A smartphone sensor-based digital outcome assessment of multiple sclerosis.

BACKGROUND: Sensor-based monitoring tools fill a critical gap in multiple sclerosis (MS) research and clinical care. OBJECTIVE: The aim of this study is to assess performance characteristics of the Floodlight Proof-of-Concept (PoC) app. METHODS: In a 24-week study (clinicaltrials.gov: NCT02952911), smartphone-based active tests and passive monitoring assessed cognition (electronic Symbol Digit Modalities Test), upper extremity function (Pinching Test, Draw a Shape Test), and gait and balance (Static Balance Test, U-Turn Test, Walk Test, Passive Monitoring). Intraclass correlation coefficients (ICCs) and age- or sex-adjusted Spearman's rank correlation determined test-retest reliability and correlations with clinical and magnetic resonance imaging (MRI) outcome measures, respectively. RESULTS: Seventy-six people with MS (PwMS) and 25 healthy controls were enrolled. In PwMS, ICCs were moderate-to-good (ICC(2,1) = 0.61-0.85) across tests. Correlations with domain-specific standard clinical disability measures were significant for all tests in the cognitive (r = 0.82, p < 0.001), upper extremity function (|r|= 0.40-0.64, all p < 0.001), and gait and balance domains (r = -0.25 to -0.52, all p < 0.05; except for Static Balance Test: r = -0.20, p > 0.05). Most tests also correlated with Expanded Disability Status Scale, 29-item Multiple Sclerosis Impact Scale items or subscales, and/or normalized brain volume. CONCLUSION: The Floodlight PoC app captures reliable and clinically relevant measures of functional impairment in MS, supporting its potential use in clinical research and practice.

Mapping pathological changes in brain structure by combining T1- and T2-weighted MR imaging data.

INTRODUCTION: A workflow based on the ratio between standardized T1-weighted (T1-w) and T2-weighted (T2-w) MR images has been proposed as a new tool to study brain structure. This approach was previously used to map structural properties in the healthy brain. Here, we evaluate whether the T1-w/T2-w approach can support the assessment of structural impairments in the diseased brain. We use schizophrenia data to demonstrate the potential clinical utility of the technique. METHODS: We analyzed T1-w and T2-w images of 36 schizophrenic patients and 35 age-matched controls. These were collected for the Function Biomedical Informatics Research Network (fBIRN) collaborative project, which had an IRB approval and followed the HIPAA guidelines. We computed T1-w/T2-w images for each individual and compared intensities in schizophrenic and control groups on a voxel-wise basis, as well as in regions of interest (ROIs). RESULTS: Our results revealed that the T1-w/T2-w image permits to discriminate brain regions showing group-level differences between patients and controls with greater accuracy than conventional T1-w and T2-w images. Both the ROIs and the voxel-wise analysis showed globally reduced gray and white matter values in patients compared to controls. Significantly reduced values were found in regions such as insula, primary auditory cortex, hippocampus, inferior longitudinal fasciculus, and inferior fronto-occipital fasciculus. CONCLUSION: Our findings were consistent with previous meta-analyses in schizophrenia corroborating the hypothesis of a potential "disconnection" syndrome in conjunction with structural alterations in local gray matter regions. Overall, our study suggested that the T1-w/T2-w technique permits to reliably map structural differences between the brains of patients and healthy individuals.

Large-scale analysis of neural activity and connectivity from high-density electroencephalographic data.

INTRODUCTION: High-density electroencephalography (hdEEG) is a technique used for the characterization of the neural activity and connectivity in the human brain. The analysis of EEG data involves several steps, including signal pre-processing, head modelling, source localization and activity/connectivity quantification. Visual check of the analysis steps is often necessary, making the process time- and resource-consuming and, therefore, not feasible for large datasets. FINDINGS: Here we present the Noninvasive Electrophysiology Toolbox (NET), an open-source software for large-scale analysis of hdEEG data, running on the cross-platform MATLAB environment. NET combines all the tools required for a complete hdEEG analysis workflow, from raw signals to final measured values. By relying on reconstructed neural signals in the brain, NET can perform traditional analyses of time-locked neural responses, as well as more advanced functional connectivity and brain mapping analyses. The extracted quantitative neural data can be exported to provide broad compatibility with other software. CONCLUSIONS: NET is freely available (https://github.com/bind-group-kul/net) under the GNU public license for non-commercial use and open-source development, together with a graphical user interface (GUI) and a user tutorial. While NET can be used interactively with the GUI, it is primarily aimed at unsupervised automation to process large hdEEG datasets efficiently. Its implementation creates indeed a highly customizable program suitable for analysis automation and tight integration into existing workflows.

Concurrent validity of vertical jump performance assessment systems.

The aim of this study was to examine the concurrent validity of 2 portable systems for vertical jump (VJ) assessment under field conditions. The VJ flight times assessed using an optical mat (Optojump) and an accelerometer-based (Myotest) system were compared with that of a force platform. The flight times recorded during a countermovement jump (CMJ) were collected from 20 rugby players (n = 86 jumps) concurrently using the 3 tracking systems. Significant bias between the Force platform and either the Optojump (bias = 0.006 ± 0.007; 95% confidence interval [CI] 0.004-0.007 seconds) and Myotest (bias = -0.031 ± 0.021; 95% CI 0.035 to -0.026s; p < 0.0001) occurred. A nearly perfect correlation was found between force platform and Optojump (r = 0.99; 95% CI 0.098-0.99; p < 0.0001). Force platform and Myotest (r = 0.89; 95% CI 0.084-0.93; p < 0.0001) flight times showed very large association. Difference between Optojump and Myotest systems was significant (-0.036 ± 0.021 seconds; 95% CI -0.041 to -0.032; p < 0.0001), which results in Myotest mean flight time being approximately 7.2% longer than the Optojump flight time. The association between Optojump and Myotest was nearly perfect (r = 0.91, 95% CI 0.86-0.94; p < 0.0001). This study showed that the Optojump and Myotest systems possess convergent validity and can be successfully used under field conditions to assess VJ while performing a CMJ. However, caution should be exercised when interpreting data obtained from different portable systems for field measurement.

Preliminary validity of the Draw a Shape Test for upper extremity assessment in multiple sclerosis.

OBJECTIVE: To validate the smartphone sensor-based Draw a Shape Test - a part of the Floodlight Proof-of-Concept app for remotely assessing multiple sclerosis-related upper extremity impairment by tracing six different shapes. METHODS: People with multiple sclerosis, classified functionally normal/abnormal via their Nine-Hole Peg Test time, and healthy controls participated in a 24-week, nonrandomized study. Spatial (trace accuracy), temporal (mean and variability in linear, angular, and radial drawing velocities, and dwell time ratio), and spatiotemporal features (trace celerity) were cross-sectionally analyzed for correlation with standard clinical and brain magnetic resonance imaging (normalized brain volume and total lesion volume) disease burden measures, and for capacity to differentiate people with multiple sclerosis from healthy controls. RESULTS: Data from 69 people with multiple sclerosis and 18 healthy controls were analyzed. Trace accuracy (all shapes), linear velocity variability (circle, figure-of-8, spiral shapes), and radial velocity variability (spiral shape) had a mostly fair/moderate-to-good correlation (|r| = 0.14-0.66) with all disease burden measures. Trace celerity also had mostly fair/moderate-to-good correlation (|r| = 0.18-0.41) with Nine-Hole Peg Test performance, cerebellar functional system score, and brain magnetic resonance imaging. Furthermore, partial correlation analysis related these results to motor impairment. People with multiple sclerosis showed greater drawing velocity variability, though slower mean velocity, than healthy controls. Linear velocity (spiral shape) and angular velocity (circle shape) potentially differentiate functionally normal people with multiple sclerosis from healthy controls. INTERPRETATION: The Draw a Shape Test objectively assesses upper extremity impairment and correlates with all disease burden measures, thus aiding multiple sclerosis-related upper extremity impairment characterization.

Neural correlates of digital measures shown by structural MRI: a post-hoc analysis of a smartphone-based remote assessment feasibility study in multiple sclerosis.

BACKGROUND: A study was undertaken to evaluate remote monitoring via smartphone sensor-based tests in people with multiple sclerosis (PwMS). This analysis aimed to explore regional neural correlates of digital measures derived from these tests. METHODS: In a 24-week, non-randomized, interventional, feasibility study (NCT02952911), sensor-based tests on the Floodlight Proof-of-Concept app were used to assess cognition (smartphone-based electronic Symbol Digit Modalities Test), upper extremity function (Draw a Shape Test, Pinching Test), and gait and balance (Static Balance Test, Two-Minute Walk Test, U-Turn Test). In this post-hoc analysis, digital measures and standard clinical measures (e.g., Nine-Hole Peg Test [9HPT]) were correlated against regional structural magnetic resonance imaging outcomes. Seventy-six PwMS aged 18-55 years with an Expanded Disability Status Scale score of 0.0-5.5 were enrolled from two different sites (USA and Spain). Sixty-two PwMS were included in this analysis. RESULTS: Worse performance on digital and clinical measures was associated with smaller regional brain volumes and larger ventricular volumes. Whereas digital and clinical measures had many neural correlates in common (e.g., putamen, globus pallidus, caudate nucleus, lateral occipital cortex), some were observed only for digital measures. For example, Draw a Shape Test and Pinching Test measures, but not 9HPT score, correlated with volume of the hippocampus (r = 0.37 [drawing accuracy over time on the Draw a Shape Test]/ - 0.45 [touching asynchrony on the Pinching Test]), thalamus (r = 0.38/ - 0.41), and pons (r = 0.35/ - 0.35). CONCLUSIONS: Multiple neural correlates were identified for the digital measures in a cohort of people with early MS. Digital measures showed associations with brain regions that clinical measures were unable to demonstrate, thus providing potential novel information on functional ability compared with standard clinical assessments.

RT-NET: real-time reconstruction of neural activity using high-density electroencephalography.

High-density electroencephalography (hdEEG) has been successfully used for large-scale investigations of neural activity in the healthy and diseased human brain. Because of their high computational demand, analyses of source-projected hdEEG data are typically performed offline. Here, we present a real-time noninvasive electrophysiology toolbox, RT-NET, which has been specifically developed for online reconstruction of neural activity using hdEEG. RT-NET relies on the Lab Streaming Layer for acquiring raw data from a large number of EEG amplifiers and for streaming the processed data to external applications. RT-NET estimates a spatial filter for artifact removal and source activity reconstruction using a calibration dataset. This spatial filter is then applied to the hdEEG data as they are acquired, thereby ensuring low latencies and computation times. Overall, our analyses show that RT-NET can estimate real-time neural activity with performance comparable to offline analysis methods. It may therefore enable the development of novel brain-computer interface applications such as source-based neurofeedback.

fMRI data processing in MRTOOL: to what extent does anatomical registration affect the reliability of functional results?

Spatial registration is an essential step in the analysis of fMRI data because it enables between-subject analyses of brain activity, measured either during task performance or in the resting state. In this study, we investigated how anatomical registration with MRTOOL affects the reliability of task-related fMRI activity. We used as a benchmark the results from two other spatial registration methods implemented in SPM12: the Unified Segmentation algorithm and the DARTEL toolbox. Structural alignment accuracy and the impact on functional activation maps were assessed with high-resolution T1-weighted images and a set of task-related functional volumes acquired in 10 healthy volunteers. Our findings confirmed that anatomical registration is a crucial step in fMRI data processing, contributing significantly to the total inter-subject variance of the activation maps. MRTOOL and DARTEL provided greater registration accuracy than Unified Segmentation. Although DARTEL had superior gray matter and white matter tissue alignment than MRTOOL, there were no significant differences between DARTEL and MRTOOL in test-retest reliability. Likewise, we found only limited differences in BOLD activation morphology between MRTOOL and DARTEL. The test-retest reliability of task-related responses was comparable between MRTOOL and DARTEL, and both proved superior to Unified Segmentation. We conclude that MRTOOL, which is suitable for single-subject processing of structural and functional MR images, is a valid alternative to other SPM12-based approaches that are intended for group analysis. MRTOOL now includes a normalization module for fMRI data and is freely available to the scientific community.

Spatial localization of EEG electrodes using 3D scanning.

OBJECTIVE: A reliable reconstruction of neural activity using high-density electroencephalography (EEG) requires an accurate spatial localization of EEG electrodes aligned to the structural magnetic resonance (MR) image of an individual's head. Current technologies for electrode positioning, such as electromagnetic digitization, are yet characterized by non-negligible localization and co-registration errors. In this study, we propose an automated method for spatial localization of EEG electrodes using 3D scanning, a non-invasive and easy-to-use technology with potential applications in clinical settings. APPROACH: Our method consists of three main steps: (1) the 3D scan is ambient light-corrected and spatially aligned to the head surface extracted from the anatomical MR image; (2) electrode positions are identified by segmenting the 3D scan based on predefined colour and topological properties; (3) electrode labelling is performed by aligning an EEG montage template to the electrode positions. The performance of the method was assessed on data collected in eight participants wearing high-density EEG caps with 128 sensors, from three different manufacturers. We estimated the co-registration error using the distance between the MR-based head shape and the closest 3D scan points. Also, we quantified the positioning error using the distance between the detected electrode positions and the corresponding locations manually selected on the 3D scan data. MAIN RESULTS: For all participants and EEG caps, we obtained a median error of co-registration below 3.0 mm and of spatial localization below 1.4 mm. The method based on 3D scanning data was significantly more precise compared to the electromagnetic digitization technique, and the total time required for obtaining electrode positions was reduced by about half. SIGNIFICANCE: We have introduced a method to automatically detect EEG electrodes based on 3D scanning information. We believe that our work can contribute to a more effective, reliable and widespread use of high-density EEG as brain imaging tool.

A new computational approach to estimate whole-brain effective connectivity from functional and structural MRI, applied to language development.

Recently introduced effective connectivity methods allow for the in-vivo investigation of large-scale functional interactions between brain regions. However, dynamic causal modeling, the most widely used technique to date, typically captures only a few predefined regions of interest. In this study, we present an alternative computational approach to infer effective connectivity within the entire connectome and show its performance on a developmental cohort with emerging language capacities. The novel approach provides new opportunities to quantify effective connectivity changes in the human brain.

A Spatial Registration Toolbox for Structural MR Imaging of the Aging Brain.

During aging the brain undergoes a series of structural changes, in size, shape as well as tissue composition. In particular, cortical atrophy and ventricular enlargement are often present in the brain of elderly individuals. This poses serious challenges in the spatial registration of structural MR images. In this study, we addressed this open issue by proposing an enhanced framework for MR registration and segmentation. Our solution was compared with other approaches based on the tools available in SPM12, a widely used software package. Performance of the different methods was assessed on 229 T1-weighted images collected in healthy individuals, with age ranging between 55 and 90 years old. Our method showed a consistent improvement as compared to other solutions, especially for subjects with enlarged lateral ventricles. It also provided a superior inter-subject alignment in cortical regions, with the most marked improvement in the frontal lobe. We conclude that our method is a valid alternative to standard approaches based on SPM12, and is particularly suitable for the processing of structural MR images of brains with cortical atrophy and ventricular enlargement. The method is integrated in our software toolbox MRTool, which is freely available to the scientific community.

Detecting Large-Scale Brain Networks Using EEG: Impact of Electrode Density, Head Modeling and Source Localization.

Resting state networks (RSNs) in the human brain were recently detected using high-density electroencephalography (hdEEG). This was done by using an advanced analysis workflow to estimate neural signals in the cortex and to assess functional connectivity (FC) between distant cortical regions. FC analyses were conducted either using temporal (tICA) or spatial independent component analysis (sICA). Notably, EEG-RSNs obtained with sICA were very similar to RSNs retrieved with sICA from functional magnetic resonance imaging data. It still remains to be clarified, however, what technological aspects of hdEEG acquisition and analysis primarily influence this correspondence. Here we examined to what extent the detection of EEG-RSN maps by sICA depends on the electrode density, the accuracy of the head model, and the source localization algorithm employed. Our analyses revealed that the collection of EEG data using a high-density montage is crucial for RSN detection by sICA, but also the use of appropriate methods for head modeling and source localization have a substantial effect on RSN reconstruction. Overall, our results confirm the potential of hdEEG for mapping the functional architecture of the human brain, and highlight at the same time the interplay between acquisition technology and innovative solutions in data analysis.

Online EEG artifact removal for BCI applications by adaptive spatial filtering.

OBJECTIVE: The performance of brain-computer interfaces (BCIs) based on electroencephalography (EEG) data strongly depends on the effective attenuation of artifacts that are mixed in the recordings. To address this problem, we have developed a novel online EEG artifact removal method for BCI applications, which combines blind source separation (BSS) and regression (REG) analysis. APPROACH: The BSS-REG method relies on the availability of a calibration dataset of limited duration for the initialization of a spatial filter using BSS. Online artifact removal is implemented by dynamically adjusting the spatial filter in the actual experiment, based on a linear regression technique. MAIN RESULTS: Our results showed that the BSS-REG method is capable of attenuating different kinds of artifacts, including ocular and muscular, while preserving true neural activity. Thanks to its low computational requirements, BSS-REG can be applied to low-density as well as high-density EEG data. SIGNIFICANCE: We argue that BSS-REG may enable the development of novel BCI applications requiring high-density recordings, such as source-based neurofeedback and closed-loop neuromodulation.

Intensity Inhomogeneity Correction of Structural MR Images: A Data-Driven Approach to Define Input Algorithm Parameters.

Intensity non-uniformity (INU) in magnetic resonance (MR) imaging is a major issue when conducting analyses of brain structural properties. An inaccurate INU correction may result in qualitative and quantitative misinterpretations. Several INU correction methods exist, whose performance largely depend on the specific parameter settings that need to be chosen by the user. Here we addressed the question of how to select the best input parameters for a specific INU correction algorithm. Our investigation was based on the INU correction algorithm implemented in SPM, but this can be in principle extended to any other algorithm requiring the selection of input parameters. We conducted a comprehensive comparison of indirect metrics for the assessment of INU correction performance, namely the coefficient of variation of white matter (CVWM), the coefficient of variation of gray matter (CVGM), and the coefficient of joint variation between white matter and gray matter (CJV). Using simulated MR data, we observed the CJV to be more accurate than CVWM and CVGM, provided that the noise level in the INU-corrected image was controlled by means of spatial smoothing. Based on the CJV, we developed a data-driven approach for selecting INU correction parameters, which could effectively work on actual MR images. To this end, we implemented an enhanced procedure for the definition of white and gray matter masks, based on which the CJV was calculated. Our approach was validated using actual T1-weighted images collected with 1.5 T, 3 T, and 7 T MR scanners. We found that our procedure can reliably assist the selection of valid INU correction algorithm parameters, thereby contributing to an enhanced inhomogeneity correction in MR images.

Quantitative Evaluation of Intensity Inhomogeneity Correction Methods for Structural MR Brain Images.

The correction of intensity non-uniformity (INU) in magnetic resonance (MR) images is extremely important to ensure both within-subject and across-subject reliability. Here we tackled the problem of objectively comparing INU correction techniques for T1-weighted images, which are the most commonly used in structural brain imaging. We focused our investigations on the methods integrated in widely used software packages for MR data analysis: FreeSurfer, BrainVoyager, SPM and FSL. We used simulated data to assess the INU fields reconstructed by those methods for controlled inhomogeneity magnitudes and noise levels. For each method, we evaluated a wide range of input parameters and defined an enhanced configuration associated with best reconstruction performance. By comparing enhanced and default configurations, we found that the former often provide much more accurate results. Accordingly, we used enhanced configurations for a more objective comparison between methods. For different levels of INU magnitude and noise, SPM and FSL, which integrate INU correction with brain segmentation, generally outperformed FreeSurfer and BrainVoyager, whose methods are exclusively dedicated to INU correction. Nonetheless, accurate INU field reconstructions can be obtained with FreeSurfer on images with low noise and with BrainVoyager for slow and smooth inhomogeneity profiles. Our study may prove helpful for an accurate selection of the INU correction method to be used based on the characteristics of actual MR data.

Whole brain myelin mapping using T1- and T2-weighted MR imaging data.

Despite recent advancements in MR imaging, non-invasive mapping of myelin in the brain still remains an open issue. Here we attempted to provide a potential solution. Specifically, we developed a processing workflow based on T1-w and T2-w MR data to generate an optimized myelin enhanced contrast image. The workflow allows whole brain mapping using the T1-w/T2-w technique, which was originally introduced as a non-invasive method for assessing cortical myelin content. The hallmark of our approach is a retrospective calibration algorithm, applied to bias-corrected T1-w and T2-w images, that relies on image intensities outside the brain. This permits standardizing the intensity histogram of the ratio image, thereby allowing for across-subject statistical analyses. Quantitative comparisons of image histograms within and across different datasets confirmed the effectiveness of our normalization procedure. Not only did the calibrated T1-w/T2-w images exhibit a comparable intensity range, but also the shape of the intensity histograms was largely corresponding. We also assessed the reliability and specificity of the ratio image compared to other MR-based techniques, such as magnetization transfer ratio (MTR), fractional anisotropy (FA), and fluid-attenuated inversion recovery (FLAIR). With respect to these other techniques, T1-w/T2-w had consistently high values, as well as low inter-subject variability, in brain structures where myelin is most abundant. Overall, our results suggested that the T1-w/T2-w technique may be a valid tool supporting the non-invasive mapping of myelin in the brain. Therefore, it might find important applications in the study of brain development, aging and disease.