Anatomical and functional visual network patterns in progressive multiple sclerosis.

The gradual accrual of disability over time in progressive multiple sclerosis is believed to be driven by widespread degeneration. Yet another facet of the problem may reside in the loss of the brain's ability to adapt to the damage incurred as the disease progresses. In this study, we attempted to examine whether changes associated with optic neuritis in the structural and functional visual networks can still be discerned in progressive patients even years after the acute insult. Forty-eight progressive multiple sclerosis patients, 21 with and 27 without prior optic neuritis, underwent structural and functional MRI, including DTI and resting state fMRI. Anatomical and functional visual networks were analyzed using graph theory-based methods. While no functional metrics were significantly different between the two groups, anatomical global efficiency and density were significantly lower in the optic neuritis group, despite no significant difference in lesion load between the groups. We conclude that long-standing distal damage to the optic nerve causes trans-synaptic effects and the early ability of the cortex to adapt may be altered, or possibly nullified. We suggest that this limited ability of the brain to compensate should be considered when attempting to explain the accumulation of disability in progressive multiple sclerosis patients.

Beneficial effects of autologous mesenchymal stem cell transplantation in active progressive multiple sclerosis.

In this study (trial registration: NCT02166021), we aimed to evaluate the optimal way of administration, the safety and the clinical efficacy of mesenchymal stem cell (MSC) transplantation in patients with active and progressive multiple sclerosis. Forty-eight patients (28 males and 20 females) with progressive multiple sclerosis (Expanded Disability Status Scale: 3.0-6.5, mean : 5.6 ± 0.8, mean age: 47.5 ± 12.3) and evidence of either clinical worsening or activity during the previous year, were enrolled (between 2015 and 2018). Patients were randomized into three groups and treated intrathecally (IT) or intravenously (IV) with autologous MSCs (1 × 106/kg) or sham injections. After 6 months, half of the patients from the MSC-IT and MSC-IV groups were retreated with MSCs, and the other half with sham injections. Patients initially assigned to sham treatment were divided into two subgroups and treated with either MSC-IT or MSC-IV. The study duration was 14 months. No serious treatment-related safety issues were detected. Significantly fewer patients experienced treatment failure in the MSC-IT and MSC-IV groups compared with those in the sham-treated group (6.7%, 9.7%, and 41.9%, respectively, P = 0.0003 and P = 0.0008). During the 1-year follow-up, 58.6% and 40.6% of patients treated with MSC-IT and MSC-IV, respectively, exhibited no evidence of disease activity compared with 9.7% in the sham-treated group (P < 0.0001 and P < 0.0048, respectively). MSC-IT transplantation induced additional benefits on the relapse rate, on the monthly changes of the T2 lesion load on MRI, and on the timed 25-foot walking test, 9-hole peg test, optical coherence tomography, functional MRI and cognitive tests. Treatment with MSCs was well-tolerated in progressive multiple sclerosis and induced short-term beneficial effects regarding the primary end points, especially in the patients with active disease. The intrathecal administration was more efficacious than the intravenous in several parameters of the disease. A phase III trial is warranted to confirm these findings.

Conduction delays in the visual pathways of progressive multiple sclerosis patients covary with brain structure.

In developed countries, multiple sclerosis (MS) is the leading cause of non-traumatic neurological disability in young adults. MS is a chronic demyelinating disease of the central nervous system, in which myelin is attacked, changing white matter structure and leaving lesions. The demyelination has a direct effect on white matter conductivity. This effect can be examined in the visual system, where damage is highly prevalent in MS, leading to substantial delays in conduction, commonly measured with visual evoked potentials (VEPs). The structural damage to the visual system in MS is often estimated with MRI measurements in the white matter. Recent developments in quantitative MRI (qMRI) provide improved sensitivity to myelin content and new structural methods allow better modeling of the axonal structure, leading researchers to link white matter microstructure to conduction properties of action potentials along fiber tracts. This study attempts to explain the variance in conduction latencies down the visual pathway using structural measurements of both the retina and the optic radiation (OR). Forty-eight progressive MS patients, participants in a longitudinal stem-cell therapy clinical trial, were included in this study, three and six months post final treatment. Twenty-seven patients had no history of optic neuritis, and were the main focus of this study. All participants underwent conventional MRI scans, as well as diffusion MRI and qMRI sequences to account for white matter microstructure. Optical coherence tomography scans were also obtained, and peripapillary retinal nerve fiber layer (pRNFL) thickness and macular volume measurements were extracted. Finally, latencies of recorded VEPs were estimated. Our results show that in non-optic neuritis progressive MS patients there is a relationship between the VEP latency and both retinal damage and OR lesion load. In addition, we find that qMRI values, sampled along the OR, are also correlated with VEP latency. Finally, we show that combining these parameters using PCA we can explain more than 40% of the inter-subject variance in VEP latency. In conclusion, this study contributes to understanding the relationship between the structural properties and conduction in the visual system in disease. We focus on the visual system, where the conduction latencies can be estimated, but the conclusions could be generalized to other brain systems where the white matter structure can be measured. It also highlights the importance of having multiple parameters when assessing the clinical stages of MS patients, which could have major implications for future studies of other white matter diseases.

Global Brain Involvement in Posterior Cortical Atrophy: Multimodal MR Imaging Investigation.

Posterior cortical atrophy (PCA), considered a visual variant of Alzheimer's disease, has similar pathological characteristics yet shows a selective visual manifestation with relative preservation of other cortical areas, at least at early stages of disease. Using a gamut of imaging methods, we aim to evaluate the global aspect of this relatively local disease and describe the interplay of the involvement of the different brain components. Ten PCA patients and 14 age-matched controls underwent MRI scans. Cortical thickness was examined to identify areas of cortical thinning. Hippocampal volume was assessed using voxel-based morphometry. The integrity of 20 fiber tracts was assessed by Diffusion Tensor Imaging. Regions of difference in global functional connectivity were identified by resting-state fMRI, using multi-variant pattern analysis. Correlations were examined to evaluate the connection between grey matter atrophy, the network changes and the disease load. The patients presented bilateral cortical thinning, primarily in their brains' posterior segments. Impaired segments of white matter integrity were evident only within three fiber tracts in the left hemisphere. Four areas were identified as different in their global connectivity pattern. The visual network-related areas showed reduced connectivity and was correlated to atrophy. Right Broadman area 39 showed in addition increased connectivity to the frontal areas. Global structural and functional imaging pointed to the highly localized nature of PCA. Functional connectivity followed grey matter atrophy in visual regions. White matter involvement seemed less prominent, however damage is directly related to presence of disease and not mediated only by grey matter damage.

Cortical topological network changes following optic neuritis.

OBJECTIVE: To differentiate between visual cortical network topology changes following optic neuritis (ON) stemming from different inflammatory disease types, we used mathematical graph theory-based tools to analyze functional imaging data. METHODS: Sixty-two patients were recruited into this cross-sectional study, 23 of whom had neuromyelitis optica spectrum disorder (NMOSD) with ON, 18 with clinically isolated syndrome (CIS)-ON, and 21 with other CIS episodes. Twenty-six healthy controls (HCs) were also recruited. All participants underwent resting-state functional MRI. Visual networks were defined using 50 visual regions of interest. Analysis included graph theory metrics, including degree, density, modularity, and local and global efficiency. RESULTS: Visual network density shows decreased connectivity in all patient groups compared with controls. A higher degree of connections is seen in both ON groups (CIS and NMOSD) compared with the the non-ON group. This pattern is most pronounced in dorsal-lateral regions. Information transfer efficiency and modularity were reduced in both CIS groups, but not in the NMOSD group, compared with the HC group. CONCLUSIONS: Visual network density appears affected by the neurologic deficit sustained (ON), and connectivity changes are more evident in dorsal-lateral regions. Efficiency and modularity appear to be associated with the specific disease type (CIS vs NMOSD). Thus, topological cortical changes in the visual system are associated with the type of neurologic deficit within the limits set on them by the underlying pathophysiology. We suggest that cortical patterns of activity should be considered in the outcome of the patients despite the localized nature of ON.

Vision and Vision-Related Measures in Progressive Multiple Sclerosis.

Background: Over the last few years there has been growing interest in use of visual measures as useful tools for multiple sclerosis (MS) prognosis and tracking. Optic neuritis (ON) being a prevalent and often-presenting symptom of the disease, as well as the high occurrence rate of posterior visual system damage independent of ON (optic radiation lesions), make the visual system a prime candidate for such endeavors. However, while the visual system makes for a convenient model in early stages of MS, processes which may be true in those stages may drastically change as the disease progresses, due to accumulated disease load. Here, we examine whether vision-related tools reflect demyelinative and axonal damage of the visual pathways and may be used for assessment in the clinical setup in progressive multiple sclerosis (MS) patients, in whom disease load may alter the early stage picture. Methods: Forty-eight progressive MS patients, with and without prior optic neuritis (ON), underwent a battery of behavioral tests, visual evoked potential (VEP) tests, optical coherence tomography (OCT), and structural MRI scans, at two time-points. Data were analyzed for stability between visits and for correlation between behavioral and electrophysiological data. Results: All measures were stable between visits. Significant differences were found in all measures between the affected and fellow eyes of ON patients and in VEP latencies between the affected and non-ON eyes. Motion perception differentially correlated with latencies of both ON eyes and with the non-ON eyes. Retinal nerve fiber layer thickness correlated with the latencies of non-ON eyes but not of either ON eye. No difference in lesion load was found between the ON and non-ON patients. Conclusions: ON still leaves its mark in the patient's visual system over time, with all visual measures of the affected eyes notably reduced compared to fellow eyes. Motion perception, reflecting myelination level along the visual pathway, shows its usefulness also in progressive MS. In the non-ON eyes, axonal loss appears to explain prolonged latencies, unlike in ON eyes, where demyelination appears to be the main mechanism. Lastly, the visual measures assessed herein are applicable as valid assessment tools in therapeutic studies.

The impact of localized grey matter damage on neighboring connectivity: posterior cortical atrophy and the visual network.

Posterior cortical atrophy (PCA), a localized neurodegenerative syndrome involving the occipito-parietal cortices, can serve as a good model to elaborate on the consequence of a localized damage on the anatomical and functional connectivity within an affected system. Ten PCA patients and 14 aged-matched controls were enrolled. Structural connectivity was measured via Diffusion Tensor Imaging (DTI) and probabilistic tractography. The optic tracts and radiations and the splenial fibers were delineated and their microstructural properties were evaluated. Functional connectivity was measured by resting state functional MRI (rsfMRI). Voxel-based morphometry (VBM) was used to assess atrophy. Dorsal stream visual functions were tested and correlation between these behavioral data, volume measures, white matter integrity and connectivity were examined. Impaired white matter integrity was evident in patients' optic radiations and occipito-callosal fibers, in the segments located in close proximity to the occipital cortex, suggesting a localized damage. Degeneration did not proceed to the optic tracts, opposing trans-synaptic changes. rsfMRI revealed reduced connectivity within the visual network and between the visual and other related areas such as the frontal eye field. Correlations were found between grey matter volume and spatial perception abilities and between the integrity of the affected fibers and motion perception. White matter involvement in PCA seems to be grey matter dependent. Functional connectivity, on the other hand, showed a more diffuse pattern of damage. Correlations were found between the integrity of the affected fibers and patients' visual abilities suggesting that fiber integrity plays a role in determining behavioral manifestation.

Comparison of probabilistic tractography and tract-based spatial statistics for assessing optic radiation damage in patients with autoimmune inflammatory disorders of the central nervous system.

Background: Diffusion Tensor Imaging (DTI) can evaluate microstructural tissue damage in the optic radiation (OR) of patients with clinically isolated syndrome (CIS), early relapsing-remitting multiple sclerosis and neuromyelitis optica spectrum disorders (NMOSD). Different post-processing techniques, e.g. tract-based spatial statistics (TBSS) and probabilistic tractography, exist to quantify this damage. Objective: To evaluate the capacity of TBSS-based atlas region-of-interest (ROI) combination with 1) posterior thalamic radiation ROIs from the Johns Hopkins University atlas (JHU-TBSS), 2) Juelich Probabilistic ROIs (JUEL-TBSS) and tractography methods using 3) ConTrack (CON-PROB) and 4) constrained spherical deconvolution tractography (CSD-PROB) to detect OR damage in patients with a) NMOSD with prior ON (NMOSD-ON), b) CIS and early RRMS patients with ON (CIS/RRMS-ON) and c) CIS and early RRMS patients without prior ON (CIS/RRMS-NON) against healthy controls (HCs). Methods: Twenty-three NMOSD-ON, 18 CIS/RRMS-ON, 21 CIS/RRMS-NON, and 26 HCs underwent 3 T MRI. DTI data analysis was carried out using JUEL-TBSS, JHU-TBSS, CON-PROB and CSD-PROB. Optical coherence tomography (OCT) and visual acuity testing was performed in the majority of patients and HCs. Results: Absolute OR fractional anisotropy (FA) values differed between all methods but showed good correlation and agreement in Bland-Altman analysis. OR FA values between NMOSD and HC differed throughout the methodologies (p-values ranging from p < 0.0001 to 0.0043). ROC-analysis and effect size estimation revealed higher AUCs and R2 for CSD-PROB (AUC = 0.812; R2 = 0.282) and JHU-TBSS (AUC = 0.756; R2 = 0.262), compared to CON-PROB (AUC = 0.742; R2 = 0.179) and JUEL-TBSS (AUC = 0.719; R2 = 0.161). Differences between CIS/RRMS-NON and HC were only observable in CSD-PROB (AUC = 0.796; R2 = 0.094). No significant differences between CIS/RRMS-ON and HC were detected by any of the methods. Conclusions: All DTI post-processing techniques facilitated the detection of OR damage in patient groups with severe microstructural OR degradation. The comparison of distinct disease groups by use of different methods may lead to different - either false-positive or false-negative - results. Since different DTI post-processing approaches seem to provide complementary information on OR damage, application of distinct methods may depend on the relevant research question.

Keep Your Eyes Wide Open: On Visual- and Vision-Related Measurements to Better Understand Multiple Sclerosis Pathophysiology.

BACKGROUND: Multiple sclerosis (MS), a demyelinating disease of the central nervous system, is multifaceted. It manifests as acute episodes as well as an accumulative chronic disability; myelin involvement as well as axonal damage; local as well as global effects; and disease load elements as well as compensatory mechanisms. The visual system, with its clear structural organization and relatively direct reflection of damage, may serve as an appropriate model to study MS. METHODS: In recent years, we have witnessed a blossoming in the field of visual measures in MS. Because it is impossible to cover all different aspects of these measures, we chose to focus on several hot topics in MS literature and shed light on them through studies conducted in the visual system. RESULTS: We argue that numerous methods can be used to study axonal and demyelinating aspects of the disease. Although optical coherence tomography and static visual functions better reflect the axonal aspects of the disease, conduction velocity as measured by visual-evoked potential latencies and dynamic visual function mirrors myelin levels. We also posit that the classic disease load parameters cannot be the only means by which we assess a patient's condition. Novel imaging methods such as diffusion tensor imaging and functional magnetic resonance imaging can be used to assess the global effects of local damage on neighboring white matter and compensatory abilities of the brain. CONCLUSIONS: There have been great advances in therapeutic research in MS. However, the stratification of patients according to their prognosis and predictive outcomes in response to treatment is still in its infancy. The many facets of MS make it difficult to piece all the data together into one cohesive conclusion for the individual patient. The visual system, with our ability to assess both structure and function, offers a promising opportunity to study both pathophysiologic mechanisms and novel therapies.

Anatomical Wiring and Functional Networking Changes in the Visual System Following Optic Neuritis.

Importance: Clinical outcome in multiple sclerosis was suggested to be driven by not only remyelination but also adaptive reorganization. This mechanism needs to be further understood. Objective: To explore anatomical and functional visual networks in patients with optic neuritis (ON) to assess the relative weight of each connectivity modality to expedite visual recovery. Design, Setting, and Participants: Between March 11, 2011, and May 26, 2014, 39 patients with either clinically isolated syndrome (CIS) ON (n = 18) or other CIS (non-ON) (n = 21) were recruited 1 to 28 months following an initial clinical event. These patients enrolled in an ongoing prospective cohort study (107 participants at the time of this present study) about the disease course of CIS and multiple sclerosis. Inclusion criteria were an age of 18 to 65 years, the suggestive clinical and paraclinical diagnosis of CIS or multiple sclerosis after relevant differential diagnoses have been ruled out, the existence of complete imaging data, and no ocular comorbidities. Anatomical connectivity was evaluated by diffusion tensor imaging, and functional connectivity was evaluated by resting-state functional magnetic resonance imaging. The visual pathways, including optic tracts, optic radiations, and splenial fibers, were delineated, and the resting-state visual networks were detected. Data analysis took place from September 1, 2015, to December 1, 2015. Main Outcomes and Measures: Connectivity changes were quantified and compared to determine the association of ON with the visual network. Results: This study included 18 patients with CIS ON, 11 (61%) of whom were women with a mean (SD) age of 32.83 (8.53) years, and 21 patients with CIS non-ON (11 [52%] of whom were women with a mean [SD] age of 30.86 [7.54] years). With the use of diffusion tensor imaging, reduced diffusivity (mean [SD] fractional anisotropy, 0.35 [0.03] vs 0.38 [0.03]; P < .01) was evident along the optic tracts of patients with ON, suggesting the extension of axonal injury from the damaged optic nerve. Neither the optic radiations nor the splenial fibers showed evidence of loss of integrity. Yet, in the presence of an intact postgeniculate anatomical network, the functional connectivity within the visual network was higher in the ON cohort. Functional connectivity observed in cortical motion-related areas was inversely correlated with the visual evoked potential-measured conduction velocity (r = -0.59; P < .05). Conclusions and Relevance: In this cohort, local optic nerve demyelinating damage does not affect distant wiring, but even in the presence of an intact anatomical network, functional modification may occur. These functional network changes may be part of the recovery process, but further research is needed to elucidate this process.