Fully automated delineation of the optic radiation for surgical planning using clinically feasible sequences

[EN] Quadrantanopia caused by inadvertent severing of Meyer's Loop of the optic radiation is a well-recognised complication of temporal lobectomy for conditions such as epilepsy. Dissection studies indicate that the anterior extent of Meyer's Loop varies considerably between individuals. Quantifying this for individual patients is thus an important step to improve the safety profile of temporal lobectomies. Previous attempts to delineate Meyer's Loop using diffusion MRI tractography have had difficulty estimating its full anterior extent, required manual ROI placement, and/or relied on advanced diffusion sequences that cannot be acquired routinely in most clinics. Here we present CONSULT: a pipeline that can delineate the optic radiation from raw DICOM data in a completely automated way via a combination of robust pre-processing, segmentation, and alignment stages, plus simple improvements that bolster the efficiency and reliability of standard tractography. We tested CONSULT on 696 scans of predominantly healthy participants (539 unique brains), including both advanced acquisitions and simpler acquisitions that could be acquired in clinically acceptable timeframes. Delineations completed without error in 99.4% of the scans. The distance between Meyer's Loop and the temporal pole closely matched both averages and ranges reported in dissection studies for all tested sequences. Median scan-rescan error of this distance was 1¿mm. When tested on two participants with considerable pathology, delineations were successful and realistic. Through this, we demonstrate not only how to identify Meyer's Loop with clinically feasible sequences, but also that this can be achieved without fundamental changes to tractography algorithms or complex post-processing methods.Advance Queensland, Grant/Award Number: R-09964-01; Fundacion Merck Salud; Proyecto Societat Catalana Neurologia; Ministerio de Economia, Industria y Competitividad of Spain, Grant/Award Number: DPI2017-87743-R; Red Espanola de Esclerosis Multiple, Grant/Award Numbers: RD12/0032/0002, RD12/0060/01-02, RD16/0015/0002, RD16/0015/0003; Spanish Government; Instituto de Salud Carlos III, Grant/Award Numbers: FIS 2015 PI15/00061, FIS 2015 - PI15/00587, FIS 2018 - PI18/01030Reid, LB.; Martínez-Heras, E.; Manjón Herrera, JV.; Jeffree, RL.; Alexander, H.; Trinder, J.; Solana, E.... (2021). Fully automated delineation of the optic radiation for surgical planning using clinically feasible sequences. Human Brain Mapping. 42(18):5911-5926. https://doi.org/10.1002/hbm.25658S59115926421

Assessing biological and methodological aspects of brain volume loss in multiple sclerosis

Importance: Before using brain volume loss (BVL) as a marker of therapeutic response in multiple sclerosis (MS), certain biological and methodological issues must be clarified. Objectives: To assess the dynamics of BVL as MS progresses and to evaluate the repeatability and exchangeability of BVL estimates with Jacobian Integration (JI) and Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL) (specifically, the Structural Image Evaluation, Using Normalisation, of Atrophy-Cross-Sectional [SIENA-X] tool or FMRIB's Integrated Registration and Segmentation Tool [FIRST]). Design, Setting, and Participants: A cohort of patients who had either clinically isolated syndrome or MS was enrolled from February 2011 through October 2015. All underwent a series of annual magnetic resonance imaging (MRI) scans. Images from 2 cohorts of healthy volunteers were used to evaluate short-term repeatability of the MRI measurements (n = 34) and annual BVL (n = 20). Data analysis occurred from January to May 2017. Main Outcomes and Measures: The goodness of fit of different models to the dynamics of BVL throughout the MS disease course was assessed. The short-term test-retest error was used as a measure of JI and FSL repeatability. The correlations (R2) of the changes quantified in the brain using JI and FSL, together with the accuracy of the annual BVL cutoffs to discriminate patients with MS from healthy volunteers, were used to measure compatibility of imaging methods. Results: A total of 140 patients with clinically isolated syndrome or MS were enrolled, including 95 women (67.9%); the group had a median (interquartile range) age of 40.7 (33.6-48.1) years. Patients underwent 4 MRI scans with a median (interquartile range) interscan period of 364 (351-379) days. The 34 healthy volunteers (of whom 18 [53%] were women; median [IQR] age, 33.5 [26.2-42.5] years) and 20 healthy volunteers (of whom 10 [50%] were women; median [IQR] age, 33.0 [28.7-39.2] years) underwent 2 MRI scans within a median (IQR) of 24.5 (0.0-74.5) days and 384.5 (366.3-407.8) days for the short-term and long-term MRI follow-up, respectively. The BVL rates were higher in the first 5 years after MS onset (R2 = 0.65 for whole-brain volume change and R2 = 0.52 for gray matter volume change) with a direct association with steroids (β = 0.280; P = .02) and an inverse association with age at MS onset, particularly in the first 5 years (β = 0.015; P = .047). The reproducibility of FSL (SIENA) and JI was similar for whole-brain volume loss, while JI gave more precise, less biased estimates for specific brain regions than FSL (SIENA-X and FIRST). The correlation between whole-brain volume loss using JI and FSL was high (R2 = 0.92), but the same correlations were poor for specific brain regions. The area under curve of the whole-brain volume change to discriminate between patients with MS and healthy volunteers was similar, although the thresholds and accuracy index were distinct for JI and FSL. Conclusions and Relevance: The proposed BVL threshold of less than 0.4% per year as a marker of therapeutic efficiency should be reconsidered because of the different dynamics of BVL as MS progresses and because of the limited reproducibility and variability of estimates using different imaging methods

Influence of corpus callosum damage on cognition and physical disability in multiple sclerosis: a multimodal study.

Background Corpus callosum (CC) is a common target for multiple sclerosis (MS) pathology. We investigated the influence of CC damage on physical disability and cognitive dysfunction using a multimodal approach. Methods Twenty-one relapsing-remitting MS patients and 13 healthy controls underwent structural MRI and diffusion tensor of the CC (fractional anisotropy; mean diffusivity, MD; radial diffusivity, RD; axial diffusivity). Interhemisferic transfer of motor inhibition was assessed by recording the ipsilateral silent period (iSP) to transcranial magnetic stimulation. We evaluated cognitive function using the Brief Repeatable Battery and physical disability using the Expanded Disability Status Scale (EDSS) and the MS Functional Composite (MSFC) z-score. Results The iSP latency correlated with physical disability scores (r ranged from 0.596 to 0.657, P values from 0.004 to 0.001), and with results of visual memory (r = −0.645, P = 0.002), processing speed (r = −0.51, P = 0.018) and executive cognitive domain tests (r = −0.452, P = 0.039). The area of the rostrum correlated with the EDSS (r = −0.442, P = 0.045). MD and RD correlated with cognitive performance, mainly with results of visual and verbal memory tests (r ranged from −0.446 to −0.546, P values from 0.048 to 0.011). The iSP latency correlated with CC area (r = −0.345, P = 0.049), volume (r = −0.401, P = 0.002), MD (r = 0.404, P = 0.002) and RD (r = 0.415, P = 0.016). Conclusions We found evidence for structural and microstructural CC abnormalities associated with impairment of motor callosal inhibitory conduction in MS. CC damage may contribute to cognitive dysfunction and in less extent to physical disability likely through a disconnection mechanism

The multiple sclerosis visual pathway cohort: understanding neurodegeneration in MS

BACKGROUND: Multiple Sclerosis (MS) is an immune-mediated disease of the Central Nervous System with two major underlying etiopathogenic processes: inflammation and neurodegeneration. The latter determines the prognosis of this disease. MS is the main cause of non-traumatic disability in middle-aged populations. FINDINGS: The MS-VisualPath Cohort was set up to study the neurodegenerative component of MS using advanced imaging techniques by focusing on analysis of the visual pathway in a middle-aged MS population in Barcelona, Spain. We started the recruitment of patients in the early phase of MS in 2010 and it remains permanently open. All patients undergo a complete neurological and ophthalmological examination including measurements of physical and disability (Expanded Disability Status Scale; Multiple Sclerosis Functional Composite and neuropsychological tests), disease activity (relapses) and visual function testing (visual acuity, color vision and visual field). The MS-VisualPath protocol also assesses the presence of anxiety and depressive symptoms (Hospital Anxiety and Depression Scale), general quality of life (SF-36) and visual quality of life (25-Item National Eye Institute Visual Function Questionnaire with the 10-Item Neuro-Ophthalmic Supplement). In addition, the imaging protocol includes both retinal (Optical Coherence Tomography and Wide-Field Fundus Imaging) and brain imaging (Magnetic Resonance Imaging). Finally, multifocal Visual Evoked Potentials are used to perform neurophysiological assessment of the visual pathway. DISCUSSION: The analysis of the visual pathway with advance imaging and electrophysilogical tools in parallel with clinical information will provide significant and new knowledge regarding neurodegeneration in MS and provide new clinical and imaging biomarkers to help monitor disease progression in these patients

Intense long-term training impairs brain health compared with moderate exercise: Experimental evidence and mechanisms

The consequences of extremely intense long-term exercise for brain health remain unknown. We studied the effects of strenuous exercise on brain structure and function, its dose-response relationship, and mechanisms in a rat model of endurance training. Five-week-old male Wistar rats were assigned to moderate (MOD) or intense (INT) exercise or a sedentary (SED) group for 16 weeks. MOD rats showed the highest motivation and learning capacity in operant conditioning experiments; SED and INT presented similar results. In vivo MRI demonstrated enhanced global and regional connectivity efficiency and clustering as well as a higher cerebral blood flow (CBF) in MOD but not INT rats compared with SED. In the cortex, downregulation of oxidative phosphorylation complex IV and AMPK activation denoted mitochondrial dysfunction in INT rats. An imbalance in cortical antioxidant capacity was found between MOD and INT rats. The MOD group showed the lowest hippocampal brain-derived neurotrophic factor levels. The mRNA and protein levels of inflammatory markers were similar in all groups. In conclusion, strenuous long-term exercise yields a lesser improvement in learning ability than moderate exercise. Blunting of MOD-induced improvements in CBF and connectivity efficiency, accompanied by impaired mitochondrial energetics and, possibly, transient local oxidative stress, may underlie the findings in intensively trained rats

Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis.

OBJECTIVE: Uncontrolled studies of mesenchymal stem cells (MSCs) in multiple sclerosis suggested some beneficial effect. In this randomized, double-blind, placebo-controlled, crossover phase II study we investigated their safety and efficacy in relapsing-remitting multiple sclerosis patients. Efficacy was evaluated in terms of cumulative number of gadolinium-enhancing lesions (GEL) on magnetic resonance imaging (MRI) at 6 months and at the end of the study. METHODS: Patients unresponsive to conventional therapy, defined by at least 1 relapse and/or GEL on MRI scan in past 12 months, disease duration 2 to 10 years and Expanded Disability Status Scale (EDSS) 3.0-6.5 were randomized to receive IV 1-2×10(6) bone-marrow-derived-MSCs/Kg or placebo. After 6 months, the treatment was reversed and patients were followed-up for another 6 months. Secondary endpoints were clinical outcomes (relapses and disability by EDSS and MS Functional Composite), and several brain MRI and optical coherence tomography measures. Immunological tests were explored to assess the immunomodulatory effects. RESULTS: At baseline 9 patients were randomized to receive MSCs (n = 5) or placebo (n = 4). One patient on placebo withdrew after having 3 relapses in the first 5 months. We did not identify any serious adverse events. At 6 months, patients treated with MSCs had a trend to lower mean cumulative number of GEL (3.1, 95% CI = 1.1-8.8 vs 12.3, 95% CI = 4.4-34.5, p = 0.064), and at the end of study to reduced mean GEL (-2.8±5.9 vs 3±5.4, p = 0.075). No significant treatment differences were detected in the secondary endpoints. We observed a non-significant decrease of the frequency of Th1 (CD4+ IFN-γ+) cells in blood of MSCs treated patients. CONCLUSION: Bone-marrow-MSCs are safe and may reduce inflammatory MRI parameters supporting their immunomodulatory properties. ClinicalTrials.gov NCT01228266

Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer’s disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (p = 4.22 × 10−20) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.P.G.-G. (Pablo García-González) is supported by CIBERNED employment plan CNV-304-PRF-866. CIBERNED is integrated into ISCIII (Instituto de Salud Carlos III). I.d.R is supported by a national grant from the Instituto de Salud Carlos III FI20/00215. A.C. (Amanda Cano) acknowledges the support of the Spanish Ministry of Science, Innovation, and Universities under the grant Juan de la Cierva (FJC2018-036012-I). M.B. (Mercé Boada) and A.R. (Agustín Ruiz) are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240, and PI19/01301. The Genome Research @ Fundació ACE project (GR@ACE) is supported by Grifols SA, Fundación bancaria “La Caixa”, Fundació ACE, and CIBERNED. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)—Subdirección General de Evaluación—and the Fondo Europeo de Desarrollo Regional (FEDER—“Una manera de hacer Europa”). Genotyping of the ACE MCI-EADB samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Program—Neurodegenerative Disease Research (JPND). Partial funding for open access charge: Universidad de Málag

Desarrollo de una metodología de reconstrucción de fibras de sustancia blanca en difusión por resonancia magnética y su aplicación al estudio de la relación entre la conectividad estructural cerebral y el rendimiento cognitivo en pacientes con esclerosis múltiple

[spa] Esta memoria de tesis se presenta en formato de artículos originales que corresponden a una misma unidad temática: el desarrollo de una metodología de reconstrucción de fibras de sustancia blanca basada en técnicas de difusión por resonancia magnética y su implementación en el estudio de conectividad estructural en pacientes con esclerosis múltiple. Para el primer artículo, seleccionamos las radiaciones ópticas para validar nuestra metodología de reconstrucción. Para ello, empleamos modelos avanzados de tractografía y un postprocesado basado en criterios de exclusión anatómicos propios de cada sujeto. La reconstrucción final de las radiaciones ópticas fue evaluada a través de un atlas histológico validado por la comunidad científica, obteniendo una precisión y exactitud volumétrica muy cercana a la anatomía real tanto en voluntarios sanos como en pacientes con esclerosis múltiple. En el segundo artículo se empleó la misma metodología desarrollada en el artículo precedente, con el fin de proporcionar reconstrucciones más precisas de las conexiones de sustancia blanca cerebral y obtener datos cuantitativos y patológicamente más específicos. Esto permitió conocer los cambios acontecidos en la conectividad cerebral estructural en pacientes con esclerosis múltiple y sus consecuencias sobre el rendimiento cognitivo. Pudimos identificar un daño difuso generalizado de la red cerebral así como la presencia de fenómenos de desconexión en regiones frontoparietales, sustancia gris subcortical e ínsula, relacionados con el rendimiento en funciones atencionales y ejecutivas. Además, evidenciamos posibles mecanismos de reestructuración cerebral a través de incrementos en la conectividad en conexiones específicas. Dichos mecanismos de plasticidad podrían ser tanto, herramientas para compensar el daño tisular como cambios estructurales maladaptativos. Estos estudios han permitido desarrollar y aplicar una nueva metodología de reconstrucción de fibras de sustancia blanca más precisa y reproducible, así como detectar aquellas redes más vulnerables sobre el rendimiento cognitivo. La identificación de estas redes permite contar con un biomarcador sensible a la discapacidad cognitiva y podrían llegar a utilizarse como diana para evaluar el efecto de nuevas intervenciones terapéuticas.[eng] This thesis was submitted with original research articles belonging to the same subject area: the development of an improved framework for tractography reconstruction of white matter fibers based on diffusion-weighted magnetic resonance imaging and its implementation in the study of structural connectivity in patients with multiple sclerosis. The purpose of the first original paper was to introduce an improved tractography framework to reconstruct the optic radiations in healthy volunteers and multiple sclerosis patients. The framework combined advanced diffusion models and an automatic post-processing based on anatomical exclusion criteria. The quantitative evaluation of the optic radiation was done by comparing the final reconstruction with a histological reference data. The proposed methodology was capable to reconstruct the optic radiation with a high accuracy and reliability. Moreover, the reconstruction was possible even in the presence of tissue damage. This framework could also be applied to other tracts with complex configuration in order to reduce the presence of anatomically implausible fibers. The second article used the same methodology developed in the previous article, in order to provide more precisely reconstructions of white matter connections. We aimed to investigate changes in structural connectivity in multiple sclerosis patients and their association with attention and executive performance. The structural brain connectivity is disturbed in multiple sclerosis due to widespread impairment of white matter connections and gray matter structures. The worse attention and executive performance was related to the decrease of integrity in frontoparietal networks, deep gray nuclei and insula. Contrarily, the increased edge connectivity suggests the presence of reorganization mechanisms at the structural level. These changes could be compensatory mechanisms to the maintenance of the normal level of cognitive performance or reflect maladaptative changes. These studies developed and improved framework for tractography reconstruction, useful to evaluate the changes in brain connectivity in patients with multiple sclerosis. The strategic networks related to attention and executive performance could be used as biomarkers to detect cognitive disability and targets to assess the effect of new therapeutic interventions

Desarrollo de una metodología de reconstrucción de fibras de sustancia blanca en difusión por resonancia magnética y su aplicación al estudio de la relación entre la conectividad estructural cerebral y el rendimiento cognitivo en pacientes con esclerosis múltiple

Esta memoria de tesis se presenta en formato de artículos originales que corresponden a una misma unidad temática: el desarrollo de una metodología de reconstrucción de fibras de sustancia blanca basada en técnicas de difusión por resonancia magnética y su implementación en el estudio de conectividad estructural en pacientes con esclerosis múltiple. Para el primer artículo, seleccionamos las radiaciones ópticas para validar nuestra metodología de reconstrucción. Para ello, empleamos modelos avanzados de tractografía y un postprocesado basado en criterios de exclusión anatómicos propios de cada sujeto. La reconstrucción final de las radiaciones ópticas fue evaluada a través de un atlas histológico validado por la comunidad científica, obteniendo una precisión y exactitud volumétrica muy cercana a la anatomía real tanto en voluntarios sanos como en pacientes con esclerosis múltiple. En el segundo artículo se empleó la misma metodología desarrollada en el artículo precedente, con el fin de proporcionar reconstrucciones más precisas de las conexiones de sustancia blanca cerebral y obtener datos cuantitativos y patológicamente más específicos. Esto permitió conocer los cambios acontecidos en la conectividad cerebral estructural en pacientes con esclerosis múltiple y sus consecuencias sobre el rendimiento cognitivo. Pudimos identificar un daño difuso generalizado de la red cerebral así como la presencia de fenómenos de desconexión en regiones frontoparietales, sustancia gris subcortical e ínsula, relacionados con el rendimiento en funciones atencionales y ejecutivas. Además, evidenciamos posibles mecanismos de reestructuración cerebral a través de incrementos en la conectividad en conexiones específicas. Dichos mecanismos de plasticidad podrían ser tanto, herramientas para compensar el daño tisular como cambios estructurales maladaptativos. Estos estudios han permitido desarrollar y aplicar una nueva metodología de reconstrucción de fibras de sustancia blanca más precisa y reproducible, así como detectar aquellas redes más vulnerables sobre el rendimiento cognitivo. La identificación de estas redes permite contar con un biomarcador sensible a la discapacidad cognitiva y podrían llegar a utilizarse como diana para evaluar el efecto de nuevas intervenciones terapéuticas.This thesis was submitted with original research articles belonging to the same subject area: the development of an improved framework for tractography reconstruction of white matter fibers based on diffusion-weighted magnetic resonance imaging and its implementation in the study of structural connectivity in patients with multiple sclerosis. The purpose of the first original paper was to introduce an improved tractography framework to reconstruct the optic radiations in healthy volunteers and multiple sclerosis patients. The framework combined advanced diffusion models and an automatic post-processing based on anatomical exclusion criteria. The quantitative evaluation of the optic radiation was done by comparing the final reconstruction with a histological reference data. The proposed methodology was capable to reconstruct the optic radiation with a high accuracy and reliability. Moreover, the reconstruction was possible even in the presence of tissue damage. This framework could also be applied to other tracts with complex configuration in order to reduce the presence of anatomically implausible fibers. The second article used the same methodology developed in the previous article, in order to provide more precisely reconstructions of white matter connections. We aimed to investigate changes in structural connectivity in multiple sclerosis patients and their association with attention and executive performance. The structural brain connectivity is disturbed in multiple sclerosis due to widespread impairment of white matter connections and gray matter structures. The worse attention and executive performance was related to the decrease of integrity in frontoparietal networks, deep gray nuclei and insula. Contrarily, the increased edge connectivity suggests the presence of reorganization mechanisms at the structural level. These changes could be compensatory mechanisms to the maintenance of the normal level of cognitive performance or reflect maladaptative changes. These studies developed and improved framework for tractography reconstruction, useful to evaluate the changes in brain connectivity in patients with multiple sclerosis. The strategic networks related to attention and executive performance could be used as biomarkers to detect cognitive disability and targets to assess the effect of new therapeutic interventions