Focal cortical dysplasia (FCD) is often characterized by minor structural changes that may go unrecognized by standard radiological analysis. Visual assessment of morphological characteristics of FCD ...and sulci harbouring them is difficult due to the complexity of brain convolutions. Our purpose was to elucidate and quantify the spatial relationship between FCD lesions and brain sulci using automated sulcal extraction and morphometry. We studied 43 consecutive FCD patients using high-resolution MRI. Lesions were classified into small and large using qualitative (detection on initial clinical assessment of conventional MRI) and quantitative (volume) criteria. Sulci were identified and labelled automatically using an algorithm based on a congregation of neural networks. Segmented FCD lesions and sulci were then simultaneously visualized in 3D. We measured mean and maximum depth of sulci related to each FCD and of the corresponding sulci in 21 healthy controls. In addition, we calculated sulcal depth within the FCD neighbourhood. Twenty-one (21/43 = 49%) patients had small FCD lesions (volume range: 128–3093 mm3). Among them, 17 (81%) had been overlooked during initial radiological evaluation and were subsequently identified using image processing. Eighteen (18/21 = 86%) small FCD lesions were located at the bottom of a sulcus. Two others were related to the walls of two sulci and one was located at the crown of a gyrus. Mean and maximum depth of sulci related to the FCD was higher than that of the corresponding sulci in controls (P < 0.008). Sulcal depth within lesional neighbourhood had larger mean depth than that of the entire sulcus (P < 0.0002). Evidence that small FCD lesions are preferentially located at the bottom of an abnormally deep sulcus may be used to direct the search for developmental abnormalities, particularly in patients in whom large-scale MRI features are only mildly abnormal or absent.
Our knowledge on temporal lobe epilepsy (TLE) with hippocampal sclerosis has evolved towards the view that this syndrome affects widespread brain networks. Diffusion weighted imaging studies have ...shown alterations of large white matter tracts, most notably in left temporal lobe epilepsy, but the degree of altered connections between cortical and subcortical structures remains to be clarified. We performed a whole brain connectome analysis in 39 patients with refractory temporal lobe epilepsy and unilateral hippocampal sclerosis (20 right and 19 left) and 28 healthy subjects. We performed whole-brain probabilistic fiber tracking using MRtrix and segmented 164 cortical and subcortical structures with Freesurfer. Individual structural connectivity graphs based on these 164 nodes were computed by mapping the mean fractional anisotropy (FA) onto each tract. Connectomes were then compared using two complementary methods: permutation tests for pair-wise connections and Network Based Statistics to probe for differences in large network components. Comparison of pair-wise connections revealed a marked reduction of connectivity between left TLE patients and controls, which was strongly lateralized to the ipsilateral temporal lobe. Specifically, infero-lateral cortex and temporal pole were strongly affected, and so was the perisylvian cortex. In contrast, for right TLE, focal connectivity loss was much less pronounced and restricted to bilateral limbic structures and right temporal cortex. Analysis of large network components revealed furthermore that both left and right hippocampal sclerosis affected diffuse global and interhemispheric connectivity. Thus, left temporal lobe epilepsy was associated with a much more pronounced pattern of reduced FA, that included major landmarks of perisylvian language circuitry. These distinct patterns of connectivity associated with unilateral hippocampal sclerosis show how a focal pathology influences global network architecture, and how left or right-sided lesions may have differential and specific impacts on cerebral connectivity.
•We computed the structural network of 39 temporal lobe epilepsy (TLE) patients.•Two strategies, pairwise connection analysis and network based statistics, were used.•Widespread disconnections were found in TLE patients with respect to controls.•Left TLE patients were much more affected than right TLE patients.•Left TLE showed a strongly lateralized fronto-temporal disconnection pattern.
High-definition transcranial direct current stimulation (HD-tDCS) using a 4 × 1 electrode montage has been previously shown using modeling and physiological studies to constrain the electric field ...within the spatial extent of the electrodes. The aim of this proof-of-concept study was to determine if functional near-infrared spectroscopy (fNIRS) neuroimaging can be used to determine a hemodynamic correlate of this 4 × 1 HD-tDCS electric field on the brain.
In a three session cross-over study design, 13 healthy males received one sham (2 mA, 30 sec) and two real (HD-tDCS-1 and HD-tDCS-2, 2 mA, 10 min) anodal HD-tDCS targeting the left M1 via a 4 × 1 electrode montage (anode on C3 and 4 return electrodes 3.5 cm from anode). The two real HD-tDCS sessions afforded a within-subject replication of the findings. fNIRS was used to measure changes in brain hemodynamics (oxygenated hemoglobin integral-O
Hb
) during each 10 min session from two regions of interest (ROIs) in the stimulated left hemisphere that corresponded to "within" (L
) and "outside" (L
) the spatial extent of the 4 × 1 electrode montage, and two corresponding ROIs (R
and R
) in the right hemisphere.
The ANOVA showed that both real anodal HD-tDCS compared to sham induced a significantly greater O
Hb
in the L
than L
ROIs of the stimulated left hemisphere; while there were no significant differences between the real and sham sessions for the right hemisphere ROIs. Intra-class correlation coefficients showed "fair-to-good" reproducibility for the left stimulated hemisphere ROIs.
The greater O
Hb
"within" than "outside" the spatial extent of the 4 × 1 electrode montage represents a hemodynamic correlate of the electrical field distribution, and thus provides a prospective reliable method to determine the dose of stimulation that is necessary to optimize HD-tDCS parameters in various applications.
The SK3 channel, a potassium channel, was recently shown to control cancer cell migration, a critical step in metastasis outgrowth. Here, we report that expression of the SK3 channel was markedly ...associated with bone metastasis. The SK3 channel was shown to control constitutive Ca(2+) entry and cancer cell migration through an interaction with the Ca(2+) channel Orai1. We found that the SK3 channel triggers an association with the Orai1 channel within lipid rafts. This localization of an SK3-Orai1 complex seemed essential to control cancer cell migration. This suggests that the formation of this complex in lipid rafts is a gain-of-function, because we showed that none of the individual proteins were able to promote the complete phenotype. We identified the alkyl-lipid Ohmline as a disrupting agent for SK3-Orai1 lipid raft localization. Upon Ohmline treatment, the SK3-Orai1 complex moved away from lipid rafts, and SK3-dependent Ca(2+) entry, migration, and bone metastases were subsequently impaired. The colocalization of SK3 and Orai1 in primary human tumors and bone metastases further emphasized the clinical relevance of our observations. Targeting SK3-Orai1 in lipid rafts may inaugurate innovative approaches to inhibit bone metastases.
Quantitative MRI techniques have the potential to characterize spinal cord tissue impairments occurring in various pathologies, from both microstructural and functional perspectives. By enabling very ...high image resolution and enhanced tissue contrast, ultra-high field imaging may offer further opportunities for such characterization. In this study, a multi-parametric high-resolution quantitative MRI protocol is proposed to characterize in vivo the human cervical spinal cord at 7T. Multi-parametric quantitative MRI acquizitions including T1, T2* relaxometry mapping and axial diffusion MRI were performed on ten healthy volunteers with a whole-body 7T system using a commercial prototype coil-array dedicated to cervical spinal cord imaging. Automatic cord segmentation and multi-parametric data registration to spinal cord templates enabled robust regional studies within atlas-based WM tracts and GM horns at the C3 cervical level. T1 value, cross-sectional area and GM/WM ratio evolutions along the cervical cord were also reported. An original correction method for B1+-biased T1 mapping sequence was additionally proposed and validated on phantom. As a result, relaxometry and diffusion parameters derived from high-resolution quantitative MRI acquizitions were reported at 7T for the first time. Obtained images, with unmatched resolutions compared to lower field investigations, provided exquisite anatomical details and clear delineation of the spinal cord substructures within an acquisition time of 30min, compatible with clinical investigations. Regional statistically significant differences were highlighted between WM and GM based on T1 and T2* maps (p<10−3), as well as between sensory and motor tracts based on diffusion tensor imaging maps (p<0.05). The proposed protocol demonstrates that ultra-high field spinal cord high-resolution quantitative MRI is feasible and lays the groundwork for future clinical investigations of degenerative spinal cord pathologies.
Display omitted
•Sub-millimetric anatomical and structural characterization of the cervical spinal cord at 7T.•Acquisitions of spinal cord T1-w and T2*-w images with high white and gray matter contrast.•Robust and fast T1 relaxometry mapping of the cervical WM and GM at 7T.•Robust diffusion tensor imaging quantification of the spinal cord GM/WM sub-regions at 7T.•First use of automatic processing tools for GM/WM segmentation of 7T images.
Abstract
Loss of epithelial polarity and gain in invasiveness by carcinoma cells are critical events in the aggressive progression of cancers and depend on phenotypic transition programs such as the ...epithelial-to-mesenchymal transition (EMT). Many studies have reported the aberrant expression of voltage-gated sodium channels (Na
V
) in carcinomas and specifically the Na
V
1.5 isoform, encoded by the
SCN5A
gene, in breast cancer. Na
V
1.5 activity, through an entry of sodium ions, in breast cancer cells is associated with increased invasiveness, but its participation to the EMT has to be clarified. In this study, we show that reducing the expression of Na
V
1.5 in highly aggressive human MDA-MB-231 breast cancer cells reverted the mesenchymal phenotype, reduced cancer cell invasiveness and the expression of the EMT-promoting transcription factor
SNAI1
. The heterologous expression of Na
V
1.5 in weakly invasive MCF-7 breast cancer cells induced their expression of both
SNAI1
and
ZEB1
and increased their invasive capacities. In MCF-7 cells the stimulation with the EMT-activator signal TGF-β1 increased the expression of
SCN5A
. Moreover, the reduction of the salt-inducible kinase 1 (SIK1) expression promoted Na
V
1.5-dependent invasiveness and expression of EMT-associated transcription factor SNAI1. Altogether, these results indicated a prominent role of SIK1 in regulating Na
V
1.5-dependent EMT and invasiveness.
Transcranial direct current stimulation (tDCS) is a non-invasive electrical brain stimulation technique that can modulate cortical neuronal excitability and activity. This study utilized functional ...near infrared spectroscopy (fNIRS) neuroimaging to determine the effects of anodal high-definition (HD)-tDCS on bilateral sensorimotor cortex (SMC) activation. Before (Pre), during (Online), and after (Offline) anodal HD-tDCS (2 mA, 20 min) targeting the left SMC, eight healthy subjects performed a simple finger sequence (SFS) task with their right or left hand in an alternating blocked design (30-s rest and 30-s SFS task, repeated five times). In order to determine the level of bilateral SMC activation during the SFS task, an Oxymon MkIII fNIRS system was used to measure from the left and right SMC, changes in oxygenated (O2Hb) and deoxygenated (HHb) haemoglobin concentration values. The fNIRS data suggests a finding that compared to the Pre condition both the "Online" and "Offline" anodal HD-tDCS conditions induced a significant reduction in bilateral SMC activation (i.e., smaller decrease in HHb) for a similar motor output (i.e., SFS tap rate). These findings could be related to anodal HD-tDCS inducing a greater efficiency of neuronal transmission in the bilateral SMC to perform the same SFS task.
The relationship of human brain structure to cognitive function is complex, and how this relationship differs between childhood and adulthood is poorly understood. One strong hypothesis suggests the ...cognitive function of Fluid Intelligence (Gf) is dependent on prefrontal cortex and parietal cortex. In this work, we developed a novel graph convolutional neural networks (gCNNs) for the analysis of localized anatomic shape and prediction of Gf. Morphologic information of the cortical ribbons and subcortical structures was extracted from T1-weighted MRIs within two independent cohorts, the Adolescent Brain Cognitive Development Study (ABCD; age: 9.93 ± 0.62 years) of children and the Human Connectome Project (HCP; age: 28.81 ± 3.70 years). Prediction combining cortical and subcortical surfaces together yielded the highest accuracy of Gf for both ABCD (R = 0.314) and HCP datasets (R = 0.454), outperforming the state-of-the-art prediction of Gf from any other brain measures in the literature. Across both datasets, the morphology of the amygdala, hippocampus, and nucleus accumbens, along with temporal, parietal and cingulate cortex consistently drove the prediction of Gf, suggesting a significant reframing of the relationship between brain morphology and Gf to include systems involved with reward/aversion processing, judgment and decision-making, motivation, and emotion.
Voltage-gated sodium channels (NaV) are functionally expressed in highly metastatic cancer cells derived from nonexcitable epithelial tissues (breast, prostate, lung, and cervix). MDA-MB-231 breast ...cancer cells express functional sodium channel complexes, consisting of NaV1.5 and associated auxiliary β-subunits, that are responsible for a sustained inward sodium current at the membrane potential. Although these channels do not regulate cellular multiplication or migration, their inhibition by the specific blocker tetrodotoxin impairs both the extracellular gelatinolytic activity (monitored with DQ-gelatin) and cell invasiveness leading to the attenuation of colony growth and cell spreading in three-dimensional Matrigel®-composed matrices. MDA-MB-231 cells express functional cysteine cathepsins, which we found play a predominant role (∼65%) in cancer invasiveness. Matrigel® invasion is significantly decreased in the presence of specific inhibitors of cathepsins B and S (CA-074 and Z-FL-COCHO, respectively), and co-application of tetrodotoxin does not further reduce cell invasion. This suggests that cathepsins B and S are involved in invasiveness and that their proteolytic activity partly depends on NaV function. Inhibiting NaV has no consequence for cathepsins at the transcription, translation, and secretion levels. However, NaV activity leads to an intracellular alkalinization and a perimembrane acidification favorable for the extracellular activity of these acidic proteases. We propose that Nav enhance the invasiveness of cancer cells by favoring the pH-dependent activity of cysteine cathepsins. This general mechanism could lead to the identification of new targets allowing the therapeutic prevention of metastases.
Interest for neuromodulation, and transcranial random noise stimulation (tRNS) in particular, is growing. It concerns patients rehabilitation, but also healthy people who want or need to improve ...their cognitive and learning abilities. However, there is no consensus yet regarding the efficacy of tRNS on learning and performing a complex task. In particular, the most effective electrode montage is yet to be determined. Here, we examined the effect of two different tRNS montages on learning rate, short- and long-term performance in a video game (Space Fortress) that engages multiple cognitive abilities. Sixty-one participants were randomly assigned to one of three groups (sham vs. simple-definition tRNS vs. high-definition tRNS) in a double-blind protocol. Their performance on the Space Fortress task was monitored during a 15-day experiment with baseline (day 1), stimulation (day 2 to 4), short- (day 5) and long-term (day 15) evaluations. Our results show that the high-definition tRNS group improved more on the long term than simple-definition tRNS group, tended to learn faster and had better performance retention compared to both simple-definition tRNS and sham groups. This study is the first to report that high-definition tRNS is more effective than conventional simple-definition tRNS to enhance performance in a complex task.
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