Linking Microstructural Integrity and Motor Cortex Excitability in Multiple Sclerosis

Motor skills are frequently impaired in multiple sclerosis (MS) patients following grey and white matter damage with cortical excitability abnormalities. We applied advanced diffusion imaging with 3T magnetic resonance tomography for neurite orientation dispersion and density imaging (NODDI), as well as diffusion tensor imaging (DTI) in 50 MS patients and 49 age-matched healthy controls to quantify microstructural integrity of the motor system. To assess excitability, we determined resting motor thresholds using non-invasive transcranial magnetic stimulation. As measures of cognitive-motor performance, we conducted neuropsychological assessments including the Nine-Hole Peg Test, Trail Making Test part A and B (TMT-A and TMT-B) and the Symbol Digit Modalities Test (SDMT). Patients were evaluated clinically including assessments with the Expanded Disability Status Scale. A hierarchical regression model revealed that lower neurite density index (NDI) in primary motor cortex, suggestive for axonal loss in the grey matter, predicted higher motor thresholds, i.e. reduced excitability in MS patients (p = .009, adjusted r² = 0.117). Furthermore, lower NDI was indicative of decreased cognitive-motor performance (p = .007, adjusted r² = .142 for TMT-A; p = .009, adjusted r² = .129 for TMT-B; p = .006, adjusted r² = .142 for SDMT). Motor WM tracts of patients were characterized by overlapping clusters of lowered NDI (p <.05, Cohen’s d = 0.367) and DTI-based fractional anisotropy (FA) (p <.05, Cohen’s d = 0.300), with NDI exclusively detecting a higher amount of abnormally appearing voxels. Further, orientation dispersion index of motor tracts was increased in patients compared to controls, suggesting a decreased fiber coherence (p <.05, Cohen’s d = 0.232). This study establishes a link between microstructural characteristics and excitability of neural tissue, as well as cognitive-motor performance in multiple sclerosis. We further demonstrate that the NODDI parameters neurite density index and orientation dispersion index detect a larger amount of abnormally appearing voxels in patients compared to healthy controls, as opposed to the classical DTI parameter FA. Our work outlines the potential for microstructure imaging using advanced biophysical models to forecast excitability alterations in neuroinflammation.

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Myelin and axon pathology in multiple sclerosis assessed by myelin water and multi-shell diffusion imaging

Brain ◽

10.1093/brain/awab088 ◽

2021 ◽

Author(s):

Reza Rahmanzadeh ◽

Po-Jui Lu ◽

Muhamed Barakovic ◽

Matthias Weigel ◽

Pietro Maggi ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

White Matter Lesions ◽

Healthy Controls ◽

Neurofilament Light Chain ◽

Water Fraction ◽

Neurite Density ◽

Relapsing Remitting ◽

Density Index ◽

Myelin Water Fraction

Abstract Damage to the myelin sheath and the neuroaxonal unit is a cardinal feature of multiple sclerosis; however, a detailed characterization of the interaction between myelin and axon damage in vivo remains challenging. We applied myelin water and multi-shell diffusion imaging to quantify the relative damage to myelin and axons (i) among different lesion types; (ii) in normal-appearing tissue; and (iii) across multiple sclerosis clinical subtypes and healthy controls. We also assessed the relation of focal myelin/axon damage with disability and serum neurofilament light chain as a global biological measure of neuroaxonal damage. Ninety-one multiple sclerosis patients (62 relapsing-remitting, 29 progressive) and 72 healthy controls were enrolled in the study. Differences in myelin water fraction and neurite density index were substantial when lesions were compared to healthy controls and normal-appearing MS tissue: both white matter and cortical lesions exhibited a decreased myelin water fraction and neurite density index compared with healthy (P < 0.0001) and peri-plaque white matter (P < 0.0001). Periventricular lesions showed decreased myelin water fraction and neurite density index compared with lesions in the juxtacortical region (P < 0.0001 and P < 0.05). Similarly, lesions with paramagnetic rims showed decreased myelin water fraction and neurite density index relative to lesions without a rim (P < 0.0001). Also, in 75% of white matter lesions, the reduction in neurite density index was higher than the reduction in the myelin water fraction. Besides, normal-appearing white and grey matter revealed diffuse reduction of myelin water fraction and neurite density index in multiple sclerosis compared to healthy controls (P < 0.01). Further, a more extensive reduction in myelin water fraction and neurite density index in normal-appearing cortex was observed in progressive versus relapsing-remitting participants. Neurite density index in white matter lesions correlated with disability in patients with clinical deficits (P < 0.01, beta=-10.00); and neurite density index and myelin water fraction in white matter lesions were associated to serum neurofilament light chain in the entire patients cohort (P < 0.01, beta=-3.60 and P < 0.01, beta=0.13, respectively). These findings suggest that (i) myelin and axon pathology in multiple sclerosis is extensive in both lesions and normal-appearing tissue; (ii) particular types of lesions exhibit more damage to myelin and axons than others; (iii) progressive patients differ from relapsing-remitting because of more extensive axon/myelin damage in the cortex; and (iv) myelin and axon pathology in lesions is related to disability in patients with clinical deficits and global measures of neuroaxonal damage.

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Highly Predictive Transdiagnostic Features Shared across Schizophrenia, Bipolar Disorder, and ADHD Identified Using a Machine Learning Based Approach

10.1101/453951 ◽

2018 ◽

Cited By ~ 1

Author(s):

Yuelu Liu ◽

Monika S. Mellem ◽

Humberto Gonzalez ◽

Matthew Kollada ◽

Atul R. Mahableshwarkar ◽

...

Keyword(s):

Machine Learning ◽

Bipolar Disorder ◽

Psychiatric Disorders ◽

Patient Group ◽

Attention Deficit ◽

The United States ◽

Self Report ◽

Healthy Controls ◽

Cohen’S D ◽

Cohen's D

AbstractThe Diagnostic and Statistical Manual of Mental Disorders (DSM) is the standard for diagnosing psychiatric disorders in the United States. However, evidence has suggested that symptoms in psychiatric disorders are not restricted to the boundaries between DSM categories, implying an underlying latent transdiagnostic structure of psychopathology. Here, we applied an importance-guided machine learning technique for model selection to item-level data from self-reported instruments contained within the Consortium for Neuropsychiatric Phenomics dataset. From 578 questionnaire items, we identified a set of features which consisted of 85 items that were shared across diagnoses of schizophrenia (SCZ), bipolar disorder (BD), and attention deficit/hyperactivity disorder (ADHD). A classifier trained on the transdiagnostic features reliably distinguished the patient group as a whole from healthy controls (classification AUC = 0.95) and only 10 items were needed to attain the performance level of AUC being 0.90. A sum score created from the items produced high separability between patients and healthy controls (Cohen’s d = 2.85), and it outperformed predefined sum scores and sub-scores within the instruments (Cohen’s d ranging between 0.13 and 1.21). The transdiagnostic features comprised both symptom domains (e.g. dysregulated mood, attention deficit, and anhedonia) and personality traits (e.g. neuroticism, impulsivity, and extraversion). Moreover, by comparing the features that were common across the three patient groups with those that were most predictive of a single patient category, we can describe the unique features for each patient group superimposed on the transdiagnostic feature structure. Overall, our results reveal a latent transdiagnostic symptom/behavioral phenotypic structure shared across SCZ, BD, and ADHD and present a new perspective to understand insights offered by self-report psychiatric instruments.

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Modulating Observation-Execution-Related Motor Cortex Activity by Cathodal Transcranial Direct Current Stimulation

Brain Sciences ◽

10.3390/brainsci9050121 ◽

2019 ◽

Vol 9 (5) ◽

pp. 121 ◽

Cited By ~ 1

Author(s):

Fengxue Qi ◽

Michael A. Nitsche ◽

Volker R. Zschorlich

Keyword(s):

Motor Cortex ◽

Direct Current ◽

Transcranial Direct Current Stimulation ◽

Movement Execution ◽

Movement Observation ◽

Direct Current Stimulation ◽

Cohen’S D ◽

Right Hand ◽

The Right ◽

Cohen's D

The aim of this randomized sham-controlled study was to examine the impact of cathodal transcranial direct current stimulation (ctDCS) of the primary motor cortex (M1) during movement observation on subsequent execution-related motor cortex activity. Thirty healthy participants received sham or real ctDCS (1 mA) over the left M1 for 10 minutes, respectively. The participants observed a video showing repeated button pressing tasks of the right hand during the sham or real ctDCS, followed by performance of these tasks by the right hand. Motor-evoked potentials (MEP) were recorded from the resting right first dorsal interosseous muscle before movement observation during the sham or real ctDCS, immediately after observation of actions, and after subsequent movement execution. The results of the ANOVA showed a significant main effect on the group (F1,28 = 4.60, p = 0.041) and a significant interaction between time and the group (F2,56 = 5.34, p = 0.008). As revealed by respective post hoc tests, ctDCS induced a significant reduction of MEP amplitudes in connection with movement observation (p = 0.026, Cohen’s d = 0.861) and after subsequent movement execution (p = 0.018, Cohen’s d = 0.914) in comparison with the sham stimulation. It is concluded that ctDCS during movement observation was effective in terms of modulating motor cortex excitability. Moreover, it subsequently influenced execution-related motor cortex activity. This indicates a possible application for rehabilitative treatment in syndromes with pathologically enhanced cortical activity.

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Corticospinal tract integrity is related to primary motor cortex thinning in relapsing–remitting multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458515576985 ◽

2015 ◽

Vol 21 (14) ◽

pp. 1771-1780 ◽

Cited By ~ 22

Author(s):

Niels Bergsland ◽

Maria Marcella Laganà ◽

Eleonora Tavazzi ◽

Matteo Caffini ◽

Paola Tortorella ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Motor Cortex ◽

Linear Regression ◽

Multiple Linear Regression ◽

Primary Motor Cortex ◽

Corticospinal Tract ◽

Healthy Controls ◽

Relapsing Remitting ◽

Relapsing Remitting Multiple Sclerosis

Background: The relationship between white matter injury and cortical atrophy development in relapsing–remitting multiple sclerosis (RRMS) remains unclear. Objectives: To investigate the associations between corticospinal tract integrity and cortical morphology measures of the primary motor cortex in RRMS patients and healthy controls. Methods: 51 RRMS patients and 30 healthy controls underwent MRI examination for cortical reconstruction and assessment of corticospinal tract integrity. Partial correlation and multiple linear regression analyses were used to investigate the associations of focal and normal appearing white matter (NAWM) injury of the corticospinal tract with thickness and surface area measures of the primary motor cortex. Relationships between MRI measures and clinical disability as assessed by the Expanded Disability Status Scale and disease duration were also investigated. Results: In patients only, decreased cortical thickness was related to increased corticospinal tract NAWM mean, axial and radial diffusivities in addition to corticospinal tract lesion volume. The final multiple linear regression model for PMC thickness retained only NAWM axial diffusivity as a significant predictor (adjusted R2= 0.270, p= 0.001). Clinical measures were associated with NAWM corticospinal tract integrity measures. Conclusions: Primary motor cortex thinning in RRMS is related to alterations in connected white matter and is best explained by decreased NAWM integrity.

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Linking microstructural integrity and motor cortex excitability in multiple sclerosis

10.1101/2020.10.15.20213090 ◽

2020 ◽

Author(s):

Angela Radetz ◽

Kalina Mladenova ◽

Dumitru Ciolac ◽

Gabriel Gonzalez-Escamilla ◽

Vinzenz Fleischer ◽

...

Keyword(s):

Multiple Sclerosis ◽

Diffusion Tensor ◽

Cortical Excitability ◽

Diffusion Imaging ◽

Hierarchical Regression ◽

Biophysical Models ◽

Neurite Density ◽

Hierarchical Regression Model ◽

Motor Cortex Excitability ◽

Microstructural Integrity

AbstractMotor skills are frequently impaired in multiple sclerosis (MS) patients following grey (GM) and white matter (WM) damage with cortical excitability abnormalities. We performed advanced diffusion imaging for neurite orientation dispersion and density modeling and diffusion tensor imaging within the motor system of 50 MS patients and 49 age-matched healthy controls. To assess excitability, we determined resting motor thresholds using non-invasive transcranial magnetic stimulation. A hierarchical regression model revealed that lower neurite density index (NDI), suggestive for axonal loss in the GM, predicted higher motor thresholds, i.e. reduced excitability in MS patients. Furthermore, lower NDI was indicative of decreased cognitive-motor performance. Interconnected motor WM tracts of patients were characterized by overlapping clusters of lowered fractional anisotropy and NDI, with NDI exclusively capturing a higher amount of abnormally appearing voxels. Our work outlines the potential of microstructure imaging using advanced biophysical models to forecast neurodegeneration and excitability alterations in neuroinflammation.

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Abnormal Neurite Density and Orientation Dispersion in Frontal Lobe Link to Elevated Hyperactive/Impulsive Behaviors in Young Adults with Traumatic Brain Injury

10.1101/2021.08.18.456850 ◽

2021 ◽

Author(s):

Meng Cao ◽

Yuyang Luo ◽

Ziyan Wu ◽

Kai Wu ◽

Xiaobo Li

Keyword(s):

Traumatic Brain Injury ◽

Young Adults ◽

Brain Injury ◽

White Matter ◽

Diffusion Weighted Mri ◽

Dispersion Index ◽

Superior Longitudinal Fasciculus ◽

Neurite Density ◽

Density Index ◽

Post Traumatic

Traumatic brain injury is a major public health concern. A significant proportion of individuals experience post-traumatic brain injury behavioral impairments, especially in attention and inhibitory control domains. Traditional diffusion-weighted MRI techniques, such as diffusion tensor imaging, have provided tools to assess white matter structural disruptions reflecting the long-term brain tissue alterations associated with traumatic brain injury. The recently developed neurite orientation dispersion and density imaging is a more advanced diffusion-weighted MRI modality, which provides more refined characterization of brain tissue microstructures by assessing the neurite orientation dispersion and neurite density properties. In this study, we investigated the morphometrical and microstructural alterations at chronic brain injury stage and their relationships with the functional outcomes. Neurite orientation dispersion and density imaging data from 44 young adults with chronic traumatic brain injury (ranging from 18 - 27 years of age; 23 males/21 females) who had no prior-traumatic brain injury history of attention deficits and/or hyperactivity and 45 group-matched normal controls (23 males /22 females) were collected. Maps of fractional anisotropy, neurite orientation dispersion index, and neurite density index were calculated. Vertex-wise and voxel-wise analyses were conducted for gray matter and white matter, respectively. Post-hoc region of interest-based analyses were also performed. Compared to the controls, the group of traumatic brain injury showed significantly increased orientation dispersion index in various gray matter regions and significantly decreased orientation dispersion index in several white matter regions. Brain-behavioral association analyses indicated that the reduced neurite density index of left precentral gyrus and the reduced orientation dispersion index of left superior longitudinal fasciculus were significantly associated with elevated hyperactive/impulsive symptoms in the patients with traumatic brain injury. These findings suggest that traumatic brain injury-induced chronic neurite orientation dispersion alterations of left superior longitudinal fasciculus and left precentral may significantly contribute to post-traumatic brain injury hyperactive/impulsive behaviors in young adults with traumatic brain injury.

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Lower Leg Muscle Function: A Contributory Risk Factor of Gait and Balance Impairment after Six Minutes Walk among People with Multiple Sclerosis

Medical Research Archives ◽

10.18103/mra.v9i3.2331 ◽

2021 ◽

Vol 9 (3) ◽

Author(s):

Adeola Sanni ◽

Robert Lynall ◽

Deborah Backus ◽

Kevin McCully

Keyword(s):

Multiple Sclerosis ◽

Muscle Function ◽

Lower Leg ◽

Gait Variability ◽

Eyes Closed ◽

Cohen’S D ◽

Gait Asymmetry ◽

Slight Elevation ◽

Leg Muscle ◽

Cohen's D

Background/Purpose: Multiple sclerosis (MS) is a progressive neurological disease that results in increased fatigue, decreased muscle function, and impaired gait and balance. The purpose of this study was to evaluate the relationship between lower leg muscle function and changes in gait and balance immediately and 20 minutes after 6mins walk-induced fatigue. Methods: Six persons with MS (Patient-Determined Disease Steps 3-5) participated in the study. Perceived fatigue and demographic information were taken at baseline. Muscle fatigability and mitochondria capacity was measured in the lower leg muscles before walking. Reported fatigue (VAFS, 0-10), gait variability, gait asymmetry, and static balance were measured before and immediately after a self-paced 6 minutes treadmill walk with slight elevation, and after 20 minutes of rest. Results: Participant’s baseline MFIS score ranged from 14 - 71. There was a 173% increase in reported fatigue scores after walking. Gait was impaired with a ~26% increase in gait variability and ~40% increase in gait asymmetry immediately after walking (Cohen’s D = 0.4, 0.3 respectively). There was also ~69% increase in balance postural sway with eyes opened and a ~20% increase with eyes closed (Cohen’s D = 0.5, 0.2 respectively). Gait and balance remained impaired after 20 minutes of rest. The decline in gait parameters after walking had a negative correlation with muscle endurance (r=-0.80, p=0.03), and mitochondrial capacity (r=-0.92, p<0.01). The changes in gait and balance were more evident in participants with a higher disability. Conclusions: Six minutes of self-paced walking with slight elevation worsened gait and balance among people with MS (PwMS), which did not completely recover after 20 minutes of rest. The changes in gait after walking were associated with lower leg muscle function. Lower leg muscle function might be an important intervention target to improve gait and balance fall risk among PwMS.

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GAMER-MRI in Multiple Sclerosis Identifies the Diffusion-Based Microstructural Measures That Are Most Sensitive to Focal Damage: A Deep-Learning-Based Analysis and Clinico-Biological Validation

Frontiers in Neuroscience ◽

10.3389/fnins.2021.647535 ◽

2021 ◽

Vol 15 ◽

Author(s):

Po-Jui Lu ◽

Muhamed Barakovic ◽

Matthias Weigel ◽

Reza Rahmanzadeh ◽

Riccardo Galbusera ◽

...

Keyword(s):

Multiple Sclerosis ◽

Deep Learning ◽

Bayesian Approach ◽

Disease Diagnosis ◽

Response To Therapy ◽

Imaging Data ◽

Neurofilament Light Chain ◽

Biological Validation ◽

Neurite Density ◽

Density Index

Conventional magnetic resonance imaging (cMRI) in multiple sclerosis (MS) patients provides measures of focal brain damage and activity, which are fundamental for disease diagnosis, prognosis, and the evaluation of response to therapy. However, cMRI is insensitive to the damage to the microenvironment of the brain tissue and the heterogeneity of MS lesions. In contrast, the damaged tissue can be characterized by mathematical models on multishell diffusion imaging data, which measure different compartmental water diffusion. In this work, we obtained 12 diffusion measures from eight diffusion models, and we applied a deep-learning attention-based convolutional neural network (CNN) (GAMER-MRI) to select the most discriminating measures in the classification of MS lesions and the perilesional tissue by attention weights. Furthermore, we provided clinical and biological validation of the chosen metrics—and of their most discriminative combinations—by correlating their respective mean values in MS patients with the corresponding Expanded Disability Status Scale (EDSS) and the serum level of neurofilament light chain (sNfL), which are measures of disability and neuroaxonal damage. Our results show that the neurite density index from neurite orientation and dispersion density imaging (NODDI), the measures of the intra-axonal and isotropic compartments from microstructural Bayesian approach, and the measure of the intra-axonal compartment from the spherical mean technique NODDI were the most discriminating (respective attention weights were 0.12, 0.12, 0.15, and 0.13). In addition, the combination of the neurite density index from NODDI and the measures for the intra-axonal and isotropic compartments from the microstructural Bayesian approach exhibited a stronger correlation with EDSS and sNfL than the individual measures. This work demonstrates that the proposed method might be useful to select the microstructural measures that are most discriminative of focal tissue damage and that may also be combined to a unique contrast to achieve stronger correlations to clinical disability and neuroaxonal damage.

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Selective atrophy of the connected deepest cortical layers following small subcortical infarct

Neurology ◽

10.1212/wnl.0000000000006884 ◽

2019 ◽

Vol 92 (6) ◽

pp. e567-e575 ◽

Cited By ~ 1

Author(s):

Eyal Lotan ◽

Ido Tavor ◽

Daniel Barazany ◽

Shani Ben-Amitay ◽

Chen Hoffmann ◽

...

Keyword(s):

Motor Cortex ◽

Primary Motor Cortex ◽

Corticospinal Tract ◽

Healthy Controls ◽

Cortical Layers ◽

Clinical Symptomatology ◽

Cortical Thinning ◽

Corticospinal Tracts ◽

Microstructural Integrity ◽

Subcortical Infarct

ObjectiveTo explore whether in patients with chronic small subcortical infarct the cortical layers of the connected cortex are differentially affected and whether these differences correlate with clinical symptomatology.MethodsTwenty patients with a history of chronic small subcortical infarct affecting the corticospinal tracts and 15 healthy controls were included. Connected primary motor cortex was identified with tractography starting from infarct. T1-component probability maps were calculated from T1 relaxation 3T MRI, dividing the cortex into 5 laminar gaussian classes.ResultsFocal cortical thinning was observed in the connected cortex and specifically only in its deepest laminar class compared to the nonaffected mirrored cortex (p < 0.001). There was loss of microstructural integrity of the affected corticospinal tract with increased mean diffusivity and decreased fractional anisotropy compared to the contralateral nonaffected tract (p ≤ 0.002). Clinical scores were correlated with microstructural damage of the corticospinal tracts and with thinning of the cortex and specifically only its deepest laminar class (p < 0.001). No differences were found in the laminar thickness pattern of the bilateral primary motor cortices or in the microstructural integrity of the bilateral corticospinal tracts in the healthy controls.ConclusionOur results support the concept of secondary neurodegeneration of connected primary motor cortex after a small subcortical infarct affecting the corticospinal tract, with observations that the main cortical thinning occurs in the deepest cortex and that the clinical symptomatology is correlated with this cortical atrophy pattern. Our findings may contribute to a better understanding of structural reorganization and functional outcomes after stroke.

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Effects of Tamoxifen and Exemestane on Cognitive Functioning of Postmenopausal Patients With Breast Cancer: Results From the Neuropsychological Side Study of the Tamoxifen and Exemestane Adjuvant Multinational Trial

Journal of Clinical Oncology ◽

10.1200/jco.2008.21.3553 ◽

2010 ◽

Vol 28 (8) ◽

pp. 1294-1300 ◽

Cited By ~ 170

Author(s):

Christina M. Schilder ◽

Caroline Seynaeve ◽

Louk V. Beex ◽

Willem Boogerd ◽

Sabine C. Linn ◽

...

Keyword(s):

Breast Cancer ◽

Adjuvant Therapy ◽

Executive Functioning ◽

Cognitive Functioning ◽

Verbal Memory ◽

Endocrine Treatment ◽

Healthy Controls ◽

Cohen’S D ◽

Multinational Trial ◽

Cohen's D

PurposeTo evaluate the influence of adjuvant tamoxifen and exemestane on cognitive functioning in postmenopausal patients with breast cancer (BC).Patients and MethodsNeuropsychological assessments were performed before the start (T1) and after 1 year of adjuvant endocrine treatment (T2) in Dutch postmenopausal patients with BC, who did not receive chemotherapy. Patients participated in the international Tamoxifen and Exemestane Adjuvant Multinational trial, a prospective randomized study investigating tamoxifen versus exemestane as adjuvant therapy for hormone-sensitive BC.ResultsParticipants included 80 tamoxifen users (mean age, 68.7 years; range 51 to 84), 99 exemestane users (mean age, 68.3 years; range, 50 to 82), and 120 healthy controls (mean age, 66.2 years; range, 49 to 86). At T2, after adjustment for T1 performance, exemestane users did not perform statistically significantly worse than healthy controls on any cognitive domain. In contrast, tamoxifen users performed statistically significantly worse than healthy controls on verbal memory (P < .01; Cohen's d = .43) and executive functioning (P = .01; Cohen's d = .40), and statistically significantly worse than exemestane users on information processing speed (P = .02; Cohen's d = .36). With respect to visual memory, working memory, verbal fluency, reaction speed, and motor speed, no significant differences between the three groups were found.ConclusionAfter 1 year of adjuvant therapy, tamoxifen use is associated with statistically significant lower functioning in verbal memory and executive functioning, whereas exemestane use is not associated with statistically significant lower cognitive functioning in postmenopausal patients with BC. Our results accentuate the need to include assessments of cognitive effects of adjuvant endocrine treatment in long-term safety studies.

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