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Decreased long-range temporal correlations (LRTC) in brain signals can be used to measure cognitive effort during task execution. Here, we examined how learning a motor sequence affects long-range temporal memory within resting-state functional magnetic resonance imaging signal. Using the Hurst exponent (HE), we estimated voxel-wise LRTC and assessed changes over 5 consecutive days of training, followed by a retention scan 12 days later. The experimental group learned a complex visuomotor sequence while a complementary control group performed tightly matched movements. An interaction analysis revealed that HE decreases were specific to the complex sequence and occurred in well-known motor sequence learning associated regions including left supplementary motor area, left premotor cortex, left M1, left pars opercularis, bilateral thalamus, and right striatum. Five regions exhibited moderate to strong negative correlations with overall behavioral performance improvements. Following learning, HE values returned to pretraining levels in some regions, whereas in others, they remained decreased even 2 weeks after training. Our study presents new evidence of HE's possible relevance for functional plasticity during the resting-state and suggests that a cortical subset of sequence-specific regions may continue to represent a functional signature of learning reflected in decreased long-range temporal dependence after a period of inactivity., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: A stroke frequently results in impaired performance of activities of daily life. Many of these are highly dependent on effective coordination between the two arms. In the context of bimanual movements, cyclic rhythmical bilateral arm coordination patterns can be classified into two fundamental modes: in-phase (bilateral homologous muscles contract simultaneously) and anti-phase (bilateral muscles contract alternately) movements. We aimed to investigate how patients with left (LHS) and right (RHS) hemispheric stroke are differentially affected in both individual-limb control and inter-limb coordination during bilateral movements., Methods: We used kinematic measurements to assess bilateral coordination abilities of 18 chronic hemiparetic stroke patients (9 LHS; 9 RHS) and 18 age- and sex-matched controls. Using KINARM upper-limb exoskeleton system, we examined individual-limb control by quantifying trajectory variability in each hand and inter-limb coordination by computing the phase synchronization between hands during anti- and in-phase movements., Results: RHS patients exhibited greater impairment in individual- and inter-limb control during anti-phase movements, whilst LHS patients showed greater impairment in individual-limb control during in-phase movements alone. However, LHS patients further showed a swap in hand dominance during in-phase movements., Conclusions: The current study used individual-limb and inter-limb kinematic profiles and showed that bilateral movements are differently impaired in patients with left vs. right hemispheric strokes. Our results demonstrate that both fundamental bilateral coordination modes are differently controlled in both hemispheres using a lesion model approach. From a clinical perspective, we suggest that lesion side should be taken into account for more individually targeted bilateral coordination training strategies., Trial Registration: the current experiment is not a health care intervention study., (© 2023. The Author(s).)

Resting-state (rs) functional magnetic resonance imaging (fMRI) is used to detect low-frequency fluctuations in the blood oxygen-level dependent (BOLD) signal across brain regions. Correlations between temporal BOLD signal fluctuations are commonly used to infer functional connectivity. However, because BOLD is based on the dilution of deoxyhemoglobin, it is sensitive to veins of all sizes, and its amplitude is biased by draining veins. These biases affect local BOLD signal location and amplitude, and may also influence BOLD-derived connectivity measures, but the magnitude of this venous bias and its relation to vein size and proximity is unknown. Here, veins were identified using high-resolution quantitative susceptibility maps and utilized in a biophysical model to investigate systematic venous biases on common local rsfMRI-derived measures. Specifically, we studied the impact of vein diameter and distance to veins on the amplitude of low-frequency fluctuations (ALFF), fractional ALFF (fALFF), Hurst exponent (HE), regional homogeneity (ReHo), and eigenvector centrality values in the grey matter. Values were higher across all distances in smaller veins, and decreased with increasing vein diameter. Additionally, rsfMRI values associated with larger veins decrease with increasing distance from the veins. ALFF and ReHo were the most biased by veins, while HE and fALFF exhibited the smallest bias. Across all metrics, the amplitude of the bias was limited in voxel-wise data, confirming that venous structure is not the dominant source of contrast in these rsfMRI metrics. Finally, the models presented can be used to correct this venous bias in rsfMRI metrics., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

A body of current evidence suggests that there is a sensitive period for musical training: people who begin training before the age of seven show better performance on tests of musical skill, and also show differences in brain structure-especially in motor cortical and cerebellar regions-compared with those who start later. We used support vector machine models-a subtype of supervised machine learning-to investigate distributed patterns of structural differences between early-trained (ET) and late-trained (LT) musicians and to better understand the age boundaries of the sensitive period for early musicianship. After selecting regions of interest from the cerebellum and cortical sensorimotor regions, we applied recursive feature elimination with cross-validation to produce a model which optimally and accurately classified ET and LT musicians. This model identified a combination of 17 regions, including 9 cerebellar and 8 sensorimotor regions, and maintained a high accuracy and sensitivity (true positives, i.e., ET musicians) without sacrificing specificity (true negatives, i.e., LT musicians). Critically, this model-which defined ET musicians as those who began their training before the age of 7-outperformed all other models in which age of start was earlier or later (between ages 5-10). Our model's ability to accurately classify ET and LT musicians provides additional evidence that musical training before age 7 affects cortico-cerebellar structure in adulthood, and is consistent with the hypothesis that connected brain regions interact during development to reciprocally influence brain and behavioral maturation., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Performing endovascular medical interventions safely and efficiently requires a diverse set of skills that need to be practised in dedicated training sessions. Here, we used multimodal magnetic resonance (MR) imaging to determine the structural and functional plasticity and core skills associated with skill acquisition. A training group learned to perform a simulator-based endovascular procedure, while a control group performed a simplified version of the task; multimodal MR images were acquired before and after training. Using a well-controlled interaction design, we found strong multimodal evidence for the role of the intraparietal sulcus (IPS) in endovascular skill acquisition that is in line with previous work implicating the structure in visuospatial transformations including simple visuo-motor and mental rotation tasks. Our results provide a unique window into the multimodal nature of rapid structural and functional plasticity of the human brain while learning a multifaceted and complex clinical skill. Further, our results provide a detailed description of the plasticity process associated with endovascular skill acquisition and highlight specific facets of skills that could enhance current medical pedagogy and be useful to explicitly target during clinical resident training., Competing Interests: Competing interest statement The authors declare no competing interest., (Copyright © 2022. Published by Elsevier Inc.)

The cerebellum's involvement in cognitive, affective and motor functions is mediated by connections to different regions of the cerebral cortex. A distinctive feature of cortico-cerebellar loops that has been demonstrated in the animal work is a topographic organization that is preserved across its corticopontine, pontocerebellar, and cerebello-thalmo-cortical segments. Here we used tractography derived from diffusion imaging data to characterize the connections between the pons and the individual lobules of the cerebellum and generate a parcellation of the pons and middle cerebellar peduncle based on the pattern of connectivity. We identified a rostral to caudal gradient in the pons, similar to that observed in the animal work, such that rostral regions were preferentially connected to cerebellar lobules involved in non-motor, and caudal regions with motor regions. These findings advance our fundamental understanding of the cerebellum, and the parcellations we generated provide context for future research into the pontocerebellar tract's involvement in health and disease., (Copyright © 2022. Published by Elsevier Inc.)

Previous literature has focused on predicting a diagnostic label from structural brain imaging. Since subtle changes in the brain precede a cognitive decline in healthy and pathological aging, our study predicts future decline as a continuous trajectory instead. Here, we tested whether baseline multimodal neuroimaging data improve the prediction of future cognitive decline in healthy and pathological aging. Nonbrain data (demographics, clinical, and neuropsychological scores), structural MRI, and functional connectivity data from OASIS-3 (N = 662; age = 46-96 years) were entered into cross-validated multitarget random forest models to predict future cognitive decline (measured by CDR and MMSE), on average 5.8 years into the future. The analysis was preregistered, and all analysis code is publicly available. Combining non-brain with structural data improved the continuous prediction of future cognitive decline (best test-set performance: R2 = 0.42). Cognitive performance, daily functioning, and subcortical volume drove the performance of our model. Including functional connectivity did not improve predictive accuracy. In the future, the prognosis of age-related cognitive decline may enable earlier and more effective individualized cognitive, pharmacological, and behavioral interventions., Competing Interests: Disclosure statement The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier Inc.)

In motor learning, sequence specificity, i.e. the learning of specific sequential associations, has predominantly been studied using task-based fMRI paradigms. However, offline changes in resting state functional connectivity after sequence-specific motor learning are less well understood. Previous research has established that plastic changes following motor learning can be divided into stages including fast learning, slow learning and retention. A description of how resting state functional connectivity after sequence-specific motor sequence learning (MSL) develops across these stages is missing. This study aimed to identify plastic alterations in whole-brain functional connectivity after learning a complex motor sequence by contrasting an active group who learned a complex sequence with a control group who performed a control task matched for motor execution. Resting state fMRI and behavioural performance were collected in both groups over the course of 5 consecutive training days and at follow-up after 12 days to encompass fast learning, slow learning, overall learning and retention. Between-group interaction analyses showed sequence-specific decreases in functional connectivity during overall learning in the right supplementary motor area (SMA). We found that connectivity changes in a key region of the motor network, the superior parietal cortex (SPC) were not a result of sequence-specific learning but were instead linked to motor execution. Our study confirms the sequence-specific role of SMA that has previously been identified in online task-based learning studies, and extends it to resting state network changes after sequence-specific MSL., (© 2021. The Author(s).)

The striatum is a major subcortical connection hub that has been heavily implicated in a wide array of motor and cognitive functions. Here, we developed a normative multimodal, data-driven microstructural parcellation of the striatum using non-negative matrix factorization (NMF) based on multiple magnetic resonance imaging-based metrics (mean diffusivity, fractional anisotropy, and the ratio between T1- and T2-weighted structural scans) from the Human Connectome Project Young Adult dataset (n = 329 unrelated participants, age range: 22-35, F/M: 185/144). We further explored the biological and functional relationships of this parcellation by relating our findings to motor and cognitive performance in tasks known to involve the striatum as well as demographics. We identified 5 spatially distinct striatal components for each hemisphere. We also show the gain in component stability when using multimodal versus unimodal metrics. Our findings suggest distinct microstructural patterns in the human striatum that are largely symmetric and that relate mostly to age and sex. Our work also highlights the putative functional relevance of these striatal components to different designations based on a Neurosynth meta-analysis., (Copyright © 2021. Published by Elsevier Inc.)

Adult abilities in complex cognitive domains such as music appear to depend critically on the age at which training or experience begins, and relevant experience has greater long-term effects during periods of peak maturational change. Previous work has shown that early trained musicians (ET; < age 7) out-perform later-trained musicians (LT; > age 7) on tests of musical skill, and also have larger volumes of the ventral premotor cortex (vPMC) and smaller volumes of the cerebellum. These cortico-cerebellar networks mature and function in relation to one another, suggesting that early training may promote coordinated developmental plasticity. To test this hypothesis, we examined structural covariation between cerebellar volume and cortical thickness (CT) in sensorimotor regions in ET and LT musicians and non-musicians (NMs). Results show that ETs have smaller volumes in cerebellar lobules connected to sensorimotor cortices, while both musician groups had greater cortical thickness in right pre-supplementary motor area (SMA) and right PMC compared to NMs. Importantly, early musical training had a specific effect on structural covariance between the cerebellum and cortex: NMs showed negative correlations between left lobule VI and right pre-SMA and PMC, but this relationship was reduced in ET musicians. ETs instead showed a significant negative correlation between vermal IV and right pre-SMA and dPMC. Together, these results suggest that early musical training has differential impacts on the maturation of cortico-cerebellar networks important for optimizing sensorimotor performance. This conclusion is consistent with the hypothesis that connected brain regions interact during development to reciprocally influence brain and behavioral maturation., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Due to the increasing complexity of diseases in the aging population and rapid progress in catheter-based technology, the demands on operators' skills in conducting endovascular interventions (EI) has increased dramatically, putting more emphasis on training. However, it is not well understood which factors influence learning and performance. In the present study, we examined the ability of EI naïve medical students to acquire basic catheter skills and the role of pre-existing cognitive ability and manual dexterity in predicting performance. Nineteen medical students practised an internal carotid artery angiography during a three-day training on an endovascular simulator. Prior to the training they completed a battery of tests. Skill acquisition was assessed using quantitative and clinical performance measures; the outcome measures from the test battery were used to predict the learning rate. The quantitative metrics indicated that participants' performance improved significantly across the training, but the clinical evaluation revealed that participants did not significantly improve on the more complex part of the procedure. Mental rotation ability (MRA) predicted quantitative, but not clinical performance. We suggest that MRA tests in combination with simulator sessions could be used to assess the trainee's early competence level and tailor the training to individual needs., (© 2021. The Author(s).)

It is well established that sex differences exist in the manifestation of vascular diseases. Arterial stiffness (AS) has been associated with changes in cerebrovascular reactivity (CVR) and cognitive decline in aging. Specifically, older adults with increased AS show a decline on executive function (EF) tasks. Interestingly, the relationship between AS and CVR is more complex, where some studies show decreased CVR with increased AS, and others demonstrate preserved CVR despite higher AS. Here, we investigated the possible role of sex on these hemodynamic relationships. Acquisitions were completed in 48 older adults. Pseudo-continuous arterial spin labeling (pCASL) data were collected during a hypercapnia challenge. Aortic pulse wave velocity (PWV) data was acquired using cine phase contrast velocity series. Cognitive function was assessed with a comprehensive neuropsychological battery, and a composite score for EF was calculated using four cognitive tests from the neuropsychological battery. A moderation model test revealed that sex moderated the relationship between PWV and CVR and PWV and EF, but not between CVR and EF. Together, our results indicate that the relationships between central stiffness, cerebral hemodynamics and cognition are in part mediated by sex., Competing Interests: The authors have declared that no competing interests exist.

Bilateral in-phase (IP) and anti-phase (AP) movements represent two fundamental modes of bilateral coordination that are essential for daily living. Although previous studies have shown that aging is behaviorally associated with decline in bilateral coordination, especially in AP movements, the underlying neural mechanisms remain unclear. Here, we use kinematic measurements and electroencephalography to compare motor performance of young and older adults executing bilateral IP and AP hand movements. On the behavioral level, inter-limb synchronization was reduced during AP movements compared to IP and this reduction was stronger in the older adults. On the neural level, we found interactions between group and condition for task-related power change in different frequency bands. The interaction was driven by smaller alpha power decreases over the non-dominant cortical motor area in young adults during IP movements and larger beta power decreases over the midline region in older adults during AP movements. In addition, the decrease in inter-limb synchronization during AP movements was predicted by stronger directional connectivity in the beta-band: an effect more pronounced in older adults. Our results therefore show that age-related differences in the two bilateral coordination modes are reflected on the neural level by differences in alpha and beta oscillatory power as well as interhemispheric directional connectivity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Efficient neural transmission is crucial for optimal brain function, yet the plastic potential of white matter (WM) has long been overlooked. Growing evidence now shows that modifications to axons and myelin occur not only as a result of long-term learning, but also after short training periods. Motor sequence learning (MSL), a common paradigm used to study neuroplasticity, occurs in overlapping learning stages and different neural circuits are involved in each stage. However, most studies investigating short-term WM plasticity have used a pre-post design, in which the temporal dynamics of changes across learning stages cannot be assessed. In this study, we used multiple magnetic resonance imaging (MRI) scans at 7 T to investigate changes in WM in a group learning a complex visuomotor sequence (LRN) and in a control group (SMP) performing a simple sequence, for five consecutive days. Consistent with behavioral results, where most improvements occurred between the two first days, structural changes in WM were observed only in the early phase of learning (d1-d2), and in overall learning (d1-d5). In LRNs, WM microstructure was altered in the tracts underlying the primary motor and sensorimotor cortices. Moreover, our structural findings in WM were related to changes in functional connectivity, assessed with resting-state functional MRI data in the same cohort, through analyses in regions of interest (ROIs). Significant changes in WM microstructure were found in a ROI underlying the right supplementary motor area. Together, our findings provide evidence for highly dynamic WM plasticity in the sensorimotor network during short-term MSL.

The contribution of selective serotonin reuptake inhibitors to motor learning by inducing motor cortical plasticity remains controversial given diverse findings from positive preclinical data to negative findings in recent clinical trials. To empirically address this translational disparity, we use functional magnetic resonance imaging in a double-blind, randomized controlled study to assess whether 20 mg escitalopram improves sequence-specific motor performance and modulates cortical motor response in 64 healthy female participants. We found decreased left premotor cortex responses during sequence-specific learning performance comparing single dose and steady escitalopram state. Escitalopram plasma levels negatively correlated with the premotor cortex response. We did not find evidence in support of improved motor performance after a week of escitalopram intake. These findings do not support the conclusion that one week escitalopram intake increases motor performance but could reflect early adaptive plasticity with improved neural processing underlying similar task performance when steady peripheral escitalopram levels are reached.

Objective: Historically, preoperative planning for functional neurosurgery has depended on the indirect localization of target brain structures using visible anatomical landmarks. However, recent technological advances in neuroimaging have permitted marked improvements in MRI-based direct target visualization, allowing for refinement of "first-pass" targeting. The authors reviewed studies relating to direct MRI visualization of the most common functional neurosurgery targets (subthalamic nucleus, globus pallidus, and thalamus) and summarize sequence specifications for the various approaches described in this literature., Methods: The peer-reviewed literature on MRI visualization of the subthalamic nucleus, globus pallidus, and thalamus was obtained by searching MEDLINE. Publications examining direct MRI visualization of these deep brain stimulation targets were included for review., Results: A variety of specialized sequences and postprocessing methods for enhanced MRI visualization are in current use. These include susceptibility-based techniques such as quantitative susceptibility mapping, which exploit the amount of tissue iron in target structures, and white matter attenuated inversion recovery, which suppresses the signal from white matter to improve the distinction between gray matter nuclei. However, evidence confirming the superiority of these sequences over indirect targeting with respect to clinical outcome is sparse. Future targeting may utilize information about functional and structural networks, necessitating the use of resting-state functional MRI and diffusion-weighted imaging., Conclusions: Specialized MRI sequences have enabled considerable improvement in the visualization of common deep brain stimulation targets. With further validation of their ability to improve clinical outcomes and advances in imaging techniques, direct visualization of targets may play an increasingly important role in preoperative planning.

MRI is a valuable clinical and research tool for patients undergoing deep brain stimulation (DBS). However, risks associated with imaging DBS devices have led to stringent regulations, limiting the clinical and research utility of MRI in these patients. The main risks in patients with DBS devices undergoing MRI are heating at the electrode tips, induced currents, implantable pulse generator dysfunction, and mechanical forces. Phantom model studies indicate that electrode tip heating remains the most serious risk for modern DBS devices. The absence of adverse events in patients imaged under DBS vendor guidelines for MRI demonstrates the general safety of MRI for patients with DBS devices. Moreover, recent work indicates that-given adequate safety data-patients may be imaged outside these guidelines. At present, investigators are primarily focused on improving DBS device and MRI safety through the development of tools, including safety simulation models. Existing guidelines provide a standardized framework for performing safe MRI in patients with DBS devices. It also highlights the possibility of expanding MRI as a tool for research and clinical care in these patients going forward., (© RSNA, 2020.)

With an estimated five million new stroke survivors every year and a rapidly aging population suffering from hyperintensities and diseases of presumed vascular origin that affect white matter and contribute to cognitive decline, it is critical that we understand the impact of white matter damage on brain structure and behavior. Current techniques for assessing the impact of lesions consider only location, type, and extent, while ignoring how the affected region was connected to the rest of the brain. Regional brain function is a product of both local structure and its connectivity. Therefore, obtaining a map of white matter disconnection is a crucial step that could help us predict the behavioral deficits that patients exhibit. In the present work, we introduce a new practical method for computing lesion-based white matter disconnection maps that require only moderate computational resources. We achieve this by creating diffusion tractography models of the brains of healthy adults and assessing the connectivity between small regions. We then interrupt these connectivity models by projecting patients' lesions into them to compute predicted white matter disconnection. A quantified disconnection map can be computed for an individual patient in approximately 35 seconds using a single core CPU-based computation. In comparison, a similar quantification performed with other tools provided by MRtrix3 takes 5.47 minutes.

Aging is accompanied by vascular and structural changes in the brain, which include decreased grey matter volume (GMV), cerebral blood flow (CBF), and cerebrovascular reactivity (CVR). Enhanced fitness in aging has been related to preservation of GMV and CBF, and in some cases CVR, although there are contradictory relationships reported between CVR and fitness. To gain a better understanding of the complex interplay between fitness and GMV, CBF and CVR, the present study assessed these factors concurrently. Data from 50 participants, aged 55 to 72, were used to derive GMV, CBF, CVR and VO 2 peak. Results revealed that lower CVR was associated with higher VO 2 peak throughout large areas of the cerebral cortex. Within these regions lower fitness was associated with higher CBF and a faster hemodynamic response to hypercapnia. Overall, our results indicate that the relationships between age, fitness, cerebral health and cerebral hemodynamics are complex, likely involving changes in chemosensitivity and autoregulation in addition to changes in arterial stiffness. Future studies should collect other physiological outcomes in parallel with quantitative imaging, such as measures of chemosensitivity and autoregulation, to further understand the intricate effects of fitness on the aging brain, and how this may bias quantitative measures of cerebral health.

In this work we use non-negative matrix factorization to identify patterns of microstructural variance in the human hippocampus. We utilize high-resolution structural and diffusion magnetic resonance imaging data from the Human Connectome Project to query hippocampus microstructure on a multivariate, voxelwise basis. Application of non-negative matrix factorization identifies spatial components (clusters of voxels sharing similar covariance patterns), as well as subject weightings (individual variance across hippocampus microstructure). By assessing the stability of spatial components as well as the accuracy of factorization, we identified 4 distinct microstructural components. Furthermore, we quantified the benefit of using multiple microstructural metrics by demonstrating that using three microstructural metrics (T1-weighted/T2-weighted signal, mean diffusivity and fractional anisotropy) produced more stable spatial components than when assessing metrics individually. Finally, we related individual subject weightings to demographic and behavioural measures using a partial least squares analysis. Through this approach we identified interpretable relationships between hippocampus microstructure and demographic and behavioural measures. Taken together, our work suggests non-negative matrix factorization as a spatially specific analytical approach for neuroimaging studies and advocates for the use of multiple metrics for data-driven component analyses., Competing Interests: Declaration of competing interest Authors report no conflicts of interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To independently validate two biomarkers, a 44-gene DNA damage immune response (DDIR) signature and stromal tumor-infiltrating lymphocytes (sTILs), as prognostic markers in patients with triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG 9313., Methods: Four hundred twenty-five centrally determined patient cases with TNBC from S9313 were identified. DDIR signature was performed on RNA isolated from formalin-fixed paraffin-embedded tumor tissue, and samples were classified as DDIR negative or positive using predefined cutoffs. Evaluation of sTILs was performed as described previously. Markers were tested for prognostic value for disease-free survival (DFS) and overall survival (OS) using Cox regression models adjusted for treatment assignment, nodal status, and tumor size., Results: Among 425 patients with TNBC, 33% were node positive. DDIR was tested successfully in 90% of patients (381 of 425), 62% of which were DDIR signature positive. DDIR signature positivity was associated with improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.92; P = .015) and OS (HR, 0.61; 95% CI, 0.43 to 0.89; P = .010). sTILs density assessment was available in 99% of patients and was associated with improved DFS (HR, 0.70; 95% CI, 0.51 to 0.96; P = .026 for sTILs density ≥ 20% v < 20%) and OS (HR, 0.59; 95% CI, 0.41 to 0.85; P = .004 for sTILs density ≥ 20% v < 20%). DDIR signature score and sTILs density were moderately correlated ( r = 0.60), which precluded statistical significance for DFS in a joint model. Three-year DFS and OS in a subgroup of patients with DDIR positivity and T1c/T2N0 disease were 88% and 94%, respectively., Conclusion: The prognostic role of sTILs and DDIR in early-stage TNBC was confirmed. DDIR signature conferred improved prognosis in two thirds of patients with TNBC treated with adjuvant AC. DDIR signature has the potential to stratify outcome and to identify patients with less projected benefit after AC chemotherapy.

Objective: Current strategies to guide selection of neoadjuvant therapy in oesophageal adenocarcinoma (OAC) are inadequate. We assessed the ability of a DNA damage immune response (DDIR) assay to predict response following neoadjuvant chemotherapy in OAC., Design: Transcriptional profiling of 273 formalin-fixed paraffin-embedded prechemotherapy endoscopic OAC biopsies was performed. All patients were treated with platinum-based neoadjuvant chemotherapy and resection between 2003 and 2014 at four centres in the Oesophageal Cancer Clinical and Molecular Stratification consortium. CD8 and programmed death ligand 1 (PD-L1) immunohistochemical staining was assessed in matched resection specimens from 126 cases. Kaplan-Meier and Cox proportional hazards regression analysis were applied according to DDIR status for recurrence-free survival (RFS) and overall survival (OS)., Results: A total of 66 OAC samples (24%) were DDIR positive with the remaining 207 samples (76%) being DDIR negative. DDIR assay positivity was associated with improved RFS (HR: 0.61; 95% CI 0.38 to 0.98; p=0.042) and OS (HR: 0.52; 95% CI 0.31 to 0.88; p=0.015) following multivariate analysis. DDIR-positive patients had a higher pathological response rate (p=0.033), lower nodal burden (p=0.026) and reduced circumferential margin involvement (p=0.007). No difference in OS was observed according to DDIR status in an independent surgery-alone dataset.DDIR-positive OAC tumours were also associated with the presence of CD8+ lymphocytes (intratumoural: p<0.001; stromal: p=0.026) as well as PD-L1 expression (intratumoural: p=0.047; stromal: p=0.025)., Conclusion: The DDIR assay is strongly predictive of benefit from DNA-damaging neoadjuvant chemotherapy followed by surgical resection and is associated with a proinflammatory microenvironment in OAC., Competing Interests: Competing interests: LAK, AMM, SMW, DPH and RK are employees of Almac Diagnostics and have patent declarations. GEL and CJS are employees of Almac Diagnostics., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Ocean colour is recognised as an Essential Climate Variable (ECV) by the Global Climate Observing System (GCOS); and spectrally-resolved water-leaving radiances (or remote-sensing reflectances) in the visible domain, and chlorophyll-a concentration are identified as required ECV products. Time series of the products at the global scale and at high spatial resolution, derived from ocean-colour data, are key to studying the dynamics of phytoplankton at seasonal and inter-annual scales; their role in marine biogeochemistry; the global carbon cycle; the modulation of how phytoplankton distribute solar-induced heat in the upper layers of the ocean; and the response of the marine ecosystem to climate variability and change. However, generating a long time series of these products from ocean-colour data is not a trivial task: algorithms that are best suited for climate studies have to be selected from a number that are available for atmospheric correction of the satellite signal and for retrieval of chlorophyll-a concentration; since satellites have a finite life span, data from multiple sensors have to be merged to create a single time series, and any uncorrected inter-sensor biases could introduce artefacts in the series, e.g., different sensors monitor radiances at different wavebands such that producing a consistent time series of reflectances is not straightforward. Another requirement is that the products have to be validated against in situ observations. Furthermore, the uncertainties in the products have to be quantified, ideally on a pixel-by-pixel basis, to facilitate applications and interpretations that are consistent with the quality of the data. This paper outlines an approach that was adopted for generating an ocean-colour time series for climate studies, using data from the MERIS (MEdium spectral Resolution Imaging Spectrometer) sensor of the European Space Agency; the SeaWiFS (Sea-viewing Wide-Field-of-view Sensor) and MODIS-Aqua (Moderate-resolution Imaging Spectroradiometer-Aqua) sensors from the National Aeronautics and Space Administration (USA); and VIIRS (Visible and Infrared Imaging Radiometer Suite) from the National Oceanic and Atmospheric Administration (USA). The time series now covers the period from late 1997 to end of 2018. To ensure that the products meet, as well as possible, the requirements of the user community, marine-ecosystem modellers, and remote-sensing scientists were consulted at the outset on their immediate and longer-term requirements as well as on their expectations of ocean-colour data for use in climate research. Taking the user requirements into account, a series of objective criteria were established, against which available algorithms for processing ocean-colour data were evaluated and ranked. The algorithms that performed best with respect to the climate user requirements were selected to process data from the satellite sensors. Remote-sensing reflectance data from MODIS-Aqua, MERIS, and VIIRS were band-shifted to match the wavebands of SeaWiFS. Overlapping data were used to correct for mean biases between sensors at every pixel. The remote-sensing reflectance data derived from the sensors were merged, and the selected in-water algorithm was applied to the merged data to generate maps of chlorophyll concentration, inherent optical properties at SeaWiFS wavelengths, and the diffuse attenuation coefficient at 490 nm. The merged products were validated against in situ observations. The uncertainties established on the basis of comparisons with in situ data were combined with an optical classification of the remote-sensing reflectance data using a fuzzy-logic approach, and were used to generate uncertainties (root mean square difference and bias) for each product at each pixel.

The vascular organization of the human brain can determine neurological and neurophysiological functions, yet thus far it has not been comprehensively mapped. Aging and diseases such as dementia are known to be associated with changes to the vasculature and normative data could help detect these vascular changes in neuroimaging studies. Furthermore, given the well-known impact of venous vessels on the blood oxygen level dependent (BOLD) signal, information about the common location of veins could help detect biases in existing datasets. In this work, a quantitative atlas of the venous vasculature using quantitative susceptibility maps (QSM) acquired with a 0.6-mm isotropic resolution is presented. The Venous Neuroanatomy (VENAT) atlas was created from 5 repeated 7 Tesla MRI measurements in young and healthy volunteers (n = 20, 10 females, mean age = 25.1 ± 2.5 years) using a two-step registration method on 3D segmentations of the venous vasculature. This cerebral vein atlas includes the average vessel location, diameter (mean: 0.84 ± 0.33 mm) and curvature (0.11 ± 0.05 mm -1 ) from all participants and provides an in vivo measure of the angio-architectonic organization of the human brain and its variability. This atlas can be used as a basis to understand changes in the vasculature during aging and neurodegeneration, as well as vascular and physiological effects in neuroimaging.

Purpose of Review: Ablations and particularly deep brain stimulation (DBS) of a variety of CNS targets are established therapeutic tools for movement disorders. Accurate targeting of the intended structure is crucial for optimal clinical outcomes. However, most targets used in functional neurosurgery are sub-optimally visualized on routine MRI. This article reviews recent neuroimaging advancements for targeting in movement disorders., Recent Findings: Dedicated MRI sequences can often visualize to some degree anatomical structures commonly targeted during DBS surgery, including at 1.5-T field strengths. Due to recent technological advancements, MR images using ultra-high magnetic field strengths and new acquisition parameters allow for markedly improved visualization of common movement disorder targets. In addition, novel neuroimaging techniques have enabled group-level analysis of DBS patients and delineation of areas associated with clinical benefits. These areas might diverge from the conventionally targeted nuclei and may instead correspond to white matter tracts or hubs of functional networks. Neuroimaging advancements have enabled improved direct visualization-based targeting as well as optimization and adjustment of conventionally targeted structures.

Widespread cortical-subcortical networks are involved in the recognition and discrimination of emotional contents of facial and vocal expression, whereby the cerebellum and basal ganglia are two subcortical regions implicated in these networks with limited evidence to their specific contributions. To investigate this we compared patients with circumscribed cerebellar lesions and patients with Parkinson's disease (PD) on an approved test battery. We studied two groups with subcortical disease, focal cerebellar infarction (n = 22) and PD (n = 22), and a neurological control group with focal supratentorial ischemia (SI) (n = 16) were. Assessments were according to inpatient protocols for neuropsychological routine evaluation, including tests of memory, executive function and attention. Participants completed the Tuebingen Affect Battery, a recognized measure of recognition and discrimination of facial and vocal expression of emotion. As a result, cerebellar lesions were associated with greater impairment than PD and SI in recognition and discrimination of cues of both facial and vocal expressions of differing basic emotions. No confounding effect of other cognitive domains, particularly executive function and attention, was found. Taken together, our findings suggest a specific contribution of the cerebellum to cerebral networks that process facial and vocal emotion expression, related to rapid decisions regulating appropriate behavioral responses in social environments.

In-phase and anti-phase movements represent two basic coordination modes with different characteristics: during in-phase movements, bilateral homologous muscle groups contract synchronously, whereas during anti-phase movements, they contract in an alternating fashion. Previous studies suggested that in-phase movements represent a more stable and preferential bilateral movement template in humans. The current experiment aims at confirming and extending this notion by introducing new empirical measures of spatiotemporal dynamics during performance of a bilateral circle drawing task in an augmented-reality environment. First, we found that anti-phase compared to in-phase movements were performed with higher radial variability, a result that was mainly driven by the non-dominant hand. Second, the coupling of both limbs was higher during in-phase movements, corroborated by a lower inter-limb phase difference and higher inter-limb synchronization. Importantly, the movement acceleration profile between bilateral hands followed an in-phase relationship during in-phase movements, while no specific relationship was found in anti-phase condition. These spatiotemporal relationships between hands support the hypothesis that differential neural processes govern both bilateral coordination modes and suggest that both limbs are controlled more independently during anti-phase movements, while bilateral in-phase movements are elicited by a common neural generator.

White matter hyperintensities (WMH) are associated with cognitive decline. We aimed to identify the spatial specificity of WMH impact on cognition in non-demented, healthy elderly. We quantified WMH volume among healthy participants of a community dwelling cohort ( n = 702, age range 60 - 82 years, mean age = 69.5 years, 46% female) and investigated the effects of WMH on cognition and behavior, specifically for executive function, memory, and motor speed performance. Lesion location influenced their effect on cognition and behavior: Frontal WMH in the proximity of the frontal ventricles mainly affected executive function and parieto-temporal WMH in the proximity of the posterior horns deteriorated memory, while WMH in the upper deep white matter-including the corticospinal tract-compromised motor speed performance. This study exposes the subtle and subclinical yet detrimental effects of WMH on cognition in healthy elderly, and strongly suggests a causal influence of WMH on cognition by demonstrating the spatial specificity of these effects.

Background: There is a clear need for assays that can predict the risk of metastatic prostate cancer following curative procedures. Importantly these assays must be analytically robust in order to provide quality data for important clinical decisions. DNA microarray based gene expression assays measure several analytes simultaneously and can present specific challenges to analytical validation. This study describes the analytical validation of one such assay designed to predict metastatic recurrence in prostate cancer using primary formalin fixed paraffin embedded tumour material., Methods: Accuracy was evaluated with a method comparison study between the assay development platform (Prostate Disease Specific Array) and an alternative platform (Xcel™ microarray) using 50 formalin-fixed, paraffin-embedded prostate cancer patient samples. An additional 70 samples were used to establish the assay reportable range. Determination of assay precision and sensitivity was performed on multiple technical replicates of three prostate cancer samples across multiple variables (operators, days, runs, reagent lots, and equipment) and RNA/cDNA inputs respectively using the appropriate linear mixed model., Results: The overall agreement between the development and alternative platform was 94.7% (95% confidence interval, 86.9-98.5%). The reportable range was determined to be 0.150 to 1.107 for core needle biopsy samples and - 0.214 to 0.844 for radical prostatectomy samples. From the precision study, the standard deviations for assay repeatability and reproducibility were 0.032 and 0.040 respectively. The sensitivity study demonstrated that a total RNA input and cDNA input of 50 ng and 3.5 μg respectively was conservative., Conclusion: The Metastatic Assay was found to be highly reproducible and precise. In conclusion the studies demonstrated an acceptable analytical performance for the assay and support its potential use in the clinic.

With recent improvements in human magnetic resonance imaging (MRI) at ultra-high fields, the amount of data collected per subject in a given MRI experiment has increased considerably. Standard image processing packages are often challenged by the size of these data. Dedicated methods are needed to leverage their extraordinary spatial resolution. Here, we introduce a flexible Python toolbox that implements a set of advanced techniques for high-resolution neuroimaging. With these tools, segmentation and laminar analysis of cortical MRI data can be performed at resolutions up to 500 μm in reasonable times. Comprehensive online documentation makes the toolbox easy to use and install. An extensive developer's guide encourages contributions from other researchers that will help to accelerate progress in the promising field of high-resolution neuroimaging.

Though commonly thought of as a "motor structure", we now know that the cerebellum's reciprocal connections to the cerebral cortex underlie contributions to both motor and non-motor behavior. Further, recent research has shown that cerebellar dysfunction may contribute to a wide range of neuropsychiatric disorders. However, there has been little characterization of normative variability at the level of cerebellar structure that can facilitate and further our understanding of disease biomarkers. In this manuscript we examine normative variation of the cerebellum using data from the Human Connectome Project (HCP). The Multiple Automatically Generated Templates (MAGeT) segmentation tool was used to identify the cerebella and 33 anatomically-defined lobules from 327 individuals from the HCP. To characterize normative variation, we estimated population mean volume and variability, assessed differences in hemisphere and sex, and related lobular volume to motor and non-motor behavior. We found that the effects of hemisphere and sex were not homogeneous across all lobules of the cerebellum. Greater volume in the right hemisphere was primarily driven by lobules Crus I, II, and H VIIB, with H VIIIA exhibiting the greatest left>right asymmetry. Relative to total cerebellar gray-matter volume, females had larger Crus II (known to be connected with non-motor regions of the cerebral cortex) while males had larger motor-connected lobules including H V, and VIIIA/B. When relating lobular volume to memory, motor performance, and emotional behavior, we found some evidence for relationships that have previously been identified in the literature. Our observations of normative cerebellar structure and variability in young adults provide evidence for lobule-specific differences in volume and the relationship with sex and behavior - indicating that the cerebellum cannot be considered a single structure with uniform function, but as a set of regions with functions that are likely as diverse as their connectivity with the cerebral cortex., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Radiotherapy is an effective treatment of intermediate/high-risk locally advanced prostate cancer, however, >30% of patients relapse within 5 years. Clinicopathological parameters currently fail to identify patients prone to systemic relapse and those whom treatment intensification may be beneficial. The purpose of this study was to independently validate the performance of a 70-gene Metastatic Assay in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy., Patients and Methods: A bridging cohort of prostate cancer diagnostic biopsy specimens was profiled to enable optimization of the Metastatic Assay threshold before further independent clinical validation in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Multivariable Cox proportional hazard regression analysis was used to assess assay performance in predicting biochemical failure-free survival (BFFS) and metastasis-free survival (MFS)., Results: Gene expression analysis was carried out in 248 patients from the independent validation cohort and the Metastatic Assay applied. Ten-year MFS was 72% for Metastatic Assay positive patients and 94% for Metastatic Assay negative patients [HR = 3.21 (1.35-7.67); P = 0.003]. On multivariable analysis the Metastatic Assay remained predictive for development of distant metastases [HR = 2.71 (1.11-6.63); P = 0.030]. The assay retained independent prognostic performance for MFS when assessed with the Cancer of the Prostate Assessment Score (CAPRA) [HR = 3.23 (1.22-8.59); P = 0.019] whilst CAPRA itself was not significant [HR = 1.88, (0.52-6.77); P = 0.332]. A high concordance [100% (61.5-100)] for the assay result was noted between two separate foci taken from 11 tumours, whilst Gleason score had low concordance., Conclusions: The Metastatic Assay demonstrated significant prognostic performance in patients treated with radical radiotherapy both alone and independent of standard clinical and pathological variables. The Metastatic Assay could have clinical utility when deciding upon treatment intensification in high-risk patients. Genomic and clinical data are available as a public resource., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: Approximately 4-25% of patients with early prostate cancer develop disease recurrence following radical prostatectomy., Objective: To identify a molecular subgroup of prostate cancers with metastatic potential at presentation resulting in a high risk of recurrence following radical prostatectomy., Design, Setting, and Participants: Unsupervised hierarchical clustering was performed using gene expression data from 70 primary resections, 31 metastatic lymph nodes, and 25 normal prostate samples. Independent assay validation was performed using 322 radical prostatectomy samples from four sites with a mean follow-up of 50.3 months., Outcome Measurements and Statistical Analysis: Molecular subgroups were identified using unsupervised hierarchical clustering. A partial least squares approach was used to generate a gene expression assay. Relationships with outcome (time to biochemical and metastatic recurrence) were analysed using multivariable Cox regression and log-rank analysis., Results and Limitations: A molecular subgroup of primary prostate cancer with biology similar to metastatic disease was identified. A 70-transcript signature (metastatic assay) was developed and independently validated in the radical prostatectomy samples. Metastatic assay positive patients had increased risk of biochemical recurrence (multivariable hazard ratio [HR] 1.62 [1.13-2.33]; p=0.0092) and metastatic recurrence (multivariable HR=3.20 [1.76-5.80]; p=0.0001). A combined model with Cancer of the Prostate Risk Assessment post surgical (CAPRA-S) identified patients at an increased risk of biochemical and metastatic recurrence superior to either model alone (HR=2.67 [1.90-3.75]; p<0.0001 and HR=7.53 [4.13-13.73]; p<0.0001, respectively). The retrospective nature of the study is acknowledged as a potential limitation., Conclusions: The metastatic assay may identify a molecular subgroup of primary prostate cancers with metastatic potential., Patient Summary: The metastatic assay may improve the ability to detect patients at risk of metastatic recurrence following radical prostatectomy. The impact of adjuvant therapies should be assessed in this higher-risk population., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

During unimanual motor tasks, muscle activity may not be restricted to the contracting muscle, but rather occurs involuntarily in the contralateral resting limb, even in healthy individuals. This phenomenon has been referred to as mirror electromyographic activity (MEMG). To date, the physiological (non-pathological) form of MEMG has been observed predominately in upper extremities (UE), while remaining sparsely described in lower extremities (LE). Accordingly, evidence regarding the underlying mechanisms and modulation capability of MEMG, i.e., the extent of MEMG in dependency of exerted force during unilateral isometric contractions are insufficiently investigated in terms of LE. Furthermore, it still remains elusive if and how MEMG is affected by long-term exercise training. Here, we provide novel quantitative evidence for physiological MEMG in homologous muscles of LE (tibialis anterior (TA), rectus femoris (RF)) during submaximal unilateral dorsiflexion in healthy young adults. Furthermore, endurance athletes (EA, n = 11) show a higher extent of MEMG in LE compared to non-athletes (NA, n = 11) at high force demands (80% MVC, maximum voluntary contraction). While the underlying neurophysiological mechanisms of MEMG still remain elusive, our study indicates, at least indirectly, that sport-related long-term training might affect the amount of MEMG during strong isometric contractions specifically in trained limbs. To support this assumption of exercise-induced limb-specific MEMG modulation, future studies including different sports disciplines with contrasting movement patterns and parameters should additionally be performed.

The reciprocal cortico-cerebellar loops that underlie cerebellar contributions to motor and cognitive behavior form one of the largest systems in the primate brain. Work with non-human primates has shown that the dentate nucleus, the major output nucleus of the cerebellum, contains topographically distinct connections to both motor and non-motor regions, yet there is no evidence for how the cerebellar cortex connects to the dentate nuclei in humans. Here we used in-vivo sub-millimeter diffusion imaging to characterize this fundamental component of the cortico-cerebellar loop, and identified a pattern of superior motor and infero-lateral non-motor connectivity strikingly similar to that proposed by animal work. Crucially, we also present first evidence that the dominance for motor connectivity observed in non-human primates may be significantly reduced in man - a finding that is in accordance with the proposed increase in cerebellar contributions to higher cognitive behavior over the course of primate evolution., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: The study aims to identify the mediating factors of the relationship between education achievement and incident type 2 diabetes mellitus (T2DM) in older adults., Design: Population-based cohort study., Setting: Participants were recruited from the German federal state of Saarland., Participants: Participants were excluded if they had prevalent T2DM or missing data on prevalent T2DM, missing or zero follow-up time for incident T2DM or were under 50 years of age. The total sample consisted of 7462 individuals aged 50-75 years (42.8% men, mean age 61.7 years) at baseline (2000-02). The median follow-up time was 8.0 years., Methods: Cox proportional hazards regression was initially used to determine the direct association between education achievement and incident T2DM. Using the Baron and Kenny approach, we then investigated the associations between education achievement and incident T2DM with the potential mediators. The contribution of each of the putative mediating variables was then calculated., Results: A clear socioeconomic gradient was observed with regard to T2DM incidence with the lowest educated individuals at a greater risk of developing the disease during the follow-up period: HR (95% CI) high education: 0.52 (0.34 to 0.80); medium education: 0.80 (0.66 to 0.96). Seven of the variables considered explained a proportion of the education-T2DM relationship (body mass index, alcohol consumption, hypertension, fasting triglycerides, high-density lipoprotein (HDL) cholesterol, physical activity and smoking status), where the contribution of the variables ranged from 1.0% to 17.7%. Overall, the mediators explained 31.7% of the relationship., Conclusion: By identifying the possible mediating factors of the relationship between education achievement and incident T2DM in older adults, the results of this study can be used to assist with the development of public health strategies that aim to reduce socioeconomic inequalities in T2DM., Competing Interests: Competing interestsNone declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Computational anatomy studies typically use T1-weighted magnetic resonance imaging contrast to look at local differences in cortical thickness or grey matter volume across time or subjects. This type of analysis is a powerful and non-invasive tool to probe anatomical changes associated with neurodevelopment, aging, disease or experience-induced plasticity. However, these comparisons could suffer from biases arising from vascular and metabolic subject- or time-dependent differences. Differences in blood flow and volume could be caused by vasodilation or differences in vascular density, and result in a larger signal contribution of the blood compartment within grey matter voxels. Metabolic changes could lead to differences in dissolved oxygen in brain tissue, leading to T1 shortening. Here, we analyze T1 maps and T1-weighted images acquired during different breathing conditions (ambient air, hypercapnia (increased CO 2 ) and hyperoxia (increased O 2 )) to evaluate the effect size that can be expected from changes in blood flow, volume and dissolved O 2 concentration in computational anatomy studies. Results show that increased blood volume from vasodilation during hypercapnia is associated with an overestimation of cortical thickness (1.85%) and grey matter volume (3.32%), and that both changes in O 2 concentration and blood volume lead to changes in the T1 value of tissue. These results should be taken into consideration when interpreting existing morphometry studies and in future study design. Furthermore, this study highlights the overlap in structural and physiological MRI, which are conventionally interpreted as two independent modalities., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The rate of progress in human neurosciences is limited by the inability to easily apply a wide range of analysis methods to the plethora of different datasets acquired in labs around the world. In this work, we introduce a framework for creating, testing, versioning and archiving portable applications for analyzing neuroimaging data organized and described in compliance with the Brain Imaging Data Structure (BIDS). The portability of these applications (BIDS Apps) is achieved by using container technologies that encapsulate all binary and other dependencies in one convenient package. BIDS Apps run on all three major operating systems with no need for complex setup and configuration and thanks to the comprehensiveness of the BIDS standard they require little manual user input. Previous containerized data processing solutions were limited to single user environments and not compatible with most multi-tenant High Performance Computing systems. BIDS Apps overcome this limitation by taking advantage of the Singularity container technology. As a proof of concept, this work is accompanied by 22 ready to use BIDS Apps, packaging a diverse set of commonly used neuroimaging algorithms.

Mirror visual feedback (MVF) is a promising approach to enhance motor performance without training in healthy adults as well as in patients with focal brain lesions. There is preliminary evidence that a functional modulation within and between primary motor cortices as assessed with transcranial magnetic stimulation (TMS) might be one candidate mechanism mediating the observed behavioral effects. Recently, studies using task-based functional magnetic resonance imaging (fMRI) have indicated that MVF-induced functional changes might not be restricted to the primary motor cortex (M1) but also include higher order regions responsible for perceptual-motor coordination and visual attention. However, aside from these instantaneous task-induced brain changes, little is known about learning-related neuroplasticity induced by MVF. Thus, in the present study, we assessed MVF-induced functional network plasticity with resting-state fMRI (rs-fMRI). We performed rs-fMRI of 35 right-handed, healthy adults before and after performing a complex ball-rotation task. The primary outcome measure was the performance improvement of the untrained left hand (LH) before and after right hand (RH) training with MVF (mirror group [MG], n = 17) or without MVF (control group [CG], n = 18). Behaviorally, the MG showed superior performance improvements of the untrained LH. In resting-state functional connectivity (rs-FC), an interaction analysis between groups showed changes in left visual cortex (V1, V2) revealing an increase of centrality in the MG. Within group comparisons showed further functional alterations in bilateral primary sensorimotor cortex (SM1), left V4 and left anterior intraparietal sulcus (aIP) in the MG, only. Importantly, a correlation analysis revealed a linear positive relationship between MVF-induced improvements of the untrained LH and functional alterations in left SM1. Our results suggest that MVF-induced performance improvements are associated with functional learning-related brain plasticity and have identified additional target regions for non-invasive brain stimulation techniques, a finding of potential interest for neurorehabilitation.

Older adults frequently experience a decrease in balance control that leads to increased numbers of falls, injuries and hospitalization. Therefore, evaluating older adults' ability to maintain balance and examining new approaches to counteract age-related decline in balance control is of great importance for fall prevention and healthy aging. Non-invasive brain stimulation techniques such as transcranial direct current stimulation (tDCS) have been shown to beneficially influence motor behavior and motor learning. In the present study, we investigated the influence of tDCS applied over the leg area of the primary motor cortex (M1) on balance task learning of healthy elderly in a dynamic balance task (DBT). In total, 30 older adults were enrolled in a cross-sectional, randomized design including two consecutive DBT training sessions. Only during the first DBT session, either 20 min of anodal tDCS (a-tDCS) or sham tDCS (s-tDCS) were applied and learning improvement was compared between the two groups. Our data showed that both groups successfully learned to perform the DBT on both training sessions. Interestingly, between-group analyses revealed no difference between the a-tDCS and the s-tDCS group regarding their level of task learning. These results indicate that the concurrent application of tDCS over M1 leg area did not elicit DBT learning enhancement in our study cohort. However, a regression analysis revealed that DBT performance can be predicted by the kinematic profile of the movement, a finding that may provide new insights for individualized approaches of treating balance and gait disorders.

Cortical activity during simple unimanual actions is typically lateralized to contralateral sensorimotor areas, while a more bilateral pattern is observed with an increase in task demands. In parallel, increasing task demands are associated with subtle mirror muscle activity in the resting hand, implying a relative loss in motor selectivity. The corpus callosum (CC) is crucially involved in unimanual tasks by mediating both facilitatory and inhibitory interactions between bilateral motor cortical systems, but its association with mirror motor activity is yet unknown. Here, we used diffusion-weighted imaging and bilateral electromyographic (EMG) measurements during a unimanual task to investigate potential relationships between white matter microstructure of the CC and mirror EMG activity. Participants performed an unimanual pinch force task with both hands alternatively. Four parametrically increasing force levels were exerted while EMG activity was recorded bilaterally from first dorsal interosseus muscles. Consistent with previous findings, mirror EMG activity increased as a function of force. Additionally, there was a significant relationship between the slope of increasing mirror EMG during right-hand contractions and fractional anisotropy in transcallosal fibers connecting both M1. No significant relationships were found for fibers connecting dorsal premotor cortices or supplementary motor area, indicating the local specificity of the observed brain-physiology relationship., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Sex hormones fluctuate during the menstrual cycle. Evidence from animal studies suggests similar subtle fluctuations in hippocampal structure, predominantly linked to estrogen. Hippocampal abnormalities have been observed in several neuropsychiatric pathologies with prominent sexual dimorphism. Yet, the potential impact of subtle sex-hormonal fluctuations on human hippocampal structure in health is unclear. We tested the feasibility of longitudinal neuroimaging in conjunction with rigorous menstrual cycle monitoring to evaluate potential changes in hippocampal microstructure associated with physiological sex-hormonal changes. Thirty longitudinal diffusion weighted imaging scans of a single healthy female subject were acquired across two full menstrual cycles. We calculated hippocampal fractional anisotropy (FA), a measure sensitive to changes in microstructural integrity, and investigated potential correlations with estrogen. We observed a significant positive correlation between FA values and estrogen in the hippocampus bilaterally, revealing a peak in FA closely paralleling ovulation. This exploratory, single-subject study demonstrates the feasibility of a longitudinal DWI scanning protocol across the menstrual cycle and is the first to link subtle endogenous hormonal fluctuations to changes in FA in vivo. In light of recent attempts to neurally phenotype single humans, our findings highlight menstrual cycle monitoring in parallel with highly sampled individual neuroimaging data to address fundamental questions about the dynamics of plasticity in the adult brain.

Objective: The aim of the study was to investigate the effects of facilitatory anodal tDCS (a-tDCS) applied over the leg area of the primary motor cortex on learning a complex whole-body dynamic balancing task (DBT). We hypothesized that a-tDCS during DBT enhances learning performance compared to sham tDCS (s-tDCS)., Methods: In a randomized, parallel design, we applied either a-tDCS (n=13) or s-tDCS (n=13) in a total of 26 young subjects while they perform the DBT. Task performance and error rates were compared between groups. Additionally, we investigated the effect of tDCS on the relationship between performance and kinematic variables capturing different aspects of task execution., Results: A-tDCS over M1 leg area promotes balance performance in a DBT relative to s-tDCS, indicated by higher performance and smaller error scores. Furthermore, a-tDCS seems to mediate the relationship between DBT performance and the kinematic variable velocity., Conclusions: Our findings provide novel evidence for the ability of tDCS to improve dynamic balance learning, a fact, particularly important in the context of treating balance and gait disorders., Significance: TDCS facilitates dynamic balance performance by strengthening the inverse relationship of performance and velocity, thus making tDCS one potential technique to improve walking ability or help to prevent falls in patients in the future., (Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Over the last two decades, numerous human MRI studies of neuroplasticity have shown compelling evidence for extensive and rapid experience-induced brain plasticity in vivo. To date, most of these studies have consisted of simply detecting a difference in structural or functional images with little concern for their lack of biological specificity. Recent reviews and public debates have stressed the need for advanced imaging techniques to gain a better understanding of the nature of these differences - characterizing their extent in time and space, their underlying biological and network dynamics. The purpose of this article is to give an overview of advanced imaging techniques for an audience of cognitive neuroscientists that can assist them in the design and interpretation of future MRI studies of neuroplasticity. The review encompasses MRI methods that probe the morphology, microstructure, function, and connectivity of the brain with improved specificity. We underline the possible physiological underpinnings of these techniques and their recent applications within the framework of learning- and experience-induced plasticity in healthy adults. Finally, we discuss the advantages of a multi-modal approach to gain a more nuanced and comprehensive description of the process of learning., (Copyright © 2015 Elsevier Inc. All rights reserved.)