Transcranial direct current stimulation with functional magnetic resonance imaging: a detailed validation and operational guide [version 1; peer review: 1 approved with reservations]

Introduction: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique used to modulate human brain and behavioural function in both research and clinical interventions. The combination of functional magnetic resonance imaging (fMRI) with tDCS enables researchers to directly test causal contributions of stimulated brain regions, answering questions about the physiology and neural mechanisms underlying behaviour. Despite the promise of the technique, advances have been hampered by technical challenges and methodological variability between studies, confounding comparability/replicability. / Methods: Here tDCS-fMRI at 3T was developed for a series of experiments investigating language recovery after stroke. To validate the method, one healthy volunteer completed an fMRI paradigm with three conditions: (i) No-tDCS, (ii) Sham-tDCS, (iii) 2mA Anodal-tDCS. MR data were analysed in SPM12 with region-of-interest (ROI) analyses of the two electrodes and reference sites. / Results: Quality assessment indicated no visible signal dropouts or distortions introduced by the tDCS equipment. After modelling scanner drift, motion-related variance, and temporal autocorrelation, we found no field inhomogeneity in functional sensitivity metrics across conditions in grey matter and in the three ROIs. / Discussion: Key safety factors and risk mitigation strategies that must be taken into consideration when integrating tDCS into an fMRI environment are outlined. To obtain reliable results, we provide practical solutions to technical challenges and complications of the method. It is hoped that sharing these data and SOP will promote methodological replication in future studies, enhancing the quality of tDCS-fMRI application, and improve the reliability of scientific results in this field. / Conclusions: The method and data provided here provide a technically safe, reliable tDCS-fMRI procedure to obtain high quality MR data. The detailed framework of the Standard Operation Procedure SOP (https://doi.org/10.5281/zenodo.4606564) systematically reports the technical and procedural elements of our tDCS-fMRI approach, which we hope can be adopted and prove useful in future studies

Mitigating susceptibility-induced distortions in high-resolution 3DEPI fMRI at 7T

Geometric distortion is a major limiting factor for spatial specificity in high-resolution fMRI using EPI readouts and is exacerbated at higher field strengths due to increased B0 field inhomogeneity. Prominent correction schemes are based on B0 field-mapping or acquiring reverse phase-encoded (reversed-PE) data. However, to date, comparisons of these techniques in the context of fMRI have only been performed on 2DEPI data, either at lower field or lower resolution. In this study, we investigate distortion compensation in the context of sub-millimetre 3DEPI data at 7T. B0 field-mapping and reversed-PE distortion correction techniques were applied to both partial coverage BOLD-weighted and whole brain MT-weighted 3DEPI data with matched distortion. Qualitative assessment showed overall improvement in cortical alignment for both correction techniques in both 3DEPI fMRI and whole-brain MT-3DEPI datasets. The distortion-corrected MT-3DEPI images were quantitatively evaluated by comparing cortical alignment with an anatomical reference using dice coefficient (DC) and correlation ratio (CR) measures. These showed that B0 field-mapping and reversed-PE methods both improved correspondence between the MT-3DEPI and anatomical data, with more substantial improvements consistently obtained using the reversed-PE approach. Regional analyses demonstrated that the largest benefit of distortion correction, and in particular of the reversed-PE approach, occurred in frontal and temporal regions where susceptibility-induced distortions are known to be greatest, but had not led to complete signal dropout. In conclusion, distortion correction based on reversed-PE data has shown the greater capacity for achieving faithful alignment with anatomical data in the context of high-resolution fMRI at 7T using 3DEPI

A robust multi-scale approach to quantitative susceptibility mapping

Quantitative Susceptibility Mapping (QSM), best known as a surrogate for tissue iron content, is becoming a highly relevant MRI contrast for monitoring cellular and vascular status in aging, addiction, traumatic brain injury and, in general, a wide range of neurological disorders. In this study we present a new Bayesian QSM algorithm, named Multi-Scale Dipole Inversion (MSDI), which builds on the nonlinear Morphology-Enabled Dipole Inversion (nMEDI) framework, incorporating three additional features: (i) improved implementation of Laplace's equation to reduce the influence of background fields through variable harmonic filtering and subsequent deconvolution, (ii) improved error control through dynamic phase-reliability compensation across spatial scales, and (iii) scalewise use of the morphological prior. More generally, this new pre-conditioned QSM formalism aims to reduce the impact of dipole-incompatible fields and measurement errors such as flow effects, poor signal-to-noise ratio or other data inconsistencies that can lead to streaking and shadowing artefacts. In terms of performance, MSDI is the first algorithm to rank in the top-10 for all metrics evaluated in the 2016 QSM Reconstruction Challenge. It also demonstrated lower variance than nMEDI and more stable behaviour in scan-rescan reproducibility experiments for different MRI acquisitions at 3 and 7 Tesla. In the present work, we also explored new forms of susceptibility MRI contrast making explicit use of the differential information across spatial scales. Specifically, we show MSDI-derived examples of: (i) enhanced anatomical detail with susceptibility inversions from short-range dipole fields (hereby referred to as High-Pass Susceptibility Mapping or HPSM), (ii) high specificity to venous-blood susceptibilities for highly regularised HPSM (making a case for MSDI-based Venography or VenoMSDI), (iii) improved tissue specificity (and possibly statistical conditioning) for Macroscopic-Vessel Suppressed Susceptibility Mapping (MVSSM), and (iv) high spatial specificity and definition for HPSM-based Susceptibility-Weighted Imaging (HPSM-SWI) and related intensity projections

Reassessing associations between white matter and behaviour with multimodal microstructural imaging

Several studies have established specific relationships between White Matter (WM) and behaviour. However, these studies have typically focussed on fractional anisotropy (FA), a neuroimaging metric that is sensitive to multiple tissue properties, making it difficult to identify what biological aspects of WM may drive such relationships. Here, we carry out a pre-registered assessment of WM-behaviour relationships in 50 healthy individuals across multiple behavioural and anatomical domains, and complementing FA with myelin-sensitive quantitative MR modalities (MT, R1, R2∗). Surprisingly, we only find support for predicted relationships between FA and behaviour in one of three pre-registered tests. For one behavioural domain, where we failed to detect an FA-behaviour correlation, we instead find evidence for a correlation between behaviour and R1. This hints that multimodal approaches are able to identify a wider range of WM-behaviour relationships than focusing on FA alone. To test whether a common biological substrate such as myelin underlies WM-behaviour relationships, we then ran joint multimodal analyses, combining across all MRI parameters considered. No significant multimodal signatures were found and power analyses suggested that sample sizes of 40-200 may be required to detect such joint multimodal effects, depending on the task being considered. These results demonstrate that FA-behaviour relationships from the literature can be replicated, but may not be easily generalisable across domains. Instead, multimodal microstructural imaging may be best placed to detect a wider range of WM-behaviour relationships, as different MRI modalities provide distinct biological sensitivities. Our findings highlight a broad heterogeneity in WM's relationship with behaviour, suggesting that variable biological effects may be shaping their interaction

Profiles of Multidrug Resistance Protein-1 in the Peripheral Blood Mononuclear Cells of Patients with Refractory Epilepsy

BACKGROUND: About one third of patients with epilepsy become refractory to therapy despite receiving adequate medical treatment, possibly from multidrug resistance. P-glycoprotein, encoded by multidrug resistance protein-1 (MDR1) gene, at the blood brain barrier is considered as a major factor mediating drug efflux and contributing to resistance. Given that peripheral blood mononuclear cells (PBMNCs) express MDR1, we investigated a MDR1 status of PBMNCs in various subsets of epilepsy patients and demonstrated their association with clinical characteristics. METHODOLOGY/PRINCIPAL FINDINGS: Clinical and MDR1 data were collected from 140 patients with epilepsy, 30 healthy volunteers, and 20 control patients taking anti-epileptic drugs. PBMNCs were isolated, and basal MDR1 levels and MDR1 conformational change levels were measured by flow cytometry. MDR1 profiles were analyzed according to various clinical parameters, including seizure frequency and number of medications used in epilepsy patients. Epilepsy patients had a higher basal MDR1 level than non-epilepsy groups (p<0.01). Among epilepsy patients, there is a tendency for higher seizure frequency group to have higher basal MDR1 level (p = 0.059). The MDR1 conformational change level was significantly higher in the high-medication-use group than the low-use group (p = 0.028). Basal MDR1 (OR = 1.16 [95% CI: 1.060-1.268]) and conformational change level (OR = 1.11 [95% CI: 1.02-1.20]) were independent predictors for seizure frequency and number of medications, respectively. CONCLUSIONS/SIGNIFICANCE: The MDR1 profile of PBMNCs is associated with seizure frequency and medication conditions in patients with epilepsy

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases

Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer’s disease, atypical neurodegenerative dementias and Parkinson’s disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis