Five-Year Longitudinal Study of Neck Vessel Cross-Sectional Area in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Alterations of neck vessel cross-sectional area in multiple sclerosis have been reported. Our aim was to investigate the evolution of the neck vessel cross-sectional area in patients with MS and healthy controls during 5 years. MATERIALS AND METHODS: Sixty-nine patients with MS (44 relapsing-remitting MS, 25 progressive MS) and 22 age- and sex-matched healthy controls were examined twice, 5 years apart, on a 3T MR imaging scanner using 2D neck MR angiography. Cross-sectional areas were computed for the common carotid/internal carotid arteries, vertebral arteries, and internal jugular veins for all slices between the C3 and C7 cervical levels. Longitudinal cross-sectional area differences at each cervical level and the whole-vessel course were tested within study groups and between patients with MS with and without cardiovascular disease using mixed-model analysis and the related-samples Wilcoxon singed rank test. The Benjamini-Hochberg procedure was performed to correct for multiple comparisons. RESULTS: No significant cross-sectional area differences were seen between patients with MS and healthy controls at baseline or at follow-up. During the follow-up, significant cross-sectional area decrease was found in patients with MS for the common carotid artery-ICAs (C4: P = .048; C7: P = .005; whole vessel: P = .012), for vertebral arteries (C3: P = .028; C4: P = .028; C7: P = .028; whole vessel: P = .012), and for the internal jugular veins (C3: P = .014; C4: P = .008; C5: P = .010; C6: P = .010; C7: P = .008; whole vessel: P = .002). Patients with MS without cardiovascular disease had significantly greater change than patients with MS with cardiovascular disease for internal jugular veins at all levels. CONCLUSIONS: For 5 years, patients with MS showed significant cross-sectional area decrease of all major neck vessels, regardless of the disease course and cardiovascular status.

Preliminary profiling of blood transcriptome in a rat model of hemorrhagic shock.

Hemorrhagic shock is a leading cause of morbidity and mortality worldwide. Significant blood loss may lead to decreased blood pressure and inadequate tissue perfusion with resultant organ failure and death, even after replacement of lost blood volume. One reason for this high acuity is that the fundamental mechanisms of shock are poorly understood. Proteomic and metabolomic approaches have been used to investigate the molecular events occurring in hemorrhagic shock but, to our knowledge, a systematic analysis of the transcriptomic profile is missing. Therefore, a pilot analysis using paired-end RNA sequencing was used to identify changes that occur in the blood transcriptome of rats subjected to hemorrhagic shock after blood reinfusion. Hemorrhagic shock was induced using a Wigger's shock model. The transcriptome of whole blood from shocked animals shows modulation of genes related to inflammation and immune response (Tlr13, Il1b, Ccl6, Lgals3), antioxidant functions (Mt2A, Mt1), tissue injury and repair pathways (Gpnmb, Trim72) and lipid mediators (Alox5ap, Ltb4r, Ptger2) compared with control animals. These findings are congruent with results obtained in hemorrhagic shock analysis by other authors using metabolomics and proteomics. The analysis of blood transcriptome may be a valuable tool to understand the biological changes occurring in hemorrhagic shock and a promising approach for the identification of novel biomarkers and therapeutic targets. Impact statement This study provides the first pilot analysis of the changes occurring in transcriptome expression of whole blood in hemorrhagic shock (HS) rats. We showed that the analysis of blood transcriptome is a useful approach to investigate pathways and functional alterations in this disease condition. This pilot study encourages the possible application of transcriptome analysis in the clinical setting, for the molecular profiling of whole blood in HS patients.

Mapping temporo-parietal and temporo-occipital cortico-cortical connections of the human middle longitudinal fascicle in subject-specific, probabilistic, and stereotaxic Talairach spaces.

Originally, the middle longitudinal fascicle (MdLF) was defined as a long association fiber tract connecting the superior temporal gyrus and temporal pole with the angular gyrus. More recently its description has been expanded to include all long postrolandic cortico-cortical association connections of the superior temporal gyrus and dorsal temporal pole with the parietal and occipital lobes. Despite its location and size, which makes MdLF one of the most prominent cerebral association fiber tracts, its discovery in humans is recent. Given the absence of a gold standard in humans for this fiber tract, its precise and complete connectivity remains to be determined with certainty. In this study using high angular resolution diffusion MRI (HARDI), we delineated for the first time, six major fiber connections of the human MdLF, four of which are temporo-parietal and two temporo-occipital, by examining morphology, topography, cortical connections, biophysical measures, volume and length in seventy brains. Considering the cortical affiliations of the different connections of MdLF we suggested that this fiber tract may be related to language, attention and integrative higher level visual and auditory processing associated functions. Furthermore, given the extensive connectivity provided to superior temporal gyrus and temporal pole with the parietal and occipital lobes, MdLF may be involved in several neurological and psychiatric conditions such as primary progressive aphasia and other aphasic syndromes, some forms of behavioral variant of frontotemporal dementia, atypical forms of Alzheimer's disease, corticobasal degeneration, schizophrenia as well as attention-deficit/hyperactivity Disorder and neglect disorders.

Assessment of Internal Jugular Vein Size in Healthy Subjects with Magnetic Resonance and Semiautomatic Processing.

Background and Objectives. The hypothesized link between extracranial venous abnormalities and some neurological disorders awoke interest in the investigation of the internal jugular veins (IJVs). However, different IJV cross-sectional area (CSA) values are currently reported in literature. In this study, we introduced a semiautomatic method to measure and normalize the CSA and the degree of circularity (Circ) of IJVs along their whole length. Methods. Thirty-six healthy subjects (31.22 ± 9.29 years) were recruited and the 2D time-of-flight magnetic resonance venography was acquired with a 1.5 T Siemens scanner. The IJV were segmented on an axial slice, the contours were propagated in 3D. Then, IJV CSA and Circ were computed between the first and the seventh cervical levels (C1-C7) and normalized among subjects. Inter- and intrarater repeatability were assessed. Results. IJV CSA and Circ were significantly different among cervical levels (p < 0.001). A trend for side difference was observed for CSA (larger right IJV, p = 0.06), but not for Circ (p = 0.5). Excellent inter- and intrarater repeatability was obtained for all the measures. Conclusion. This study proposed a reliable semiautomatic method able to measure the IJV area and shape along C1-C7, and suitable for defining the normality thresholds for future clinical studies.

Mortality prediction in septic shock patients: Towards new personalized models in critical care.

We studied the problem of mortality prediction in 23 septic shock patients selected from the public database MIMIC-II. For each patient we derived hemodynamic variables, laboratory results and clinical information of the first 48 hours after shock onset and we performed univariate and multivariate analyses to predict mortality in the following 7 days. The results show interesting features that individually identify significant differences between survivors and non survivors and features which gain importance only when considered together with the others in a multivariate regression model, such as the respiratory rate (RR). This preliminary study on a small septic shock population represents a novel contribution towards new personalized models for an integration of multi-scale and multi-level patient information to improve critical care management of shock patients.

Individual Thresholding of Voxel-based Functional Connectivity Maps. Estimation of Random Errors by Means of Surrogate Time Series.

INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "Biosignal Interpretation: Advanced Methods for Neural Signals and Images". BACKGROUND: Voxel-based functional connectivity analysis is a common method for resting state fMRI data. However, correlations between the seed and other brain voxels are corrupted by random estimate errors yielding false connections within the functional connectivity map (FCmap). These errors must be taken into account for a correct interpretation of single-subject results. OBJECTIVES: We estimated the statistical range of random errors and propose two methods for an individual setting of correlation threshold for FCmaps. METHODS: We assessed the amount of random errors by means of surrogate time series and described its distribution within the brain. On the basis of these results, the FCmaps of the posterior cingulate cortex (PCC) from 15 healthy subjects were thresholded with two innovative methods: the first one consisted in the computation of a unique (global) threshold value to be applied to all brain voxels, while the second method is to set a different (local) threshold of each voxel of the FCmap. RESULTS: The distribution of random errors within the brain was observed to be homogeneous and, after thresholding with both methods, the default mode network areas were well identifiable. The two methods yielded similar results, however the application of a global threshold to all brain voxels requires a reduced computational load. The inter-subject variability of the global threshold was observed to be very low and not correlated with age. Global threshold values are also almost independent from the number of surrogates used for their computation, so the analyses can be optimized using a reduced number of surrogate time series. CONCLUSIONS: We demonstrated the efficacy of FCmaps thresholding based on random error estimation. This method can be used for a reliable single-subject analysis and could also be applied in clinical setting, to compute individual measures of disease progression or quantitative response to pharmacological or rehabilitation treatments.

Cardiac output is not a significant source of low frequency mean arterial pressure variability.

Spontaneous mean arterial pressure (MAP) variability may be mainly due to fluctuations in cardiac output (CO) and total peripheral resistance (TPR). While high frequency (HF ∼ 0.25 Hz) oscillations in MAP are ultimately driven by respiration, the source of low frequency (LF ∼ 0.1 Hz) fluctuations has not been fully elucidated. It is known that CO buffers these oscillations, but there is no evidence on its potential role in also generating them. The main goal was to determine whether CO is a source of LF variability in MAP. Six dogs were chronically instrumented to obtain beat-to-beat measurements of CO and MAP while the dogs were fully awake and at rest. A causal dynamic model was identified to relate the fluctuations in CO to MAP. The model was then used to predict the MAP fluctuations from the CO fluctuations. The CO fluctuations were able to predict about 70% of the MAP oscillations in the HF band but showed no predictive value in the LF band. Hence, respiration induces CO fluctuations in the HF band that, in turn, cause MAP oscillations, while TPR fluctuations appear to be the dominant mediator of LF fluctuations of MAP. CO is not a significant source of these oscillations, and it may only be responsible for dampening them, likely through the baroreflex.

Human middle longitudinal fascicle: variations in patterns of anatomical connections.

Based on high-resolution diffusion tensor magnetic resonance imaging (DTI) tractographic analyses in 39 healthy adult subjects, we derived patterns of connections and measures of volume and biophysical parameters, such as fractional anisotropy (FA) for the human middle longitudinal fascicle (MdLF). Compared to previous studies, we found that the cortical connections of the MdLF in humans appear to go beyond the superior temporal (STG) and angular (AG) gyri, extending to the temporal pole (TP), superior parietal lobule (SPL), supramarginal gyrus, precuneus and the occipital lobe (including the cuneus and lateral occipital areas). Importantly, the MdLF showed a striking lateralized pattern with predominant connections between the TP, STG and AG on the left and TP, STG and SPL on the right hemisphere. In light of the results of the present study, and of the known functional role of the cortical areas interconnected by the MdLF, we suggested that this fiber pathway might be related to language, high order auditory association, visuospatial and attention functions.

Interferences between baroreflex and respiration. Evaluation by symbolic analysis and conditional entropy.

BACKGROUND: The baroreflex is one of the most important short-term cardiovascular autonomic control mechanisms. Its interactions with other reflexes, mainly cardiopulmonary reflexes, are of paramount importance in controlling heart rate. OBJECTIVES: This study assesses the coupling between baroreflex and respiration during a progressive bicycle mild dynamical exercise. METHODS: The coupling was assessed by symbolic analysis and conditional entropy. RESULTS: Findings suggested the close relationship between the baroreflex sequences and the phase of respiratory signal and, thus, the interference between baroreflex and cardiopulmonary reflexes. CONCLUSIONS: Indexes describing baroreflex based on spontaneous variability are strongly affected by cardiopulmonary influences.

ML segmentation strategies for object interference compensation in FDG-PET lesion quantification.

BACKGROUND: Quantification of lesion activity by FDG uptake in oncological PET is severely limited by partial volume effects. A maximum likelihood (ML) expectation maximization (EM) algorithm considering regional basis functions (AWOSEM-region) had been previously developed. Regional basis functions are iteratively segmented and quantified, thus identifying the volume and the activity of the lesion. OBJECTIVES: Improvement of AWOSEM-region when analyzing proximal interfering hot objects is addressed by proper segmentation initialization steps and models of spill-out and partial volume effects. Conditions relevant to lung PET-CT studies are considered: 1) lesion close to hot organ (e.g. chest wall, heart and mediastinum), 2) two close lesions. METHODS: CT image was considered for pre-segmenting hot anatomical structures, never for lesion identification, solely defined by iterations on PET data. Further resolution recovery beyond the smooth standard clinical image was necessary to start lesion segmentation. A watershed algorithm was used to separate two close lesions. A subtraction of the spill-out from a nearby hot organ was introduced to enhance a lesion for the initial segmentation and start the further quantification steps. Biograph scanner blurring was modeled from phantom data in order to implement the procedure for 3D clinical lung studies. RESULTS: In simulations, the procedure was able to separate structures as close as one pixel-size (2.25 mm). Robustness against the input segmentation errors defining the addressed objects was tested showing that convergence was not sensitive to initial volume overestimates up to 130%. Poor robustness was found against underestimates. A clinical study of a small lung lesion close to chest wall displayed a good recovery of both lesion activity and volume. CONCLUSIONS: With proper initialization and models of spill-out from hot organs, AWOSEM-region can be successfully applied to lung oncological studies.

DTI parameter optimisation for acquisition at 1.5T: SNR analysis and clinical application.

BACKGROUND: Magnetic Resonance (MR) diffusion tensor imaging (DTI) is able to quantify in vivo tissue microstructure properties and to detect disease related pathology of the central nervous system. Nevertheless, DTI is limited by low spatial resolution associated with its low signal-to-noise-ratio (SNR). AIM: The aim is to select a DTI sequence for brain clinical studies, optimizing SNR and resolution. METHODS AND RESULTS: We applied 6 methods for SNR computation in 26 DTI sequences with different parameters using 4 healthy volunteers (HV). We choosed two DTI sequences for their high SNR, they differed by voxel size and b-value. Subsequently, the two selected sequences were acquired from 30 multiple sclerosis (MS) patients with different disability and lesion load and 18 age matched HV. We observed high concordance between mean diffusivity (MD) and fractional anysotropy (FA), nonetheless the DTI sequence with smaller voxel size displayed a better correlation with disease progression, despite a slightly lower SNR. The reliability of corpus callosum (CC) fiber tracking with the chosen DTI sequences was also tested. CONCLUSIONS: The sensitivity of DTI-derived indices to MS-related tissue abnormalities indicates that the optimized sequence may be a powerful tool in studies aimed at monitoring the disease course and severity.

Components of arterial systolic pressure and RR-interval oscillation spectra in a case of baroreflex failure, a human open-loop model of vascular control.

The baroreflex control of circulation is always operating and modulates blood pressure and heart rate oscillations. Thus, the study of cardiovascular variability in humans is performed in a closed-loop model and the physiology of post-sinoaortic denervation is completely unknown in humans. We dissected for the first time the different components of systolic arterial pressure (SAP) and RR-interval spectra in a patient with 'baroreflex failure' (due to mixed cranial nerve neuroma) who represents a human model to investigate the cardiovascular regulation in an open-loop condition. Interactions among cardiovascular variability signals and respiratory influences were described using the multivariate parametric ARXAR model with the following findings: (1) rhythms unrelated to respiration were detected only at frequencies lower than classical low frequency (LF; Slow-LF, around 0.02 Hz) both in SAP an RR spectra, (2) small high-frequency (HF) modulation is present and related with respiration at rest and in tilt (but for SAP only) and (3) the Slow-LF fluctuations detected both in SAP and RR oscillate independently as the multivariate model shows no relationships between SAP and RR, and these oscillations are not phase related. Thus, we showed that in a patient with impaired baroreflex arc integrity the Slow-LF rhythms for RR have a central origin that dictates fluctuations on RR at the same rhythm but unrelated to the oscillation of SAP (which may be related with both peripheral activity and central rhythms). The synchronization in LF band is a hallmark of integrity of baroreflex arc whose impairment unmasks lower frequency rhythms in SAP and RR whose fluctuations oscillate independently.

Atlas-based vs. individual-based deterministic tractography of corpus callosum in multiple sclerosis.

Diffusion tensor (DT) magnetic resonance imaging is able to quantify tissue microstructure properties and to detect pathological changes even in the normal appearing tissues. DT sequence parameters which provide optimal SNR and minimum acquisition time, and an individual-based tractography post-processing allowed corpus callosum tractography even in multiple sclerosis (MS) patients also with no need of a-priori atlas. In this preliminary study, we were able to obtain reliable individual-based tractography in 28/30 MS patients. DT-derived indices computed in tracks obtained with individual-based tractography were able to differentiate healthy volunteers from MS patients better than the same indices computed with the atlas method. This indicates that such an optimized sequence may be a reliable tool to be used in future MS studies.

Biomedical engineering education at Politecnico di Milano: development and recent changes.

The biomedical engineering (BME) programme at the Politecnico di Milano (POLIMI) is characterized by a strong interdisciplinary background in a broad range of engineering subjects applied to biology and medicine. Accordingly, the undergraduate level (3 years) provides a general education, which includes mechanics, chemistry and materials, electronics, and information technology both in the context of general engineering and within BME foundations. In contrast, the postgraduate programme (2 years) offers a broad choice of specializations in BME fields in close connection with the BME research activities and laboratories of the campus and with active interchange with the other engineering disciplines. The history of BME development at POLIMI is briefly recalled, together with the characteristics of educational and research work, which is strongly biased by a large polytechnic university with no medical school within the same campus; points of strength and weakness due to this background are discussed. The introduction of a double cycle (undergraduate and postgraduate) according to the Bologna process (2000) and the effects on the programme structure is considered. An early phase in which professional education was emphasized at undergraduate level is recalled, which was followed by the actual revision fostering basic engineering and BME education at the first level while leaving in-depth specialization to postgraduate studies or to on-the-job training.

Influence of cochlear implant-like operating conditions on wavelet speech processing.

This study assessed the influence of 'non-ideal' operating conditions typical of cochlear implants (CIs) on the behavior of the wavelet transform (WT) when used to process speech. Particular attention was given to the effect of limited stimulation rate and limited number of channels, typical of CI speech processing, on the performance of the WT. Computer simulations and psychoacoustic recognition tests of WT-processed speech were implemented. The crucial role played by the 'non-ideal' operating conditions on WT speech processing was put in evidence. Psychoacoustic recognition tests proved to be fundamental to evaluate feasibility of WT speech processing for CIs.

Model of arterial tree and peripheral control for the study of physiological and assisted circulation.

Peripheral vasomotion, interstitial liquid exchange, and cardiovascular system behaviour are investigated by means of a lumped parameter model of the systemic and peripheral circulation, from the aortic valve to the venules. This modelling work aims at combining arterial tree hemodynamics description, active peripheral flow regulation, and fluid exchange. The arterial compartment is constructed with 63 RCL segments and 30 peripheral districts including myogenic control on arterioles, metabolic control on venules, and Starling filtration through capillary membrane. The arterial behaviour is characterised as to the long term stability of pressure/flow waves in the different segments. Peripheral districts show autoregulatory capabilities against pressure changes over a wide range and also self-sustained oscillations mimicking vasomotor activity. A preliminary study was carried out as to the model response to changes induced by cardiopulmonary bypass (CPB). Among the induced alterations, the system responds mainly to hemodilution, which increased peripheral fluid loss and oedema beyond the compensatory capabilities of local regulation mechanisms. This resulted in an overall increase total arterial resistance. Local transport deficits were assessed for each district according to the different metabolic demand. This study shows the requirement of a suitable description of both arteries and peripheral mechanisms in order to describe cardiovascular response non-physiological conditions, as well as assisted circulation or other pathological conditions.

Dopamine-dependent non-linear correlation between subthalamic rhythms in Parkinson's disease.

The basic information architecture in the basal ganglia circuit is under debate. Whereas anatomical studies quantify extensive convergence/divergence patterns in the circuit, suggesting an information sharing scheme, neurophysiological studies report an absence of linear correlation between single neurones in normal animals, suggesting a segregated parallel processing scheme. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys and in parkinsonian patients single neurones become linearly correlated, thus leading to a loss of segregation between neurones. Here we propose a possible integrative solution to this debate, by extending the concept of functional segregation from the cellular level to the network level. To this end, we recorded local field potentials (LFPs) from electrodes implanted for deep brain stimulation (DBS) in the subthalamic nucleus (STN) of parkinsonian patients. By applying bispectral analysis, we found that in the absence of dopamine stimulation STN LFP rhythms became non-linearly correlated, thus leading to a loss of segregation between rhythms. Non-linear correlation was particularly consistent between the low-beta rhythm (13-20 Hz) and the high-beta rhythm (20-35 Hz). Levodopa administration significantly decreased these non-linear correlations, therefore increasing segregation between rhythms. These results suggest that the extensive convergence/divergence in the basal ganglia circuit is physiologically necessary to sustain LFP rhythms distributed in large ensembles of neurones, but is not sufficient to induce correlated firing between neurone pairs. Conversely, loss of dopamine generates pathological linear correlation between neurone pairs, alters the patterns within LFP rhythms, and induces non-linear correlation between LFP rhythms operating at different frequencies. The pathophysiology of information processing in the human basal ganglia therefore involves not only activities of individual rhythms, but also interactions between rhythms.

Movement-related frequency modulation of beta oscillatory activity in the human subthalamic nucleus.

Event-related changes of brain electrical rhythms are typically analysed as amplitude modulations of local field potential (LFP) oscillations, like radio amplitude modulation broadcasting. In telecommunications, frequency modulation (FM) is less susceptible to interference than amplitude modulation (AM) and is therefore preferred for high-fidelity transmissions. Here we hypothesized that LFP rhythms detected from deep brain stimulation (DBS) electrodes implanted in the subthalamic nucleus (STN) in patients with Parkinson's disease could represent movement-related activity not only in AM but also in FM. By combining adaptive autoregressive identification with spectral power decomposition, we were able to show that FM of low-beta (13-20 Hz) and high-beta (20-35 Hz) rhythms significantly contributes to the involvement of the human STN in movement preparation, execution and recovery, and that the FM patterns are regulated by the dopamine levels in the system. Movement-related FM of beta oscillatory activity in the human subthalamic nucleus therefore provides a novel informational domain for rhythm-based pathophysiological models of cortico-basal ganglia processing.

Altered subthalamo-pallidal synchronisation in parkinsonian dyskinesias.

The aim of this work was to study the role of subthalamo-pallidal synchronisation in the pathophysiology of dyskinesias. We recorded local field potentials (LFPs) in a patient with Parkinson's disease and left surgery induced dyskinesias with double, bilateral deep brain stimulation electrode implants in the subthalamic nucleus (STN) and the globus pallidus internus (GPi). Synchronisation was studied through coherence analysis. In the nuclei contralateral to the dyskinetic side of the body there was decreased STN-GPi coherence in the high beta range (20-30 Hz) and an enhanced coherence at low frequencies (<10 Hz). Despite the possible limitations arising from single-case observations, our findings suggest that parkinsonian dyskinesias are related to altered synchronisation between different structures of the basal ganglia. Firing abnormalities within individual basal ganglia nuclei are probably not enough to account for the complex balance between hypokinetic and hyperkinetic symptoms in human parkinsonian dyskinesias and altered interactions between nuclei should also be considered.

Preliminary study on the use of nonrigid registration for thoraco-abdominal radiosurgery.

The inclusion of organ deformation and movement in radiosurgery treatment planning is of increasing importance as research and clinical applications begin to take into consideration the effects of physiological processes, like breathing, on the shape and position of lesions. In this scenario, the challenge is to localize the target in toto (not only by means of marker sampling) and to calculate the dose distribution as the sum of all the contributions from the positions assumed by the target during the respiratory cycle. The aim of this work is to investigate the use of nonrigid registration for target tracking and dynamic treatment planning, i.e., treatment planning based not on one single CT scan but on multiple CT scans representative of the respiration. Twenty patients were CT scanned at end-inhale and end-exhale. An expert radiation oncologist identified the PTV in both examinations. The two CT data sets per patient were nonrigidly registered using a free-form deformation algorithm based on B-splines. The optimized objective function consisted of a weighted sum of a similarity criterion (Mutual Information) and a regularization factor which constrains the transformation to be locally rigid. Once the transformation was obtained and the registration validated, its parameters were applied to the target only. Finally, the deformed target was compared to the PTV delineated by the radiation oncologist in the other study. The results of this procedure show an agreement between the center of mass as well as volume of the target identified automatically by deformable registration and manually by the radiation oncologist. Moreover, obtained displacements were in agreement with body structure constraints and considerations usually accepted in radiation therapy practice. No significant influence of initial target volume on displacements was found. In conclusion, the proposed method seems to offer the possibility of using nonrigid registrations in radiosurgery treatment planning, even if more cases need to be investigated in order to give a statistical consistency to parameter setup and proposed considerations.