFC and during visit 2 day resulted in a significant decrease in subsequent memory recognition ( F = 8.95, p = 0.004; Fig. 2a). No centre effect observed ( F = 0.03, p = 0.96). Initial rTMS effects could not be replicated in the subsample (Fig. 2b). Conclusions Our findings offers positive evidence regarding the feasibility of adapting a rTMS cognitive interference protocol, to conduct new experimental research in separate independent institutions. The factors underlying the lack of test–retest reproducibility of the interference should be further investigated. [ABSTRACT FROM AUTHOR]