Mapping cell cortex rheology to tissue rheology and vice versa.

The mechanics of biological tissues mainly proceeds from the cell cortex rheology. A direct, explicit link between cortex rheology and tissue rheology remains lacking, yet would be instrumental in understanding how modulations of cortical mechanics may impact tissue mechanical behavior. Using an ordered geometry built on 3D hexagonal, incompressible cells, we build a mapping relating the cortical rheology to the monolayer tissue rheology. Our approach shows that the tissue low-frequency elastic modulus is proportional to the rest tension of the cortex, as expected from the physics of liquid foams as well as of tensegrity structures. A fractional visco-contractile cortex rheology is predicted to yield a high-frequency fractional visco-elastic monolayer rheology, where such a fractional behavior has been recently observed experimentally at each scale separately. In particular cases, the mapping may be inverted, allowing to derive from a given tissue rheology the underlying cortex rheology. Interestingly, applying the same approach to a 2D hexagonal tiling fails, which suggests that the 2D character of planar cell cortex-based models may be unsuitable to account for realistic monolayer rheologies. We provide quantitative predictions, amenable to experimental tests through standard perturbation assays of cortex constituents, and hope to foster new, challenging mechanical experiments on cell monolayers.

Language reorganization after resection of low-grade gliomas: an fMRI task based connectivity study.

Few studies addressed the evolution of brain activity before and after brain tumor resection. Using a fMRI naming task, we evaluated possible underlying plasticity phenomena. Thirty-two patients with left low-grade gliomas (16 women; age = 38.6 ± 8.31 years) and 19 healthy controls (7 women; age = 42.4 ± 12.1) were included in the study. An overt picture-naming task (DO80) was performed pre and post (3 months) surgery, as well as within the MRI in a covert manner. Exams included an injected 3DT1, a T2FLAIR, a DTI and a GE-EPI (task) sequence. Activations maps were compared with picture naming score, FA and MD maps were estimated, a VLSM analysis was performed on tumor masks, and disconnectome maps were reconstructed. Pre-surgery, the left parahippocampal gyrus (LPH) was inversely associated with task performance. Increased pre-post surgery left lingual gyrus (LLG) activity was found related to decreased picture naming performance. The evolution of left lingual gyrus (LLG) activity was negatively associated with the evolution of picture naming performance. In controls, the LPH was functionally connected to the right precentral gyrus (RPCG) and slightly to the LLG. This was not clearly retrieved in the patient group. Preoperatively, the LLG was connected to the left planum temporale and to the right lingual gyrus. The same result was found for controls. Postoperatively, the LLG was only connected to the RPCG. No association was found between evolution of FA/MD and evolution of picture naming performance. There is not one unique pattern of pre- and postoperative plasticity concerning picture-naming performance in DLGG patients.

Transient immediate postoperative homotopic functional disconnectivity in low-grade glioma patients.

Background and purpose: The aim of this longitudinal study is to evaluate large-scale perioperative resting state networks reorganization in patients with diffuse low-grade gliomas following awake surgery. Materials and methods: Eighty-two patients with diffuse low-grade gliomas were prospectively enrolled and underwent awake surgical resection. Resting-state functional images were acquired at three time points: preoperative (MRI-1), immediate postoperative (MRI-2) and three months after surgery (MRI-3). We simultaneously performed perfusion-weighted imaging. Results: Comparing functional connectivity between MRI-1 and MRI-2, we observed a statistically significant functional homotopy decrease in cortical and subcortical supratentorial structures (P < 0.05). A functional homotopy increase was observed between MRI-2 and MRI-3 in parietal lobes, cingulum and putamen (P < 0.05). No significant functional connectivity modification was noticed between MRI-1 and MRI-3. Regional cerebral blood flow appeared transiently reduced on MRI-2 (P < 0.05). No correlation between neurological deficit and interhemispheric connectivity results was found. Conclusion/interpretation: We found a supratentorial widely distributed functional homotopy disruption between preoperative and immediate postoperative time points with a complete restitution three months after surgery with simultaneous variation of regional cerebral blood flow.

Is impaired cerebral vasoreactivity an early marker of cognitive decline in multiple sclerosis patients?

OBJECTIVE: The link between cerebral vasoreactivity and cognitive status in multiple sclerosis remains unclear. The aim of the present study was to investigate a potential decrease of cerebral vasoreactivity in multiple sclerosis patients and correlate it with cognitive status. METHODS: Thirty-three patients with multiple sclerosis (nine progressive and 24 remitting forms, median age: 39 years, 12 males) and 22 controls underwent MRI with a hypercapnic challenge to assess cerebral vasoreactivity and a neuropsychological assessment. Cerebral vasoreactivity, measured as the cerebral blood flow percent increase normalised by end-tidal carbon dioxide variation, was assessed globally and by regions of interest using the blood oxygen level-dependent technique. Non-parametric statistics tests were used to assess differences between groups, and associations were estimated using linear models. RESULTS: Cerebral vasoreactivity was lower in patients with cognitive impairment than in cognitively normal patients (p=0.004) and was associated with education level in patients (R2 = 0.35; p = 0.047). There was no decrease in cerebral vasoreactivity between patients and controls. CONCLUSIONS: Cognitive impairment in multiple sclerosis may be mediated through decreased cerebral vasoreactivity. Cerebral vasoreactivity could therefore be considered as a marker of cognitive decline in multiple sclerosis. KEY POINTS: • Cerebral vasoreactivity does not differ between multiple sclerosis patients and controls. • Cerebral vasoreactivity measure is linked to cognitive impairment in multiple sclerosis. • Cerebral vasoreactivity is linked to level of education in multiple sclerosis.

Clock-dependent and system-driven oscillators interact in the suprachiasmatic nuclei to pace mammalian circadian rhythms.

Circadian clocks drive biological rhythms with a period of approximately 24 hours and keep in time with the outside world through daily resetting by environmental cues. While this external entrainment has been extensively investigated in the suprachiasmatic nuclei (SCN), the role of internal systemic rhythms, including daily fluctuations in core temperature or circulating hormones remains debated. Here, we show that lactating mice, which exhibit dampened systemic rhythms, possess normal molecular clockwork but impaired rhythms in both heat shock response gene expression and electrophysiological output in their SCN. This suggests that body rhythms regulate SCN activity downstream of the clock. Mathematical modeling predicts that systemic feedback upon the SCN functions as an internal oscillator that accounts for in vivo and ex vivo observations. Thus we are able to propose a new bottom-up hierarchical organization of circadian timekeeping in mammals, based on the interaction in the SCN between clock-dependent and system-driven oscillators.

MRI volumetric morphometry in vascular parkinsonism.

Vascular parkinsonism is a difficult clinical differential diagnosis in elderly subjects. We aimed at identifying morphometric markers in the brain of elderly patients with vascular parkinsonism (VP) compared with age-matched patients with Parkinson's disease (PD) and healthy controls. In this multicenter prospective study, 46 patients (80 ± 5 years old; male 32) with parkinsonism (32 PD and 14 VP) and 29 controls (mean age 78 ± 3 years; male 21) underwent brain MRI on a 3-T scanner including T1 MPRAGE and FLAIR sequences. Volumetric morphometry was obtained using Morphobox software and compared between patients and controls. Receiver operating characteristics curve analysis with computation of area under the curve (AUC) was used to compare diagnostic values. Caudate nucleus and white matter hyperintense lesions (WMHL) volumes appeared significantly higher in patients with VP. Normalized caudate volume of at least 0.67% and normalized WMHL of at least 1.11% identified patients with VP from patients with PD and controls with similar performances (p > 0.25). Caudate nucleus and WMHL volumes were positively correlated (ρ = 0.74, p < 0.0001), suggesting vascular disease related remodelling in elderly subjects. Caudate nucleus and WMHL MRI volumes might be used as additional markers to help identify patients with VP in the initial workup of elderly subjects with parkinsonian symptoms.

Validation of a quantitative susceptibility mapping acquisition and reconstruction pipeline using a new iron sucrose based MR susceptibility phantom.

PURPOSE: Quantitative susceptibility mapping is a new technique and its processing pipeline has to be validated before clinical practice. We described an easy to build magnetic resonance (MR) susceptibility phantom based on iron sucrose. MATERIALS AND METHODS: In a plastic container, Eppendorf tubes containing increasing iron sucrose concentration ranging from 0 to 60µg Fe/mL were inserted in an agarose gel. To estimate susceptibility, multiple coronal gradient echo acquisitions were performed with varying angle of the phantom relative to the B0 field, ranging from 30 to 90°. Quantitative susceptibility maps were reconstructed using the l1 and l2 norm of total variation using Split Bregman approach. Iron concentration was finally estimated from the susceptibility in the tubes. RESULTS: In l1norm susceptibility and estimated iron concentration were not different from the real values while l2norm underestimated the susceptibility. A correlation was found between the angle of the phantom and the difference between real and estimated iron concentrations. The results highlight the importance of this validation by emphasizing the effects of various reconstruction parameters as well as acquisition conditions. Using optimal parameters, the quantitative susceptibility mapping provides a very good estimation of the iron concentrations in the phantom.

Recovery of functional connectivity of the sensorimotor network after surgery for diffuse low-grade gliomas involving the supplementary motor area.

OBJECTIVE The supplementary motor area (SMA) syndrome is a well-studied lesional model of brain plasticity involving the sensorimotor network. Patients with diffuse low-grade gliomas in the SMA may exhibit this syndrome after resective surgery. They experience a temporary loss of motor function, which completely resolves within 3 months. The authors used functional MRI (fMRI) resting state analysis of the sensorimotor network to investigate large-scale brain plasticity between the immediate postoperative period and 3 months' follow-up. METHODS Resting state fMRI was performed preoperatively, during the immediate postoperative period, and 3 months postoperatively in 6 patients with diffuse low-grade gliomas who underwent partial surgical excision of the SMA. Correlation analysis within the sensorimotor network was carried out on those 3 time points to study modifications of its functional connectivity. RESULTS The results showed a large-scale reorganization of the sensorimotor network. Interhemispheric connectivity was decreased in the postoperative period, and increased again during the recovery process. Connectivity between the lesion side motor area and the contralateral SMA rose to higher values than in the preoperative period. Intrahemispheric connectivity was decreased during the immediate postoperative period and had returned to preoperative values at 3 months after surgery. CONCLUSIONS These results confirm the findings reported in the existing literature on the plasticity of the SMA, showing large-scale modifications of the sensorimotor network, at both inter- and intrahemispheric levels. They suggest that interhemispheric connectivity might be a correlate of SMA syndrome recovery.

Mean arterial pressure change associated with cerebral blood flow in healthy older adults.

We investigate over a 12-year period the association between regional cerebral blood flow (CBF) and cardiovascular risk factors in a prospective cohort of healthy older adults (81.96 ± 3.82 year-old) from the Cognitive REServe and Clinical ENDOphenotype (CRESCENDO) study. Cardiovascular risk factors were measured over 12 years, and gray matter CBF was measured at the end of the study from high-resolution magnetic resonance imaging using arterial spin labeling. The association between cardiovascular risk factors, their long-term change, and CBF was assessed using multivariate linear regression models. Women were observed to have higher CBF than men (p < 0.05). Increased mean arterial pressure (MAP) over the 12-year period was correlated with a low cerebral blood flow (p < 0.05, R(2) = 0.21), whereas no association was detected between CBF and MAP at the time of imaging. High levels of glycemia tended to be associated with low cerebral blood flow values (p < 0.05). Age, alcohol consumption, smoking status, body mass index, history of cardiovascular disease, and hypertension were not associated with CBF. Our main result suggests that change in MAP is the most significant predictor of future CBF in older adults.

Comparison between resting state fMRI networks and responsive cortical stimulations in glioma patients.

OBJECTIVES: To validate the functional relevance of resting state networks (RSNs) by means of a comparison of resting state connectivity (RSC) between language regions elicited by direct cortical stimulation versus RSC between random regions; and to evaluate the accuracy of resting state fMRI in surgical planning by assessing the overlap between RSNs and intraoperative functional mapping results. METHODS: Sensorimotor and language eloquent sites were identified by direct electrical cortical stimulation in 98 patients with a diffuse low-grade glioma. A seed to voxel analysis with inter-language stimulation point connectivity versus inter-random ROIs connectivity was performed (19 patients). An independant component analysis (ICA) was also applied to rsfMRI data. Language and sensorimotor components were selected over 20 independent components and compared to the corresponding stimulation points and resected cortex masks (31 and 90 patients, respectively). RESULTS: Mean connectivity value between language seeds was significantly higher than the one between random seeds (0.68 ± 0.39 and 0.12 ± 0.21 respectively, P < 10-10 ). 96 ± 11% of sensorimotor stimulation points were located within 10 mm from sensorimotor ICA maps versus 92 ± 21% for language. 3.1 and 15% of resected cortex overlapped sensorimotor and language networks, respectively. Mean sensorimotor stimulation points and resected cortex z-scores were 2.0 ± 1.2 and -0.050 ± 0.60, respectively (P < 10-10 ). Mean language stimulation points and resected cortex z-scores were 1.6 ± 1.9 and 0.68 ± 0.91, respectively, P < 0.005. CONCLUSION: The significantly higher RSC between language seeds than between random seeds validated the functional relevance of RSC. ICA partly succeeded to distinguish eloquent versus surgically removable areas and may be possibly used as a complementary tool to intraoperative mapping. Hum Brain Mapp 37:3721-3732, 2016. © 2016 Wiley Periodicals, Inc.

Working memory performance is related to intrinsic resting state functional connectivity changes in community-dwelling elderly cohort.

Characterization of normal age-related changes in resting state brain networks associated with working memory performance is a major prerequisite for studying neurodegenerative diseases. The aim of this study was to investigate the relationship between performing a working memory task (under MRI) and resting-state brain networks in a large cohort of healthy elderly subjects (n=337). Functional connectivity and interactions between networks were assessed within the default mode (DMN), salience (SN), and right and left central executive (CEN) networks in two groups of subjects classed by their performance (low and high). The low performance group showed lower functional connectivity in both the DMN and SN, and higher functional connectivity in the right and left CEN compared to the high performance group. Overall the functional connectivity within the DMN and the CEN were correlated. The lower functional connectivity within the DMN and SN in the low performance group is suggestive of altered attentional and memory processes and/or altered motivation. The higher functional connectivity within the CEN could be related to compensatory mechanisms, without which the subjects would have even lower performances. The correlation between the DMN and CEN suggests a modulation between the lower functional connectivity within the DMN and the higher functional connectivity within the CEN when performance is reduced. Finally, this study suggests that performance modifications in healthy elderly subjects are associated with reorganization of functional connectivity within the DMN, SN, and CEN.

Metabolism Regulates Exposure of Pancreatic Islets to Circulating Molecules In Vivo.

Pancreatic ß-cells modulate insulin secretion through rapid sensing of blood glucose and integration of gut-derived signals. Increased insulin demand during pregnancy and obesity alters islet function and mass and leads to gestational diabetes mellitus and type 2 diabetes in predisposed individuals. However, it is unclear how blood-borne factors dynamically access the islets of Langerhans. Thus, understanding the changes in circulating molecule distribution that accompany compensatory ß-cell expansion may be key to developing novel antidiabetic therapies. Here, using two-photon microscopy in vivo in mice, we demonstrate that islets are almost instantly exposed to peaks of circulating molecules, which rapidly pervade the tissue before clearance. In addition, both gestation and short-term high-fat-diet feeding decrease molecule extravasation and uptake rates in vivo in islets, independently of ß-cell expansion or islet blood flow velocity. Together, these data support a role for islet vascular permeability in shaping ß-cell adaptive responses to metabolic demand by modulating the access and sensing of circulating molecules.

Longitudinal Changes in Cerebellar and Thalamic Spontaneous Neuronal Activity After Wide-Awake Surgery of Brain Tumors: a Resting-State fMRI Study.

Hypometabolism has been observed in the contralesional cerebellar hemisphere after various supratentorial cortical lesions. It is unknown whether the consequences of the dee- and deafferentation subsequent to wide-awake surgery for brain diffuse low-grade glioma can be assessed within remote and unresected subcortical structures such as the cerebellum or thalamus. To answer this question, we have conducted several regional analyses. More specifically, we have performed amplitude of low-frequency fluctuations (neuronal activity magnitude) and regional homogeneity (local temporal correlations) analyses on resting state functional magnetic resonance imaging (rs-fMRI) data and at different time points, before and after surgery. Our main results demonstrated that it is possible to evaluate subtle subcortical changes using these tools dedicated to the analysis of rs-fMRI data. The observed variations of spontaneous neuronal activity were particularly significant within the cerebellum which showed altered regional homogeneity and neuronal activity intensity in very different, specialized and non-overlapping subregions, in accordance to its neuro-anatomo-functional topography. These variations were moreover observed in the immediate postoperative period and recovered after 3 months.

Working memory activation of neural networks in the elderly as a function of information processing phase and task complexity.

Changes in working memory are sensitive indicators of both normal and pathological brain aging and associated disability. The present study aims to further understanding of working memory in normal aging using a large cohort of healthy elderly in order to examine three separate phases of information processing in relation to changes in task load activation. Using covariance analysis, increasing and decreasing neural activation was observed on fMRI in response to a delayed item recognition task in 337 cognitively healthy elderly persons as part of the CRESCENDO (Cognitive REServe and Clinical ENDOphenotypes) study. During three phases of the task (stimulation, retention, probe), increased activation was observed with increasing task load in bilateral regions of the prefrontal cortex, parietal lobule, cingulate gyrus, insula and in deep gray matter nuclei, suggesting an involvement of central executive and salience networks. Decreased activation associated with increasing task load was observed during the stimulation phase, in bilateral temporal cortex, parietal lobule, cingulate gyrus and prefrontal cortex. This spatial distribution of decreased activation is suggestive of the default mode network. These findings support the hypothesis of an increased activation in salience and central executive networks and a decreased activation in default mode network concomitant to increasing task load.

Colloquium: Mechanical formalisms for tissue dynamics.

The understanding of morphogenesis in living organisms has been renewed by tremendous progress in experimental techniques that provide access to cell scale, quantitative information both on the shapes of cells within tissues and on the genes being expressed. This information suggests that our understanding of the respective contributions of gene expression and mechanics, and of their crucial entanglement, will soon leap forward. Biomechanics increasingly benefits from models, which assist the design and interpretation of experiments, point out the main ingredients and assumptions, and ultimately lead to predictions. The newly accessible local information thus calls for a reflection on how to select suitable classes of mechanical models. We review both mechanical ingredients suggested by the current knowledge of tissue behaviour, and modelling methods that can help generate a rheological diagram or a constitutive equation. We distinguish cell scale ("intra-cell") and tissue scale ("inter-cell") contributions. We recall the mathematical framework developed for continuum materials and explain how to transform a constitutive equation into a set of partial differential equations amenable to numerical resolution. We show that when plastic behaviour is relevant, the dissipation function formalism appears appropriate to generate constitutive equations; its variational nature facilitates numerical implementation, and we discuss adaptations needed in the case of large deformations. The present article gathers theoretical methods that can readily enhance the significance of the data to be extracted from recent or future high throughput biomechanical experiments.

Diffusion tensor imaging differentiates vascular parkinsonism from parkinsonian syndromes of degenerative origin in elderly subjects.

BACKGROUND AND PURPOSE: The etiologic diagnosis of parkinsonian syndromes is of particular importance when considering syndromes of vascular or degenerative origin. The purpose of this study is to find differences in the white-matter architecture between those two groups in elderly patients. MATERIALS AND METHODS: Thirty-five patients were prospectively included (multiple-system atrophy, n=5; Parkinson's disease, n=15; progressive supranuclear palsy, n=9; vascular parkinsonism, n=6), with a mean age of 76 years. Patients with multiple-system atrophy, progressive supranuclear palsy and Parkinson's disease were grouped as having parkinsonian syndromes of degenerative origin. Brain MRIs included diffusion tensor imaging. Fractional anisotropy and mean-diffusivity maps were spatially normalized, and group analyses between parkinsonian syndromes of degenerative origin and vascular parkinsonism were performed using a voxel-based approach. RESULTS: Statistical parametric-mapping analysis of diffusion tensor imaging data showed decreased fractional anisotropy value in internal capsules bilaterally in patients with vascular parkinsonism compared to parkinsonian syndromes of degenerative origin (p=0.001) and showed a lower mean diffusivity in the white matter of the left superior parietal lobule (p=0.01). Fractional anisotropy values were found decreased in the middle cerebellar peduncles in multiple-system atrophy compared to Parkinson's disease and progressive supranuclear palsy. The mean diffusivity was increased in those regions for these subgroups. CONCLUSION: Clinically defined vascular parkinsonism was associated with decreased fractional anisotropy in the deep white matter (internal capsules) compared to parkinsonian syndromes of degenerative origin. These findings are consistent with previously published neuropathological data.

Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons.

To maintain homeostasis, hypothalamic neurons in the arcuate nucleus must dynamically sense and integrate a multitude of peripheral signals. Blood-borne molecules must therefore be able to circumvent the tightly sealed vasculature of the blood-brain barrier to rapidly access their target neurons. However, how information encoded by circulating appetite-modifying hormones is conveyed to central hypothalamic neurons remains largely unexplored. Using in vivo multiphoton microscopy together with fluorescently labeled ligands, we demonstrate that circulating ghrelin, a versatile regulator of energy expenditure and feeding behavior, rapidly binds neurons in the vicinity of fenestrated capillaries, and that the number of labeled cell bodies varies with feeding status. Thus, by virtue of its vascular connections, the hypothalamus is able to directly sense peripheral signals, modifying energy status accordingly.

Existence of long-lasting experience-dependent plasticity in endocrine cell networks.

Experience-dependent plasticity of cell and tissue function is critical for survival by allowing organisms to dynamically adjust physiological processes in response to changing or harsh environmental conditions. Despite the conferred evolutionary advantage, it remains unknown whether emergent experience-dependent properties are present in cell populations organized as networks within endocrine tissues involved in regulating body-wide homeostasis. Here we show, using lactation to repeatedly activate a specific endocrine cell network in situ in the mammalian pituitary, that templates of prior demand are permanently stored through stimulus-evoked alterations to the extent and strength of cell-cell connectivity. Strikingly, following repeat stimulation, evolved population behaviour leads to improved tissue output. As such, long-lasting experience-dependent plasticity is an important feature of endocrine cell networks and underlies functional adaptation of hormone release.

The comparison between circadian oscillators in mouse liver and pituitary gland reveals different integration of feeding and light schedules.

The mammalian circadian system is composed of multiple peripheral clocks that are synchronized by a central pacemaker in the suprachiasmatic nuclei of the hypothalamus. This system keeps track of the external world rhythms through entrainment by various time cues, such as the light-dark cycle and the feeding schedule. Alterations of photoperiod and meal time modulate the phase coupling between central and peripheral oscillators. In this study, we used real-time quantitative PCR to assess circadian clock gene expression in the liver and pituitary gland from mice raised under various photoperiods, or under a temporal restricted feeding protocol. Our results revealed unexpected differences between both organs. Whereas the liver oscillator always tracked meal time, the pituitary circadian clockwork showed an intermediate response, in between entrainment by the light regimen and the feeding-fasting rhythm. The same composite response was also observed in the pituitary gland from adrenalectomized mice under daytime restricted feeding, suggesting that circulating glucocorticoids do not inhibit full entrainment of the pituitary clockwork by meal time. Altogether our results reveal further aspects in the complexity of phase entrainment in the circadian system, and suggest that the pituitary may host oscillators able to integrate multiple time cues.