Bringing a scalable adaptive hybrid modeling framework closer to industrial use: Application on a multiscale fungal fermentation.

Digitalization has paved the way for new paradigms such as digital shadows and digital twins for fermentation processes, opening the door for real-time process monitoring, control, and optimization. With a digital shadow, real-time model adaptation to accommodate complex metabolic phenomena such as metabolic shifts of a process can be monitored. Despite the many benefits of digitalization, the potential has not been fully reached in the industry. This study investigates the development of a digital shadow for a very complex fungal fermentation process in terms of microbial physiology and fermentation operation on pilot-scale at Novonesis and the challenges thereof. The process has historically been difficult to optimize and control due to a lack of offline measurements and an absence of biomass measurements. Pilot-scale and lab-scale fermentations were conducted for model development and validation. With all available pilot-scale data, a data-driven soft sensor was developed to estimate the main substrate concentration (glucose) with a normalized root mean squared error (N-RMSE) of 2%. This robust data-driven soft sensor was able to estimate accurately in lab-scale (volume < 20× pilot) with a N-RMSE of 7.8%. A hybrid soft sensor was developed by combining the data-driven soft sensor with a mass balance to estimate the glycerol and biomass concentrations on pilot-scale data with N-RMSEs of 11% and 21%, respectively. A digital shadow modeling framework was developed by coupling a mechanistic model (MM) with the hybrid soft sensor. The digital shadow modeling framework significantly improved the predictability compared with the MM. The contribution of this study brings the application of digital shadows closer to industrial implementation. It demonstrates the high potential of using this type of modeling framework for scale-up and leads the way to a new generation of in silico-based process development.

Oxygenation differs among white matter hyperintensities, intersected fiber tracts and unaffected white matter.

White matter hyperintensities of presumed vascular origin are frequently observed on magnetic resonance imaging in normal aging. They are typically found in cerebral small vessel disease and suspected culprits in the etiology of complex age- and small vessel disease-related conditions, such as late-onset depression. White matter hyperintensities may interfere with surrounding white matter metabolic demands by disrupting fiber tract integrity. Meanwhile, risk factors for small vessel disease are thought to reduce tissue oxygenation, not only by reducing regional blood supply, but also by impairing capillary function. To address white matter oxygen supply-demand balance, we estimated voxel-wise capillary density as an index of resting white matter metabolism, and combined estimates of blood supply and capillary function to calculate white matter oxygen availability. We conducted a cross-sectional study with structural, perfusion- and diffusion-weighted magnetic resonance imaging in 21 patients with late-onset depression and 21 controls. We outlined white matter hyperintensities and used tractography to identify the tracts they intersect. Perfusion data comprised cerebral blood flow, blood volume, mean transit time and relative transit time heterogeneity-the latter a marker of capillary dysfunction. Based on these, white matter oxygenation was calculated as the steady state cerebral metabolic rate of oxygen under the assumption of normal tissue oxygen tension and vice versa. The number, volume and perfusion characteristics of white matter hyperintensities did not differ significantly between groups. Hemodynamic data showed white matter hyperintensities to have lower blood flow and blood volume, but higher relative transit time heterogeneity, than normal-appearing white matter, resulting in either reduced capillary metabolic rate of oxygen or oxygen tension. Intersected tracts showed significantly lower blood flow, blood volume and capillary metabolic rate of oxygen than normal-appearing white matter. Across groups, lower lesion oxygen tension was associated with higher lesion number and volume. Compared with normal-appearing white matter, tissue oxygenation is significantly reduced in white matter hyperintensities as well as the fiber tracts they intersect, independent of parallel late-onset depression. In white matter hyperintensities, reduced microvascular blood volume and concomitant capillary dysfunction indicate a severe oxygen supply-demand imbalance with hypoxic tissue injury. In intersected fiber tracts, parallel reductions in oxygenation and microvascular blood volume are consistent with adaptations to reduced metabolic demands. We speculate, that aging and vascular risk factors impair white matter hyperintensity perfusion and capillary function to create hypoxic tissue injury, which in turn affect the function and metabolic demands of the white matter tracts they disrupt.

The porcine corticospinal decussation: A combined neuronal tracing and tractography study.

BACKGROUND: Pigs and minipigs are increasingly used as non-primate large animal models for preclinical research on nervous system disorders resulting in motor dysfunction. Knowledge of the minipig pyramidal tract is therefore essential to support such models. AIM AND METHODS: This study used 5 female Göttingen minipigs aging 11-15 months. The Göttingen minipig corticospinal tract was investigated, in the same animals, with in vivo neuronal tracing and with postmortem diffusion weighted MRI tractography to provide a thorough insight in the encephalic distribution of this primary motor pathway and its decussation at the craniocervical junction. RESULTS: The two methods similarly outlined the course of the pyramidal tract from its origin in the motor cortex down through the internal capsule to the craniocervical junction, where both methods displayed an axonal crossover at the pyramid decussation. The degree of crossover was quantified with unbiased stereology, where 81-93% of the traced corticospinal fibers crossed to the contralateral spinal cord. Accordingly, in the upper cervical spinal cord the corticospinal tract is primarily distributed in the contralateral lateral funiculus and in close relation to the gray matter, wherein some direct terminations on large ventral column gray matter neurons could be identified. DISCUSSION: The combination of neuronal tracing and tractography exploited the strengths of the respective methods to gain a better understanding of the encephalic distribution and craniocervical decussation of the Göttingen minipig corticospinal tract. Moreover, a quantification of the crossing fibers was obtained from the tracing data, which was not possible with tractography. Our data indicate that the porcine corticospinal system is quite lateralized down to the investigated upper cervical levels. However, further elucidation of this point will require a full examination of the corticospinal tracing pattern into the caudal spinal cord combined with an analysis of the direct versus indirect termination pattern on the lower motor neurons.

Changes in overall ventricular myocardial architecture in the setting of a porcine animal model of right ventricular dilation.

BACKGROUND: Chronic pulmonary regurgitation often leads to myocardial dysfunction and heart failure. It is not fully known why secondary hypertrophy cannot fully protect against the increase in wall stress brought about by the increased end-diastolic volume in ventricular dilation. It has been assumed that mural architecture is not deranged in this situation, but we hypothesised that there might be a change in the pattern of orientation of the aggregations of cardiomyocytes, which would contribute to contractile impairment. METHODS: We created pulmonary valvular regurgitation by open chest, surgical suturing of its leaflets in seven piglets, performing sham operations in seven control animals. Using cardiovascular magnetic resonance imaging after 12 weeks of recovery, we demonstrated significantly increased right ventricular volumes in the test group. After sacrifice, diffusion tensor imaging of their hearts permitted measurement of the orientation of the cardiomyocytes. RESULTS: The helical angles in the right ventricle approached a more circumferential orientation in the setting of right ventricular RV dilation (p = 0.007), with an increased proportion of surface-parallel cardiomyocytes. In contrast, this proportion decreased in the left ventricle. Also in the left ventricle a higher proportion of E3 angles with a value around zero was found, and conversely a lower proportion of angles was found with a numerical higher value. In the dilated right ventricle the proportion of E3 angles around -90° is increased, while the proportion around 90° is decreased. CONCLUSION: Contrary to traditional views, there is a change in the orientation of both the left ventricular and right ventricular cardiomyocytes subsequent to right ventricular dilation. This will change their direction of contraction and hinder the achievement of normalisation of cardiomyocytic strain, affecting overall contractility. We suggest that the aetiology of the cardiac failure induced by right vetricular dilation may be partly explained by morphological changes in the myocardium itself.

Probabilistic versus deterministic tractography for delineation of the cortico-subthalamic hyperdirect pathway in patients with Parkinson disease selected for deep brain stimulation.

OBJECTIVE Diffusion-weighted MRI (DWI) and tractography allows noninvasive mapping of the structural connections of the brain, and may provide important information for neurosurgical planning. The hyperdirect pathway, connecting the subthalamic nucleus (STN) with the motor cortex, is assumed to play a key role in mediating the effects of deep brain stimulation (DBS), which is an effective but poorly understood treatment for Parkinson disease. This study aimed to apply recent methodological advances in DWI acquisition and analysis to the delineation of the hyperdirect pathway in patients with Parkinson disease selected for surgery. METHODS High spatial and angular resolution DWI data were acquired preoperatively from 5 patients with Parkinson disease undergoing DBS. The authors compared the delineated hyperdirect pathways and associated STN target maps generated by 2 different tractography methods: a tensor-based deterministic method, typically available in clinical settings, and an advanced probabilistic method based on constrained spherical deconvolution. In addition, 10 high-resolution data sets with the same scanning parameters were acquired from a healthy control participant to assess the robustness of the tractography results. RESULTS Both tractography approaches identified connections between the ipsilateral motor cortex and the STN. However, the 2 methods provided substantially different target regions in the STN, with the target center of gravity differing by > 1.4 mm on average. The probabilistic method (based on constrained spherical deconvolution) plausibly reconstructed a continuous set of connections from the motor cortex, terminating in the dorsolateral region of the STN. In contrast, the tensor-based method reconstructed a comparatively sparser and more variable subset of connections. Furthermore, across the control scans, the probabilistic method identified considerably more consistent targeting regions within the STN compared with the deterministic tensor-based method, which demonstrated a 1.9-2.4 times higher variation. CONCLUSIONS These data provide a strong impetus for the use of a robust probabilistic tractography framework based on constrained spherical deconvolution, or similar advanced DWI models, in clinical settings. The inherent limitations and demonstrated inaccuracy of the tensor-based method leave it questionable for use in high-precision stereotactic DBS surgery. The authors have also described a straightforward method for importing tractography-derived information into any clinical neuronavigation system, based on the generation of track-density images.

Increased cortical capillary transit time heterogeneity in Alzheimer's disease: a DSC-MRI perfusion study.

Alzheimer's disease (AD) is characterized by the accumulation of hyperphosphorylated tau and neurotoxic Aß in the brain parenchyma. Hypoxia caused by microvascular changes and disturbed capillary flows could stimulate this build-up of AD-specific proteins in the brain. In this study, we compared cerebral microcirculation in a cohort of AD and mild cognitive impairment (MCI) patients with that of age-matched controls, all without a history of diabetes or of hypertension for more than 2 years, using dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI). Vascular flow disturbances were quantified using a parametric model and mapped to the mid-cortical surface for group-wise statistical analysis. We found widespread hypoperfusion in patients compared with controls and identified areas of increased relative capillary transit time heterogeneity (RTH), consistent with low tissue oxygen tension. Notably, RTH was positively correlated with white matter hyperintensities and positively correlated with symptom severity in the patient cohort. These correlations extended over large parts of the temporal, parietal, and frontal cortices. The results support the hypothesis of disturbed capillary flow patterns in AD and suggest that DSC-MRI may provide imaging biomarkers of impaired cerebral microcirculation in AD.

The myocardial architecture changes in persistent pulmonary hypertension of the newborn in an ovine animal model.

BACKGROUND: Persistent pulmonary hypertension in the newborn remains a syndrome with high mortality. Knowledge of changes in myocardial architecture in the setting of heart failure in persistent pulmonary hypertension is lacking, and could aid in the explanation of the prevailing high mortality. METHODS: Persistent pulmonary hypertension was induced by antenatal ligation of the arterial duct in six ovine fetuses. The hearts were compared ex vivo with five matched control hearts, using diffusion tensor imaging to provide the overall anatomical arrangement, and assessment of the angulations and course of the cardiomyocytes. Fibrosis was assessed with histology. RESULTS: We found an overall increase in heart size in pulmonary hypertension, with myocardial thickening confined to the interventricular septum. An increase of 3.5° in angulation of myocyte aggregations was found in hypertensive hearts. In addition, we observed a 2.2% increase in collagen content in the right ventricular free wall. Finally, we found a previously undescribed subepicardial layer of strictly longitudinally oriented cardiomyocytes confined to the right ventricle in all hearts. CONCLUSION: Myocardial fibrosis and possibly changes in angulations of myocytes seem to play a part in the etiology of persistent pulmonary hypertension. Moreover, a new anatomical arrangement of right ventricular mural architecture is described.

Optimal preservation of porcine cardiac tissue prior to diffusion tensor magnetic resonance imaging.

The effects of ex vivo preservation techniques on the quality of diffusion tensor magnetic resonance imaging in hearts are poorly understood, and the optimal handling procedure prior to investigation remains to be determined. Therefore, 24 porcine hearts were examined in six groups treated with different preservation techniques, including chemical fixation and freezing. Diffusion properties of each heart were assessed with diffusion tensor imaging in terms of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Da) and radial diffusivity (Dr). Tractography was performed to visualize the course of the cardiomyocytes, assuming greater diffusivity in the longitudinal than the transverse axis of individual cardiomyocytes. Significant differences in MD, Da and Dr were found, as well as in FA between groups (P < 0.001). Freezing of specimens resulted in the lowest mean FA of 0.21 (0.06) and highest Dr of 8.92 (1.5) mm2 s(-1) . The highest mean FA was found to be 0.43 (0.11) in hearts perfusion-fixed with formalin. Calculated tractographies were indistinguishable among groups except in frozen specimens, where no fibres could be tracked. Perfusion fixation with formalin provided the best tractography, but immersion fixation yielded diffusion data most similar to fresh hearts. These findings suggest that parameters derived from diffusion tensor imaging in ex vivo hearts are sensitive to fixation and storage methods. In particular, freezing of specimens should be avoided prior to diffusion tensor imaging investigation due to significant changes in diffusion parameters and subsequent image deteriorations.

Upper motor neuron involvement in amyotrophic lateral sclerosis evaluated by triple stimulation technique and diffusion tensor MRI.

The objective of this study was to evaluate the diagnostic value of triple stimulation technique (TST) and diffusion tensor imaging (DTI) tractography as markers of upper motor neuron (UMN) degeneration in amyotrophic lateral sclerosis (ALS). Fourteen ALS patients fulfilling the El Escorial criteria and 30 control subjects participated in the study. TST amplitude and area ratio were used as an estimate of the degree of central motor conduction failure. DTI fractional anisotropy was used as a quantitative measure of the structural integrity of the corticospinal tract and the posterior limb of the internal capsule. Mean TST amplitude and area ratio were lower in patients than controls, while there were no differences in mean fractional anisotropy of the corticospinal tract or the posterior limb of the internal capsule. TST was abnormal in 7/13 patients (sensitivity 54%) and DTI was abnormal in 3/12 (sensitivity 25%). Combining TST and DTI disclosed abnormalities in 8/11 patients (sensitivity 73%). TST confirmed UMN degeneration in one of every 2.25 patient in the diagnostic categories lower than 'probable' ALS. Using results from TST as a criterion for UMN degeneration, four patients in diagnostic categories lower than 'probable' ALS and without clinical signs of UMN degeneration in the cervical region increased in diagnostic category. Our findings indicate that TST has a significant diagnostic value as an early objective marker of UMN degeneration in ALS, while the value of DTI analysis seems limited.

Correlations between Stroop task performance and white matter lesion measures in late-onset major depression.

Cerebral white matter lesions (WMLs) are believed to play an important role in a subset of patients with late-onset depression by affecting the white matter connectivity in circuitries essential for mood and cognition. In this study we used diffusion tensor imaging-based (DTI-based) tractography to assess white matter fiber tracts affected by deep WMLs (DWMLs) in patients with late-onset major depression and age- and gender-matched controls. Tractography outcome, illustrated as pathways affected by DWMLs, was analyzed for associations with cognitive performance on the Stroop Test (ST). The patients (n=17) performed significantly worse on the ST than the controls (n=22). Poor performance on the ST correlated with higher lesion load. Regression analysis showed a significant correlation between poor performance on the ST and tracts affected by DWMLs in multiple brain areas in the control group, but very sparse correlation in the patient group. Our results suggest that DWMLs play an important role in the cognitive performance of controls,whereas their influence in depressed patients is overruled by additional, state-dependent factors. Future focus on the tract-specific localization of WMLs using DTI tractography may reveal important associations between neuroconnectivity and clinical measures.

Depression severity is correlated to the integrity of white matter fiber tracts in late-onset major depression.

Cerebral white matter lesions (WMLs) are believed to play an important role in a subset of major depression (MD). We aimed to describe the impact of WMLs on white matter pathways in MD using diffusion tensor imaging (DTI) and magnetization transfer imaging. As a novel approach, we used DTI tractography to assess pathways intersected by WMLs. We examined 22 patients with late-onset MD and 22 age- and gender-matched controls. Parametric maps of fractional anisotropy (FA), apparent diffusion coefficient (ADC), and magnetization transfer ratio (MTR) were obtained to describe tissue integrity. The association between depression severity and the tract-specific localization of WMLs was analyzed on a voxel-by-voxel basis. We showed a significant positive association between depression severity and fiber tracts intersected by WMLs in the left superior longitudinal fasciculus and the right uncinate fasciculus. In both groups, WMLs had significantly lower FA and MTR, and higher ADC than both the tracts they intersected and the normal-appearing white matter (NAWM). In turn, the tracts intersected by WMLs had significantly lower FA and higher ADC than the NAWM. In conclusion, depression severity correlates with the tract-specific localization of WMLs. WMLs have a pronounced effect on white matter integrity in the pathways they intersect.

New surgical technique reduces the susceptibility artefact at air-tissue interfaces on in vivo cerebral MRI in the Göttingen minipig.

Advanced and exclusive software solutions are offered to reduce susceptibility artefacts on MRI echo-planar sequences. We present a straightforward surgical technique to reduce the cortical distortion and signal loss that normally occur using diffusion tensor imaging (DTI) of the Göttingen minipig brain. Pronounced pneumatisation of the minipig cranium causes considerable susceptibility artefacts at the air/tissue interface around the frontal sinuses. Five Göttingen minipigs had burr holes drilled through the outer lamina of the skull bilaterally at the level of bregma. The underlying frontal sinuses were filled with a suspension of an MRI-compatible alginate. DTI was obtained before and after placing the medium in the sinus, quantifying the change using mutual information and Wilcoxon's rank-sum test. Fibertracking algorithms were applied to visualize the effect of treatment. We showed that the susceptibility artefacts were reduced at the air, bone and brain interfaces and that major cortical fiberbundles could be reliably visualized. This study demonstrated that DTI fibertracking of cortical bundles in experimental animals with extensive skull pneumatisation is feasible even when advanced software is unavailable.

Normal right ventricular three-dimensional architecture, as assessed with diffusion tensor magnetic resonance imaging, is preserved during experimentally induced right ventricular hypertrophy.

The three-dimensional architecture of the right ventricular myocardium is a major determinant of function, but as yet no investigator-independent methods have been used to characterize either the normal or hypertrophied state. We aimed to assess and compare, using diffusion tensor magnetic resonance imaging, the normal architecture with the arrangement induced by chronic hypertrophy. We randomized 20 female 5 kg piglets into pulmonary trunk banding (N = 16) and sham operation (N = 4). Right ventricular hypertrophy was assessed after 8 weeks. The excised and fixed hearts were subject to diffusion tensor imaging to determine myocyte helical angles, and the presence of any reproducible tracks formed by the aggregated myocytes. All banding animals developed significant right ventricular hypertrophy, albeit that no difference was observed in terms of helical angles or myocardial pathways between the banded animals and sham group animals. Helical angles varied from approximately 70 degrees endocardially to -50 degrees epicardially. Very few tracks were circular, with helical angles approximating zero. Reproducible patterns of chains of aggregated myocytes were observed in all hearts, regardless of group. The architecture of the myocytes aggregated in the walls of the right ventricle is comparable to that found in the left ventricle in terms of endocardial and epicardial helical angles, however the right ventricle both in the normal and the hypertrophied state lacks the extensive zone of circular myocytes seen in the mid-portion of the left ventricular walls. Without such beneficial architectural remodelling, the porcine right ventricle seems unsuited structurally to sustain a permanent increase in afterload.

The three-dimensional arrangement of the myocytes aggregated together within the mammalian ventricular myocardium.

Although myocardial architecture has been investigated extensively, as yet no evidence exists for the anatomic segregation of discrete myocardial pathways. We performed post-mortem diffusion tensor imaging on 14 pig hearts. Pathway tracking was done from 22 standardized voxel groups from within the left ventricle, the left ventricular papillary muscles, and the right ventricular outflow tract. We generated pathways with comparable patterns in the different hearts when tracking from all chosen voxels. We were unable to demonstrate discrete circular or longitudinal pathways, nor to trace any solitary tract of myocardial cells extending throughout the ventricular mass. Instead, each pathway possessed endocardial, midwall, and epicardial components, merging one into another in consistent fashion. Endocardial tracks, when followed towards the basal or apical parts of the left ventricle, changed smoothly their helical and transmural angulations, becoming continuous with circular pathways in the midwall, these circular tracks further transforming into epicardial tracks, again by smooth change of the helical and transmural angles. Tracks originating from voxels in the papillary muscles behaved similarly to endocardial tracks. This is the first study to show myocardial pathways that run through the mammalian left and right ventricles in a highly reproducible manner according to varying local helical and transmural intrusion angles. The patterns generated are an inherent feature of the three-dimensional arrangement of the individual myocytes aggregated within the walls, differing according to the regional orientation and branching of individual myocytes. We found no evidence to support the existence of individual muscles or bands. Anat Rec, 2009. (c) 2008 Wiley-Liss, Inc.

Bayesian regularization of diffusion tensor images.

Diffusion tensor imaging (DTI) is a powerful tool in the study of the course of nerve fiber bundles in the human brain. Using DTI, the local fiber orientation in each image voxel can be described by a diffusion tensor which is constructed from local measurements of diffusion coefficients along several directions. The measured diffusion coefficients and thereby the diffusion tensors are subject to noise, leading to possibly flawed representations of the 3-dimensional (3D) fiber bundles. In this paper, we develop a Bayesian procedure for regularizing the diffusion tensor field, fully utilizing the available 3D information of fiber orientation. The use of the procedure is exemplified on synthetic and in vivo data.