Relating multi-sequence longitudinal intensity profiles and clinical covariates in new multiple sclerosis lesions

Structural magnetic resonance imaging (MRI) can be used to detect lesions in the brains of multiple sclerosis (MS) patients. The formation of these lesions is a complex process involving inflammation, tissue damage, and tissue repair, all of which are visible on MRI. Here we characterize the lesion formation process on longitudinal, multi-sequence structural MRI from 34 MS patients and relate the longitudinal changes we observe within lesions to therapeutic interventions. In this article, we first outline a pipeline to extract voxel level, multi-sequence longitudinal profiles from four MRI sequences within lesion tissue. We then propose two models to relate clinical covariates to the longitudinal profiles. The first model is a principal component analysis (PCA) regression model, which collapses the information from all four profiles into a scalar value. We find that the score on the first PC identifies areas of slow, long-term intensity changes within the lesion at a voxel level, as validated by two experienced clinicians, a neuroradiologist and a neurologist. On a quality scale of 1 to 4 (4 being the highest) the neuroradiologist gave the score on the first PC a median rating of 4 (95% CI: [4,4]), and the neurologist gave it a median rating of 3 (95% CI: [3,3]). In the PCA regression model, we find that treatment with disease modifying therapies (p-value < 0.01), steroids (p-value < 0.01), and being closer to the boundary of abnormal signal intensity (p-value < 0.01) are associated with a return of a voxel to intensity values closer to that of normal-appearing tissue. The second model is a function-on-scalar regression, which allows for assessment of the individual time points at which the covariates are associated with the profiles. In the function-on-scalar regression both age and distance to the boundary were found to have a statistically significant association with the profiles

Detection of brain functional-connectivity difference in post-stroke patients using group-level covariance modeling

Functional brain connectivity, as revealed through distant correlations in the signals measured by functional Magnetic Resonance Imaging (fMRI), is a promising source of biomarkers of brain pathologies. However, establishing and using diagnostic markers requires probabilistic inter-subject comparisons. Principled comparison of functional-connectivity structures is still a challenging issue. We give a new matrix-variate probabilistic model suitable for inter-subject comparison of functional connectivity matrices on the manifold of Symmetric Positive Definite (SPD) matrices. We show that this model leads to a new algorithm for principled comparison of connectivity coefficients between pairs of regions. We apply this model to comparing separately post-stroke patients to a group of healthy controls. We find neurologically-relevant connection differences and show that our model is more sensitive that the standard procedure. To the best of our knowledge, these results are the first report of functional connectivity differences between a single-patient and a group and thus establish an important step toward using functional connectivity as a diagnostic tool

Changes in Hemodynamic Responses in Chronic Stroke Survivors Do Not Affect fMRI Signal Detection in a Block Experimental Design

The use of canonical functions to model BOLD-fMRI data in people post-stroke may lead to inaccurate descriptions of task-related brain activity. The purpose of this study was to determine whether the spatiotemporal profile of hemodynamic responses (HDRs) obtained from stroke survivors during an event-related experiment could be used to develop individualized HDR functions that would enhance BOLD-fMRI signal detection in block experiments. Our long term goal was to use this information to develop individualized HDR functions for stroke survivors that could be used to analyze brain activity associated with locomotor-like movements. We also aimed to examine the reproducibility of HDRs obtained across two scan sessions in order to determine whether data from a single event-related session could be used to analyze block data obtained in subsequent sessions. Results indicate that the spatiotemporal profile of HDRs measured with BOLD-fMRI in stroke survivors was not the same as that observed in individuals without stroke. We observed small between-group differences in the rates of rise and decline of HDRs that were more apparent in individuals with cortical as compared to subcortical stroke. There were no differences in the peak or time to peak of HDRs in people with and without stroke. Of interest, differences in HDRs were not as substantial as expected from previous reports and were not large enough to necessitate the use of individualized HDR functions to obtain valid measures of movement-related brain activity. We conclude that all strokes do not affect the spatiotemporal characteristics of HDRs in such a way as to produce inaccurate representations of brain activity as measured by BOLD-fMRI. However, care should be taken to identify individuals whose BOLD-fMRI data may not provide an accurate representation of underlying brain activation when canonical models are used. Examination of HDRs need not be done for each scan session, as our data suggest that the characteristics of HDRs in stroke survivors are reproducible across days

Resting state functional thalamic connectivity abnormalities in patients with post-stroke sleep apnoea: a pilot case-control study

OBJECTIVE: Sleep apnoea is common after stroke, and has adverse effects on the clinical outcome of affected cases. Its pathophysiological mechanisms are only partially known. Increases in brain connectivity after stroke might influence networks involved in arousal modulation and breathing control. The aim of this study was to investigate the resting state functional MRI thalamic hyper connectivity of stroke patients affected by sleep apnoea (SA) with respect to cases not affected, and to healthy controls (HC). PATIENTS AND METHODS: A series of stabilized strokes were submitted to 3T resting state functional MRI imaging and full polysomnography. The ventral-posterior-lateral thalamic nucleus was used as seed. RESULTS: At the between groups comparison analysis, in SA cases versus HC, the regions significantly hyper-connected with the seed were those encoding noxious threats (frontal eye field, somatosensory association, secondary visual cortices). Comparisons between SA cases versus those without SA, revealed in the former group significantly increased connectivity with regions modulating the response to stimuli independently to their potentiality of threat (prefrontal, primary and somatosensory association, superolateral and medial-inferior temporal, associative and secondary occipital ones). Further significantly functionally hyper connections were documented with regions involved also in the modulation of breathing during sleep (pons, midbrain, cerebellum, posterior cingulate cortices), and in the modulation of breathing response to chemical variations (anterior, posterior and para-hippocampal cingulate cortices). CONCLUSIONS: Our preliminary data support the presence of functional hyper connectivity in thalamic circuits modulating sensorial stimuli, in patients with post-stroke sleep apnoea, possibly influencing both their arousal ability and breathing modulation during sleep

Genetically engineered minipigs model the major clinical features of human neurofibromatosis type 1.

Neurofibromatosis Type 1 (NF1) is a genetic disease caused by mutations in Neurofibromin 1 (NF1). NF1 patients present with a variety of clinical manifestations and are predisposed to cancer development. Many NF1 animal models have been developed, yet none display the spectrum of disease seen in patients and the translational impact of these models has been limited. We describe a minipig model that exhibits clinical hallmarks of NF1, including café au lait macules, neurofibromas, and optic pathway glioma. Spontaneous loss of heterozygosity is observed in this model, a phenomenon also described in NF1 patients. Oral administration of a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor suppresses Ras signaling. To our knowledge, this model provides an unprecedented opportunity to study the complex biology and natural history of NF1 and could prove indispensable for development of imaging methods, biomarkers, and evaluation of safety and efficacy of NF1-targeted therapies

Wireless Sensing of Lower Lip and Thumb-Index Finger ‘Ramp-and-Hold’ Isometric Force Dynamics in a Small Cohort of Unilateral MCA Stroke: Discussion of Preliminary Findings

Automated wireless sensing of force dynamics during a visuomotor control task was used to rapidly assess residual motor function during finger pinch (right and left hand) and lower lip compression in a cohort of seven adult males with chronic, unilateral middle cerebral artery (MCA) stroke with infarct confirmed by anatomic magnetic resonance imaging (MRI). A matched cohort of 25 neurotypical adult males served as controls. Dependent variables were extracted from digitized records of ‘ramp-and-hold’ isometric contractions to target levels (0.25, 0.5, 1, and 2 Newtons) presented in a randomized block design; and included force reaction time, peak force, and dF/dtmax associated with force recruitment, and end-point accuracy and variability metrics during the contraction hold-phase (mean, SD, criterion percentage ‘on-target’). Maximum voluntary contraction force (MVCF) was also assessed to establish the force operating range. Results based on linear mixed modeling (LMM, adjusted for age and handedness) revealed significant patterns of dissolution in fine force regulation among MCA stroke participants, especially for the contralesional thumb-index finger followed by the ipsilesional digits, and the lower lip. For example, the contralesional thumb-index finger manifest increased reaction time, and greater overshoot in peak force during recruitment compared to controls. Impaired force regulation among MCA stroke participants during the contraction hold-phase was associated with significant increases in force SD, and dramatic reduction in the ability to regulate force output within prescribed target force window (±5% of target). Impaired force regulation during contraction hold-phase was greatest in the contralesional hand muscle group, followed by significant dissolution in ipsilateral digits, with smaller effects found for lower lip. These changes in fine force dynamics were accompanied by large reductions in the MVCF with the LMM marginal means for contralesional and ipsilesional pinch forces at just 34.77% (15.93 N vs. 45.82 N) and 66.45% (27.23 N vs. 40.98 N) of control performance, respectively. Biomechanical measures of fine force and MVCF performance in adult stroke survivors provide valuable information on the profile of residual motor function which can help inform clinical treatment strategies and quantitatively monitor the efficacy of rehabilitation or neuroprotection strategies

Focal Spot, Winter 2006/2007

https://digitalcommons.wustl.edu/focal_spot_archives/1104/thumbnail.jp