Signal quality as Achilles' heel of graph theory in functional magnetic resonance imaging in multiple sclerosis.

Graph-theoretical analysis is a novel tool to understand the organisation of the brain.We assessed whether altered graph theoretical parameters, as observed in multiple sclerosis (MS), reflect pathology-induced restructuring of the brain's functioning or result from a reduced signal quality in functional MRI (fMRI). In a cohort of 49 people with MS and a matched group of 25 healthy subjects (HS), we performed a cognitive evaluation and acquired fMRI. From the fMRI measurement, Pearson correlation-based networks were calculated and graph theoretical parameters reflecting global and local brain organisation were obtained. Additionally, we assessed metrics of scanning quality (signal to noise ratio (SNR)) and fMRI signal quality (temporal SNR and contrast to noise ratio (CNR)). In accordance with the literature, we found that the network parameters were altered in MS compared to HS. However, no significant link was found with cognition. Scanning quality (SNR) did not differ between both cohorts. In contrast, measures of fMRI signal quality were significantly different and explained the observed differences in GTA parameters. Our results suggest that differences in network parameters between MS and HS in fMRI do not reflect a functional reorganisation of the brain, but rather occur due to reduced fMRI signal quality.

Single MRI-Based Volumetric Assessment in Clinical Practice Is Associated With MS-Related Disability.

BACKGROUND: The added value of brain volume measurements in the clinical practice of multiple sclerosis (MS) has been questioned. PURPOSE: To investigate the contribution of volume measures obtained with magnetic resonance scans performed as part of regular care to predict measures of cognitive and physical MS disability in a real-world setting. STUDY TYPE: Retrospective. SUBJECTS: In all, 470 adults with diagnosed MS. FIELD STRENGTH/SEQUENCE: 3D fluid attenuation inversion recovery (FLAIR) and 3D T1 -weighted MR images at 3.0T MR. ASSESSMENT: Lesion and brain volume were measured by an automated method, MSmetrix, developed by icometrix. STATISTICAL TESTS: We used stepwise linear regression models to assess the added value of a single volumetric assessment in predicting Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT). Brain volumes categorized into quartiles were used as predictive variables in a time-to-event analysis and Cox proportional hazard regression with time to worsening from baseline as outcome measures. RESULTS: Brain and lesion volume in relapsing onset MS strongly contributed to the best models, with a substantial role for age in the EDSS model and a modest role for education in the SDMT model. Adding MR volumetric information increased the explained variance from 17% to 28% in the best model for EDSS and from 9% to 25% in the best model for SDMT. A significantly reduced hazard (P < 0.05) of SDMT worsening was found in the highest normalized brain volume quartiles (1375-1608 ml), compared with the lowest quartile (1201-1374 ml) in the total study population. DATA CONCLUSION: Our findings indicate that a single brain volumetric assessment contributes to the prediction of MS-related disability, with distinct patterns for EDSS as a measure of physical disability, and SDMT as a measure of cognitive disability. A threshold effect for the lowest brain volumes with regard to SDMT worsening over time was found. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1312-1321.

The effect of task modality and stimulus frequency in paced serial addition tests on functional brain activity.

INTRODUCTION: The paced serial addition test (PSAT) is regularly used to assess cognitive deficits in various neuropsychiatric conditions. Being a complex test, it reflects the status of multiple cognitive domains such as working memory, information processing speed and executive functioning. Two versions of the PSAT exist. One uses auditory stimuli through spoken numbers and is known as the PASAT, while the other one presents patients with visual stimuli and is called PVSAT. The PASAT is considered more frustrating by patients, and hence the visual version is usually preferred. Research has suggested that an interference might exist between patients' verbal answers and the auditory presentation of stimuli. We therefore removed the verbal response in this study, and aimed to investigate differences in functional brain activity through functional magnetic resonance imaging. METHODS: Fifteen healthy controls performed the two test versions inside an MRI scanner-switching between stimulus modality (auditory vs. visual) as well as inter-stimulus frequency (3s vs. 2s). We extracted 11 independent components from the data: attentional, visual, auditory, sensorimotor and default mode networks. We then performed statistical analyses of mean network activity within each component, as well as inter-network connectivity of each component pair during the different task types. RESULTS: Unsurprisingly, we noted an effect of modality on activity in the visual and auditory components. However, we also describe bilateral frontoparietal, anterior cingulate and insular attentional network activity. An effect of frequency was noted only in the sensorimotor network. Effects were found on edges linking visual and auditory regions. Task modality influenced an attentional-sensorimotor connection, while stimulus frequency had an influence on sensorimotor-default mode connections. CONCLUSIONS: Scanner noise during functional MRI may interfere with brain activation-especially during tasks involving auditory pathways. The question whether to use PVSAT or PASAT for an fMRI study is, therefore, an important one. Specific effects of both modalities should be known to study designers. We conclude that both tests should not be considered interchangeable, as significant changes were brought to light during test performance in different modalities.

Does including the full CVLT-II and BVMT-R improve BICAMS? Evidence from a Belgian (Dutch) validation study.

BACKGROUND: The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) is a fast, easy-to-administer and already widely validated neuropsychological battery for cognition in multiple sclerosis. OBJECTIVE: The goals of our study were to validate the BICAMS in a Belgian Dutch-speaking population and to investigate to what extent including extensive versions of two of the three BICAMS subtests improved its psychometric qualities. METHODS: Ninety-seven persons with MS and ninety-seven healthy controls were included and group-matched on age, education level and gender. All participants performed the BICAMS with an extensive version of the CVLT-II and BVMT-R. RESULTS: The SDMT and BVMT-R were able to dissociate between the MS and healthy control group, while the CVLT-II was not. Distributions of CVLT-II scores suggest learning effects in the MS group, indicating the need for alternative word lists or the construction of an adapted version fitted for repeated administration. Including the full CVLT-II and BVMT-R did not markedly improve the psychometric qualities of the BICAMS. CONCLUSION: This study validates the BICAMS in a Belgian Dutch-speaking population and facilitates the use of it in clinical practice, while providing evidence that including full versions of the CVLT-II and BVMT-R does not increase its psychometric qualities markedly.

The effect of morphological and microstructural integrity of the corpus callosum on cognition, fatigue and depression in mildly disabled MS patients.

AIM: To assess the value of callosal morphological and microstructural integrity in assessing different cognitive domains, fatigue and depression in mildly disabled multiple sclerosis (MS) patients. MATERIALS AND METHODS: We assessed 29 mildly disabled MS patients and 15 healthy controls using 3T magnetic resonance images (T1-weighted, FLAIR and DTI) and neuropsychological tests assessing different cognitive functions, depression and fatigue. We compared the added value of morphological measures (corpus callosum area corrected for total intracranial volume, index, circularity and the more detailed thickness profile) and diffusion features (fractional anisotropy and mean diffusivity) in multilinear models including standard clinical and whole-brain parameters in assessing neuropsychological scores. RESULTS: Even in mildly disabled MS patients, a significant reduction of the corpus callosum (p<0.001) was observed in comparison to healthy controls. Callosal area, index and circularity were significantly (p<0.002) related to whole-brain white matter volume, T2 lesion load and deep grey matter volume, but not with cortical grey matter. The combination of commonly used imaging and clinical parameters explained between 7% (Fatigue) and 50% (processing speed, verbal memory) of the adjusted variance. Inclusion of the mean diffusivity increased the adjusted R2 significantly to 69% (p=0.004) and 71% (p=0.002) for visuospatial and verbal memory respectively. CONCLUSION: Our results show that callosal features may be used as an alternative to measuring whole-brain volumes. Furthermore, the microstructural integrity of the corpus callosum can help to predict an MS patient's memory performance.

EEG Dominant Frequency Peak Differentiates Between Alzheimer's Disease and Frontotemporal Lobar Degeneration.

We investigated the power of EEG as biomarker in differential diagnosis of Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). EEG was recorded from 106 patients with AD or FTLD, of which 37 had a definite diagnosis, and 40 controls. Dominant frequency peaks were extracted for all 19 channels, for each subject. The average frequency of the largest dominant frequency peaks (maxpeak) was significantly lower in AD than FTLD patients and controls. Based on ROC analysis, classification could be made with diagnostic accuracy of 78.9%. Our findings show that quantitative analysis of EEG maxpeak frequency is an easy and useful measure for differential dementia diagnosis.

Assessing PML risk under immunotherapy: if all you have is a hammer, everything looks like a nail.

Recently, three progressive multifocal leukoencephalopathy (PML) cases have been reported in multiple sclerosis (MS) patients, two treated with fingolimod (Gilenya, Novartis), the third with dimethyl fumarate (Tecfidera, Biogen). Because our immunotherapeutic arsenal in MS and other diseases is increasing, and because PML is a very serious health risk, it is of interest to the clinical community to show how we can assess this risk in a statistically sound way. The null-hypothesis for this analysis was that there is no elevated risk for PML in patients treated with one of these recent drugs, compared to the incidence in the general population. We conclude that the null hypothesis cannot be refuted.

Do advanced statistical techniques really help in the diagnosis of the metabolic syndrome in patients treated with second-generation antipsychotics?

OBJECTIVE: Metabolic and cardiovascular diseases in patients with schizophrenia have gained a lot of interest in recent years. Developing an algorithm to detect the metabolic syndrome based on readily available variables would eliminate the need for blood sampling, which is considered expensive and inconvenient in this population. METHOD: All patients fulfilled DSM-IV diagnosis of schizophrenia or schizoaffective disorder. We used the International Diabetes Federation criteria (European population) to diagnose the metabolic syndrome. We used logistic regression and optimized artificial neural networks and support vector machines to detect the metabolic syndrome in a cohort of schizophrenic patients of the University Psychiatric Center Kortenberg, KU Leuven, Belgium. Testing was done on one-third of the included cohort (202 patients); training was performed using a 10-fold stratified cross-validation scheme. The data were collected between 2000 and 2008. RESULTS: All 3 methods yielded similar results, with satisfying accuracies of about 80%. However, none of the advanced statistical methods could improve on the results obtained using a very simple and naive model including only central obesity and information on blood pressure. CONCLUSIONS: Although so-called pattern recognition techniques bear high promise in improving clinical decision making, the results should be presented with caution and preferably in comparison with a less complicated technique.

Single-subject classification of schizophrenia patients based on a combination of oddball and mismatch evoked potential paradigms.

OBJECTIVE: The diagnostic process for schizophrenia is mainly clinical and has to be performed by an experienced psychiatrist, relying primarily on clinical signs and symptoms. Current neurophysiological measurements can distinguish groups of healthy controls and groups of schizophrenia patients. Individual classification based on neurophysiological measurements mostly shows moderate accuracy. We wanted to examine whether it is possible to distinguish controls and patients individually with a good accuracy. To this end we used a combination of features extracted from the auditory and visual P300 paradigms and the mismatch negativity paradigm. METHODS: We selected 54 patients and 54 controls, matched for age and gender, from the data available at the UPC Kortenberg. The EEG-data were high- and low-pass filtered, epoched and averaged. Features (latencies and amplitudes of component peaks) were extracted from the averaged signals. The resulting dataset was used to train and test classification algorithms. First on separate paradigms and then on all combinations, we applied Naïve Bayes, Support Vector Machine and Decision Tree, with two of its improvements: Adaboost and Random Forest. RESULTS: For at least two classifiers the performance increased significantly by combining paradigms compared to single paradigms. The classification accuracy increased from at best 79.8% when trained on features from single paradigms, to 84.7% when trained on features from all three paradigms. CONCLUSION: A combination of features originating from three evoked potential paradigms allowed us to accurately classify individual subjects as either control or patient. Classification accuracy was mostly above 80% for the machine learners evaluated in this study and close to 85% at best.

The squares test as a measure of hand function in multiple sclerosis.

Deterioration of hand function can be important in multiple sclerosis (MS). The standard way of assessing hand function in MS is the 9-hole peg test (9HPT), one of the three components of the MS functional composite measure. In this study we examine the squares test (ST), a test of hand function that is used extensively in handedness research. We evaluated reproducibility of the ST in 49 healthy controls, and both discriminatory power and concurrent validity of the ST in 38 MS patients and 18 age and gender matched controls. The ST proved to be a reliable and easy to administrate paper-and-pencil test of hand function. The ST showed a high and highly significant correlation with the standard 9HPT over a broad range of Expanded Disability Status Scale (EDSS) scores, and had high discriminatory power, also comparable to the 9HPT. Therefore, the ST is a candidate test for use in composite measures of MS related functional deficits for clinical practice and in clinical trials.

Graph theoretical analysis indicates cognitive impairment in MS stems from neural disconnection.

BACKGROUND: The mechanisms underlying cognitive impairment in MS are still poorly understood. However, due to the specific pathology of MS, one can expect alterations in connectivity leading to physical and cognitive impairment. AIM: In this study we aimed at assessing connectivity differences in EEG between cognitively impaired (CI) and cognitively preserved (CP) MS patients. We also investigated the influence of the measures used to construct networks. METHODS: We included 308 MS patients and divided them into two groups based on their cognitive score. Graph theoretical network analyses were conducted based on networks constructed using different connectivity measures, i.e. correlation, correlation in the frequency domain, coherence, partial correlation, the phase lag index and the imaginary part of coherency. The most commonly encountered network parameters were calculated and compared between the two groups using Wilcoxon's rank test. Clustering coefficients and path lengths were normalized to a randomized mean clustering coefficient and path length for each patient. False discovery rate was used to correct for the multiple comparisons and Cohen's d effect sizes are reported. RESULTS: Coherence analysis suggests that theta and delta connectivity is significantly smaller in cognitively impaired patients. Small-worldness differences are found in networks based on correlation, theta and delta coherence and correlation in the frequency domain. Modularity was related to age but not to cognition. CONCLUSION: Cognitive deterioration in MS is a symptom that seems to be caused by neural disconnections, probably the white matter tracts connecting both hemispheres, and leads to a wide range in network differences which can be assessed by applying GTA to EEG data. In the future, these results may lead to cheaper and more objective assessments of cognitive impairment in MS.

Atomic force microscopy nanomanipulation of shape persistent, spherical, self-assembled aggregates of gold nanoparticles.

Gold (Au) nanoparticles have been synthesized that are stabilized by an organic ligand bearing a dithiolane functional group for binding to Au, an oligo(p-phenylene vinylene) (OPV) chromophoric group to drive self-assembly via π-π interactions, and a hydroxy functionality for interparticle hydrogen bonding. The OPV-Au particles reversibly self-assemble in n-heptane solution, forming shape persistent, spherical, nanometer-sized aggregates that do not collapse on a substrate. Optical absorption and transmission electron microscopy tomography studies show that the size and shape persistency can be tuned by modification of the ligands, adjustment of the core size, and variation of the concentration. The spherical assemblies can be manipulated with the tip of an atomic force microscope: an aggregate can be pushed over the surface for at least 20 times with nanometer precision and without substantial loss of material.

Intensive chiroptical properties of chiral polyfluorenes associated with fibril formation.

Thin films of chiral poly{9,9-bis[(3S)-3,7-dimethyloctyl]-2,7-fluorene} (1) were studied using circular dichroism (CD) spectroscopy. Films spin coated from chloroform solution, show CD with a degree of polarization g(abs) (= +4 x 10(-4) at 400 nm) that is independent of film thickness (50-290 nm). This implies that g(abs) is an intensive property of the material and related to the chiral organization of the molecules on a length scale less than 50 nm. Atomic force microscopy (AFM) on the films reveals fibrils. Addition of nonsolvent methanol to a solution of 1 in chloroform leads to fibril formation in solution and results in CD similar in band shape to that of the pristine spin coated films from chloroform solution and a g(abs) comparable in magnitude. Thus the chiral molecular arrangement leading to circular dichroism is part of the internal structure of these fibrils.

Aggregation kinetics of macrocycles detected by magnetic birefringence.

We have used magnetic-field-induced birefringence as a new sensitive technique to probe the aggregation kinetics of macrocyclic molecules in solution. We have found three consecutive aggregation stages: disordered objects, ordered fibers, and a network. The transition from disordered objects to ordered fibers is found to be slow, taking days or weeks to complete. We attribute this to the molecular tails of the macrocycles, which hamper fiber formation. We anticipate that linking aggregation kinetics to molecular properties will lead to a better understanding of the mechanisms by which molecules self-assemble, allowing for a more rational design of the molecular building blocks.

Patterns of diacetylene-containing peptide amphiphiles using polarization holography.

The polarization dependence of a diacetylene polymerization was studied. For this purpose, peptide amphiphile fibers with a diacetylene moiety, which could only polymerize in the direction of the fiber, were employed. If nonaligned samples were illuminated with polarized light, only the fibers parallel to the polarization direction of the light were polymerized. With magnetically aligned fibers, spatially selective polymerization was accomplished using polarization holography.

Molecular organization of cylindrical sexithiophene aggregates measured by X-ray scattering and magnetic alignment.

We have determined the internal organization of elongated sexithiophene aggregates in solution by combining small-angle X-ray scattering and magnetic birefringence experiments. The different aggregate axes can be probed independently by performing the experiments on magnetically aligned aggregates. We have found multiwalled cylindrical aggregates consisting of radially oriented sexithiophene molecules with pi-pi-stacking in the tangential direction, a structure that is considerably different from those previously found in other solvents. The aggregate morphology of this semiconducting material can thus be tuned by using different solvents, which offers the attractive perspective to steer chemical self-assembly toward nanostructures with desired functionalities, especially in combination with the alignment in a magnetic field.

Insights into templated supramolecular polymerization: binding of naphthalene derivatives to ssDNA templates of different lengths.

We report on two diaminotriazine-equipped naphthalene derivatives that bind reversibly to a single-stranded DNA template or "tape-measure molecule" via hydrogen bonding, yielding monodisperse double-stranded DNA hybrids with one strand consisting of a supramolecular naphthalene backbone. These assemblies have been investigated extensively, both experimentally and theoretically. The structure and the templated self-assembly process of the complex have been characterized with UV-vis spectroscopy, circular dichroism spectroscopy, molecular dynamics simulations, cryo-transmission electron microscopy, liquid atomic force microscopy, electrospray ionization mass spectrometry, light scattering, and 1H NMR and infrared spectroscopy. We have found that the DNA hybrid complexes have a right-handed helical arrangement stabilized by pi-pi interactions and hydrogen bonds. The hydrophilic hydroxyl group at the end of the ethylene glycol of the guest molecule suppressed both the nontemplated self-assembly of the naphthalene guest molecules and the further aggregation of the entire DNA hybrid complex. Through the use of a theoretical mass-action model for the templated self-assembly, the host-guest and guest-guest interaction energies were estimated by fitting to the spectroscopic data. The differently estimated values of the interaction energies and thermodynamic parameters vary within experimental error, showing the self-consistency of the model. From the obtained correlation between the positions of the guest molecules bound on the template, we have obtained a qualitative theoretical picture of the way in which the guests are physically distributed on the templates. For short templates, the templates are filled one-by-one, even at moderate fractions of bound sites. For larger templates, the templates first have alternating sequences of filled and empty sections, after which, at large fractions of bound sites, virtually all of the binding sites for all template lengths are filled.

Using magnetic birefringence to determine the molecular arrangement of supramolecular nanostructures.

Supramolecular aggregates can be aligned in solution using a magnetic field. Because of the optical anisotropy of the molecular building blocks, the alignment results in an anisotropic refractive index of the solution parallel and perpendicular to the magnetic field. We present a model for calculating the magnetic birefringence, using solely the magnetic susceptibilities and optical polarizabilities of the molecules, for any molecular arrangement. We demonstrate that magnetic birefringence is a very sensitive tool for determining the molecular organization within supramolecular aggregates.

Oligo(p-phenylenevinylene)-peptide conjugates: synthesis and self-assembly in solution and at the solid-liquid interface.

Two oligo(p-phenylenevinylene)-peptide hybrid amphiphiles have been synthesized using solid- and liquid-phase strategies. The amphiliphiles are composed of a pi-conjugated oligo(p-phenylenevinylene) trimer (OPV) which is coupled at either a glycinyl-alanyl-glycinyl-alanyl-glycine (GAGAG) silk-inspired beta-sheet or a glycinyl-alanyl-asparagyl-prolyl-asparagy-alanyl-alanyl-glycine (GANPNAAG) beta-turn forming oligopeptide sequence. The solid-phase strategy enables one to use longer peptides if strong acidic conditions are avoided, whereas the solution-phase coupling gives better yields. The study of the two-dimensional (2D) self-assembly of OPV-GAGAG by scanning tunneling microscopy (STM) at the submolecular level demonstrated the formation of bilayers in which the molecules are lying antiparallel in a beta-sheet conformation. In the case of OPV-GANPNAAG self-assembled monolayers could not be observed. Absorption, fluorescence, and circular dichroism studies showed that OPV-GAGAG and OPV-GANPNAAG are aggregated in a variety of organic solvents. In water cryogenic temperature transmission electron microscopy (cryo-TEM), atomic force microscopy (AFM), light scattering, and optical studies reveal that self-assembled nanofibers are formed in which the helical organization of the OPV segments is dictated by the peptide sequence.