Search

Contains fulltext : 169032.pdf (Publisher’s version ) (Closed access) The right dorsal premotor cortex (PMd) of humans has been reported to be involved in a broad range of motor and cognitive functions. We explored the basis of this behavioral heterogeneity by performing a connectivity-based parcellation using meta-analytic approach applied to PMd coactivations. We compared our connectivity-based parcellation results with parcellations obtained through resting-state functional connectivity and probabilistic diffusion tractography. Functional connectivity profiles and behavioral decoding of the resulting PMd subregions allowed characterizing their respective behavior profile. These procedures divided the right PMd into 5 distinct subregions that formed a cognitive-motor gradient along a rostro-caudal axis. In particular, we found 1) a rostral subregion functionally connected with prefrontal cortex, which likely supports high-level cognitive processes, such as working memory, 2) a central subregion showing a mixed behavioral profile and functional connectivity to parietal regions of the dorsal attention network, and 3) a caudal subregion closely integrated with the motor system. Additionally, we found 4) a dorsal subregion, preferentially related to hand movements and connected to both cognitive and motor regions, and 5) a ventral subregion, whose functional profile fits the concept of an eye movement-related field. In conclusion, right PMd may be considered as a functional mosaic formed by 5 subregions. 16 p.

Item does not contain fulltext Previous studies have shown that males and females differ in personality and gender differences have also been reported in brain structure. However, effects of gender on this "personality-brain" relationship are yet unknown. We therefore investigated if the neural correlates of personality differ between males and females. Whole brain voxel-based morphometry was used to investigate the influence of gender on associations between NEO FFI personality traits and gray matter volume (GMV) in a matched sample of 182 males and 182 females. In order to assess associations independent of and dependent on gender, personality-GMV relationships were tested across the entire sample and separately for males and females. There were no significant correlations between any personality scale and GMV in the analyses across the entire sample. In contrast, significant associations with GMV were detected for neuroticism, extraversion, and conscientiousness only in males. Interestingly, GMV in left precuneus/parieto-occipital sulcus correlated with all 3 traits. Thus, our results indicate that brain structure-personality relationships are highly dependent on gender, which might be attributable to hormonal interplays or differences in brain organization between males and females. Our results thus provide possible neural substrates of personality-behavior relationships and underline the important role of gender in these associations. 15 p.

The mammalian epididymis is an exceptionally long ductal system tasked with the provision of one of the most complex intraluminal fluids found in any exocrine gland. This specialized milieu is continuously modified by the combined secretory and absorptive of the surrounding epithelium and thus finely tuned for its essential roles in promoting sperm maturation and storage. While considerable effort has been focused on defining the composition of the epididymal fluid, relatively less is known about the intracellular trafficking machinery that regulates this luminal environment. Here, we characterize the ontogeny of expression of a master regulator of this machinery, the dynamin family of mechanoenzymes. Our data show that canonical dynamin isoforms were abundantly expressed in the juvenile mouse epididymis. However, in peripubertal and adult animals dynamin takes on a heterogeneous pattern of expression such that the different isoforms displayed both cell- and segment-specific localization. Thus, dynamin 1 and 3 were predominately localized in the distal epididymal segments (corpus and cauda), where they were found within clear and principal cells, respectively. In contrast, dynamin 2 was expressed throughout the epididymis, but localized to the Golgi apparatus of the principal cells in the proximal (caput) segment and the luminal border of these cells in more distal segments. These dynamin isoforms are therefore ideally positioned to play complementary, nonredundant roles in the regulation of the epididymal milieu. In support of this hypothesis, selective inhibition of dynamin altered the profile of proteins secreted from an immortalized caput epididymal cell line.

Mammalian spermatozoa must complete an acrosome reaction prior to fertilizing an oocyte. The acrosome reaction is a unique exocytotic event involving a series of prolonged membrane fusions that ultimately result in the production of membrane vesicles and release of the acrosomal contents. This event requires the concerted action of a large number of fusion-competent signaling and scaffolding proteins. Here we show that two different members of the dynamin GTPase family localize to the developing acrosome of maturing mouse germ cells. Both dynamin 1 and 2 also remain within the periacrosomal region of mature mouse spermatozoa and are thus well positioned to regulate the acrosome reaction. Two pharmacological inhibitors of dynamin, dynasore and Dyngo-4a, blocked the in vitro induction of acrosomal exocytosis by progesterone, but not by the calcium ionophore A23187, and elicited a concomitant reduction of in vitro fertilization. In vivo treatment with these inhibitors also resulted in spermatozoa displaying reduced acrosome reaction potential. Dynamin 1 and 2 phosphorylation increased on progesterone treatment, and this was also selectively blocked by dynasore. On the basis of our collective data, we propose that dynamin could regulate specific membrane fusion events necessary for acrosomal exocytosis in mouse spermatozoa.

The mammalian epididymis is an exceptionally long ductal system tasked with the provision of one of the most complex intraluminal fluids found in any exocrine gland. This specialized milieu is continuously modified by the combined secretory and absorptive of the surrounding epithelium and thus finely tuned for its essential roles in promoting sperm maturation and storage. While considerable effort has been focused on defining the composition of the epididymal fluid, relatively less is known about the intracellular trafficking machinery that regulates this luminal environment. Here, we characterize the ontogeny of expression of a master regulator of this machinery, the dynamin family of mechanoenzymes. Our data show that canonical dynamin isoforms were abundantly expressed in the juvenile mouse epididymis. However, in peripubertal and adult animals dynamin takes on a heterogeneous pattern of expression such that the different isoforms displayed both cell- and segment-specific localization. Thus, dynamin 1 and 3 were predominately localized in the distal epididymal segments (corpus and cauda), where they were found within clear and principal cells, respectively. In contrast, dynamin 2 was expressed throughout the epididymis, but localized to the Golgi apparatus of the principal cells in the proximal (caput) segment and the luminal border of these cells in more distal segments. These dynamin isoforms are therefore ideally positioned to play complementary, nonredundant roles in the regulation of the epididymal milieu. In support of this hypothesis, selective inhibition of dynamin altered the profile of proteins secreted from an immortalized caput epididymal cell line.

Contains fulltext : 157557.pdf (Publisher’s version ) (Open Access) The organization in brain networks shows highly modular features with weak inter-modular interaction. The topology of the networks involves emergence of modules and sub-modules at different levels of constitution governed by fractal laws that are signatures of self-organization in complex networks. The modular organization, in terms of modular mass, inter-modular, and intra-modular interaction, also obeys fractal nature. The parameters which characterize topological properties of brain networks follow one parameter scaling theory in all levels of network structure, which reveals the self-similar rules governing the network structure. Further, the calculated fractal dimensions of brain networks of different species are found to decrease when one goes from lower to higher level species which implicates the more ordered and self-organized topography at higher level species. The sparsely distributed hubs in brain networks may be most influencing nodes but their absence may not cause network breakdown, and centrality parameters characterizing them also follow one parameter scaling law indicating self-similar roles of these hubs at different levels of organization in brain networks. The local-community-paradigm decomposition plot and calculated local-community-paradigm-correlation co-efficient of brain networks also shows the evidence for self-organization in these networks. 19 p.

Item does not contain fulltext Social cognition and language are two core features of the human species. Despite distributed recruitment of brain regions in each mental capacity, the left parietal lobe (LPL) represents a zone of topographical convergence. This study quantitatively summarizes previous neuroimaging studies on social cognition and language. Using connectivity-based parcellation on a meta-analytically defined volume of interest (VOI), regional coactivation patterns within this VOI allowed for the identiHcation of functionally distinct subregions. Across parcellation solutions, two clusters emerged consistently in rostro-ventral and caudo-ventral aspects of the parietal VOI. Both clusters were functionally signiHcantly associated with social-cognitive and language processing. In particular, the rostra-ventral cluster was associated with lower-level processing facets, while the caudo-ventral cluster was associated with higher-level processes across both functions. Contrarily, in the (less stable) dorsal parietal VOI, all clusters reKected computation of general-purpose processes, including working memory and matching tasks, that are frequently co-recruited by social or language processes. Our results hence favor a rostro-caudal distinction of low- vs. high-level processes underlying social cognition and language in the left inferior parietal lobe. 16 p.

Item does not contain fulltext Verbal and non-verbal intelligence in children is highly correlated, and thus, it has been difficult to differentiate their neural substrates. Nevertheless, recent studies have shown that verbal and non-verbal intelligence can be dissociated and focal cortical regions corresponding to each have been demonstrated. However, the pattern of structural covariance corresponding to verbal and non-verbal intelligence remains unexplored. In this study, we used 586 longitudinal anatomical MRI scans of subjects aged 6-18 years, who had concurrent intelligence quotient (IQ) testing on the Wechsler Abbreviated Scale of Intelligence. Structural covariance networks (SCNs) were constructed using interregional correlations in cortical thickness for low-IQ (Performance IQ=100±8, Verbal IQ=100±7) and high-IQ (PIQ=121±8, VIQ=120±9) groups. From low- to high-VIQ group, we observed constrained patterns of anatomical coupling among cortical regions, complemented by observations of higher global efficiency and modularity, and lower local efficiency in high-VIQ group, suggesting a shift towards a more optimal topological organization. Analysis of nodal topological properties (regional efficiency and participation coefficient) revealed greater involvement of left-hemispheric language related regions including inferior frontal and superior temporal gyri for high-VIQ group. From low- to high-PIQ group, we did not observe significant differences in anatomical coupling patterns, global and nodal topological properties. Our findings indicate that people with higher verbal intelligence have structural brain differences from people with lower verbal intelligence - not only in localized cortical regions, but also in the patterns of anatomical coupling among widely distributed cortical regions, possibly resulting to a system-level reorganization that might lead to a more efficient organization in high-VIQ group. 14 p.

Contains fulltext : 168981.pdf (Publisher’s version ) (Closed access) Resting-state functional connectivity analysis has become a widely used method for the investigation of human brain connectivity and pathology. The measurement of neuronal activity by functional MRI, however, is impeded by various nuisance signals that reduce the stability of functional connectivity. Several methods exist to address this predicament, but little consensus has yet been reached on the most appropriate approach. Given the crucial importance of reliability for the development of clinical applications, we here investigated the effect of various confound removal approaches on the test-retest reliability of functional-connectivity estimates in two previously defined functional brain networks. Our results showed that gray matter masking improved the reliability of connectivity estimates, whereas denoising based on principal components analysis reduced it. We additionally observed that refraining from using any correction for global signals provided the best test–retest reliability, but failed to reproduce anti-correlations between what have been previously described as antagonistic networks. This suggests that improved reliability can come at the expense of potentially poorer biological validity. Consistent with this, we observed that reliability was proportional to the retained variance, which presumably included structured noise, such as reliable nuisance signals (for instance, noise induced by cardiac processes). We conclude that compromises are necessary between maximizing test-retest reliability and removing variance that may be attributable to non-neuronal sources. 22 p.

Contains fulltext : 157552.pdf (Publisher’s version ) (Closed access) In systems neuroscience, the term "connectivity" has been defined in numerous ways, according to the particular empirical modality from which it is derived. Due to large differences in the phenomena measured by these modalities, the assumptions necessary to make inferences about axonal connections, and the limitations accompanying each, brain connectivity remains an elusive concept. Despite this, only a handful of studies have directly compared connectivity as inferred from multiple modalities, and there remains much ambiguity over what the term is actually referring to as a biological construct. Here, we perform a direct comparison based on the high-resolution and high-contrast Enhanced Nathan Klein Institute (NKI) Rockland Sample neuroimaging data set, and the CoCoMac database of tract tracing studies. We compare four types of commonly-used primate connectivity analyses: tract tracing experiments, compiled in CoCoMac; group-wise correlation of cortical thickness; tractographic networks computed from diffusion-weighted MRI (DWI); and correlational networks obtained from resting-state BOLD (fMRI). We find generally poor correspondence between all four modalities, in terms of correlated edge weights, binarized comparisons of thresholded networks, and clustering patterns. fMRI and DWI had the best agreement, followed by DWI and CoCoMac, while other comparisons showed striking divergence. Networks had the best correspondence for local ipsilateral and homotopic contralateral connections, and the worst correspondence for long-range and heterotopic contralateral connections. k-Means clustering highlighted the lowest cross-modal and cross-species consensus in lateral and medial temporal lobes, anterior cingulate, and the temporoparietal junction. Comparing the NKI results to those of the lower resolution/contrast International Consortium for Brain Imaging (ICBM) dataset, we find that the relative pattern of intermodal relationships is preserved, but the correspondence between human imaging connectomes is substantially better for NKI. These findings caution against using "connectivity" as an umbrella term for results derived from single empirical modalities, and suggest that any interpretation of these results should account for (and ideally help explain) the lack of multimodal correspondence. 21 p.

Item does not contain fulltext Recently, we functionally characterized five right dorsal premotor (PMdr) subregions (identified by coactivation based parcellation) by quantitative forward and reverse inference based on a wide range of task-based activation studies (Genon et al, in prep.). We found that the rostral subregion was associated to high-level cognitive tasks, the caudal one to motor functions, the dorsal one to hand-movements, the ventral one to visual functions while the central one showed a heterogeneous profile. Here, we aimed to reinforce and complement this characterization by using correlations between brain morphology and standard neuropsychological tests in two independent large datasets, which were matched for age, gender, education, depression and handedness (Forschungszentrum Jülich [FZJ, n=87, age range: 21-71] and Nathan Kline Institute [NKI; 135: 20-75]). T1 images were processed with the VBM8 toolbox (Friston using linear and non-linear modulation). The five PMdr subregions were used as regions of interest (ROIs), from which regional gray matter volume (GMV) was extracted. We performed partial correlations to examine correlation between each ROI GMV and neuropsychological test performance when controlling for confounding effects of age, education and handedness. To further examine the reliability of correlation, we also performed the analyses in 1000 subsamples of 30 randomly selected subjects within each sample individually. Our analyses yielded generally low correlation coefficients of which only few were statistically significant even at a lenient threshold of p < .05, uncorrected for multiple testing. Notably, a considerable number of correlations showed an inverse relationship between test performance and brain structure, i.e., higher performance was associated with lower GMV. In addition, the patterns of correlations were inconsistent across samples in magnitude, significance and direction. Finally, subsampling revealed that the pattern of correlations that could be observed varied widely when analyses were based on randomly drawn small samples. Our correlational approach, relating GMV and performance across a wide range of standard neuropsychological tests in two large population-based samples did not corroborate the profiles previously revealed using functional decoding based on fMRI-activations. On the one hand, these findings suggest that the functional specialization of some cortical regions, as highlighted by fMRI studies, does not necessarily imply a significant covariance of their actual structure with related standard task performance across individuals in the healthy population. That is, a cognitive-morphologic approach based on healthy interindividual differences may not mirror functional characterization revealed by activation studies in some brain regions. On the other hand, the fact that we found (all kinds of) significant associations in the smaller, randomly assembled subsamples also highlights the high likelihood of spurious findings when performing such correlation analyses in small samples as prevalent in current neuroimaging studies. 2 p.

Item does not contain fulltext Meta-analytic techniques allow cognitive neuroscientists to pool large amounts of data across many individual task-based functional neuroimaging experiments. These methods have been aided by the introduction of online databases such as Brainmap.org or Neurosynth.org, which collate peak activation coordinates obtained from thousands of published studies. Findings from meta-analytic studies typically include brain regions which are consistently activated across studies for specific contrasts, investigating cognitive or clinical hypotheses. These regions can be subsequently used as the basis for seed-based connectivity analysis, or formally compared to neuroimaging data in order to help interpret new findings. To facilitate such approaches, we have developed a new online repository of meta-analytic neuroimaging results, named the Archive of Neuroimaging Meta-analyses (ANIMA). The ANIMA platform consists of an intuitive online interface for querying, downloading, and contributing data from published meta-analytic studies. Additionally, to aid the process of organizing, visualizing, and working with these data, we present an open-source desktop application called Volume Viewer. Volume Viewer allows users to easily arrange imaging data into composite stacks, and save these sessions as individual files, which can also be uploaded to the ANIMA database. The application also allows users to perform basic functions, such as computing conjunctions between images, or extracting regions-of-interest or peak coordinates for further analysis. The introduction of this new resource will enhance the ability of researchers to both share their findings and incorporate existing meta-analytic results into their own research. 2 p.

Item does not contain fulltext Little is known about how several functions are organized or how putative subregions are coupled with wider brain networks in the human right PMd. To address these issues, we performed connectivity-based parcellation (CBP) based on PMd voxels' coactivations yielded by meta-analytic connectivity modeling (MACM). We additionally search for a similar cluster solution with CBP based on resting-state functional connectivity (RSFC) and probabilistic diffusion tractography. MACM and RSFC assessed FC of the MACM-CBP-derived subregions while functional characterization revealed their behavioral associations. This procedure showed that the right PMd could be divided into five distinct clusters highlighting a cognitive-motor gradient along a rostro-caudal axis including a rostral cluster functionally interacting with prefrontal cortex in supporting high-level cognitive processes and a caudal cluster closely integrated with the motor system. MACM-CBP also revealed a ventral cluster, whose functional profile fits the concept of an eye field, and a dorsal cluster, preferentially hand-related and connected to both cognitive and motor regions. Finally, MACM-CBP yielded a central cluster showing a mixed behavioral profile and FC to parietal regions of the dorsal attention network. Thus, our results showed that the right PMd may be considered as a functional mosaic formed by five subregions. 1 p.

Contains fulltext : 157740.pdf (Publisher’s version ) (Closed access) Working memory is essential for many of our distinctly human abilities, including reasoning, problem solving, and planning. Research spanning many decades has helped to refine our understanding of this high-level function as comprising several hierarchically organized components, some which maintain information in the conscious mind, and others which manipulate and reorganize this information in useful ways. In the neocortex, these processes are likely implemented by a distributed frontoparietal network, with more posterior regions serving to maintain volatile information, and more anterior regions subserving the manipulation of this information. Recent meta-analytic findings have identified the anterior lateral prefrontal cortex, in particular, as being generally engaged by working memory tasks, while the posterior lateral prefrontal cortex was more strongly associated with the cognitive load required by these tasks. These findings suggest specific roles for these regions in the cognitive control processes underlying working memory. To further characterize these regions, we applied three distinct seed-based methods for determining cortical connectivity. Specifically, we employed meta-analytic connectivity mapping across task-based fMRI experiments, resting-state BOLD correlations, and VBM-based structural covariance. We found a frontoparietal pattern of convergence which strongly resembled the working memory networks identified in previous research. A contrast between anterior and posterior parts of the lateral prefrontal cortex revealed distinct connectivity patterns consistent with the idea of a hierarchical organization of frontoparietal networks. Moreover, we found a distributed network that was anticorrelated with the anterior seed region, which included most of the default mode network and a subcomponent related to social and emotional processing. These findings fit well with the internal attention model of working memory, in which representation of information is processed according to an anteroposterior gradient of abstract-to-concrete representations. 17 p.

Contains fulltext : 110720.pdf (Publisher’s version ) (Closed access) Although gait disturbances are present in a substantial portion of patients with cerebral small vessel disease (SVD), their pathogenesis has not been clarified as they are not entirely explained by the white matter lesions (WMLs) and lacunar infarcts. The role of cortical thickness in these patients remains largely unknown. We aimed to assess the regions of cortical thickness associated with distinct gait parameters in patients with SVD, and whether these associations were dependent on WMLs and lacunar infarcts. MRI data were obtained from 415 subjects with SVD, aged between 50 and 85 years. We assessed cortical thickness using surface-based cortical thickness analysis, and gait performance using the GAITRite system. Cortical thickness of predominantly the orbitofrontal and ventrolateral prefrontal cortex, the inferior parietal lobe, cingulate areas and visual association cortices was positively related to stride length. Thickness of the primary and supplementary motor cortices and the cingulate cortex was positively related to cadence, while thickness of the orbitofrontal and ventrolateral prefrontal cortex, anterior cingulate cortex and especially the inferior parietal lobe and superior temporal gyrus was negatively related to stride width. The associations with stride length and width were partially explained by the subcortical WMLs and lacunar infarcts. Cortical thickness may therefore be important in gait disturbances in individuals with SVD, with different cortical patterns for specific gait parameters. We suggest that cortical atrophy is part of the disease processes in patients with SVD. 7 p.

Contains fulltext : 96474.pdf (Publisher’s version ) (Closed access) Brain activity can be measured with several non-invasive neuroimaging modalities, but each modality has inherent limitations with respect to resolution, contrast and interpretability. It is hoped that multimodal integration will address these limitations by using the complementary features of already available data. However, purely statistical integration can prove problematic owing to the disparate signal sources. As an alternative, we propose here an advanced neural population model implemented on an anatomically sound cortical mesh with freely adjustable connectivity, which features proper signal expression through a realistic head model for the electroencephalogram (EEG), as well as a haemodynamic model for functional magnetic resonance imaging based on blood oxygen level dependent contrast (fMRI BOLD). It hence allows simultaneous and realistic predictions of EEG and fMRI BOLD from the same underlying model of neural activity. As proof of principle, we investigate here the influence on simulated brain activity of strengthening visual connectivity. In the future we plan to fit multimodal data with this neural population model. This promises novel, model-based insights into the brain's activity in sleep, rest and task conditions.

For mammalian spermatozoa to exhibit the ability to bind the zona pellucida (ZP) they must undergo three distinct phases of maturation, namely, spermatogenesis (testis), epididymal maturation (epididymis) and capacitation (female reproductive tract). An impressive array of spermatozoa surface remodeling events accompany these phases of maturation and appear critical for recognition and adhesion of the outer vestments of the oocyte, a structure known as the ZP. It is becoming increasingly apparent that species-specific zona adhesion is not mediated by a single receptor. Instead, compelling evidence now points toward models implicating a multiplicity of receptor–ligand interactions. This notion is in keeping with emerging research that has shown that there is a dynamic aggregation of proteins believed to be important in sperm–ZP recognition to the regions of sperm that mediate this binding event. Such remodeling may in turn facilitate the assembly of a multimeric zona recognition complex (MZRC). Though formation of MZRCs raises questions regarding the nature of the block to polyspermy, formation and assembly of such a structure would no doubt explain the strenuous maturation process that sperm endure on their sojourn to functional maturity.

Contains fulltext : 89286reid.pdf (Publisher’s version ) (Closed access) Progress in functional neuroimaging of the brain increasingly relies on the integration of data from complementary imaging modalities in order to improve spatiotemporal resolution and interpretability. However, the usefulness of merely statistical combinations is limited, since neural signal sources differ between modalities and are related non-trivially. We demonstrate here that a mean field model of brain activity can simultaneously predict EEG and fMRI BOLD with proper signal generation and expression. Simulations are shown using a realistic head model based on structural MRI, which includes both dense short-range background connectivity and long-range specific connectivity between brain regions. The distribution of modeled neural masses is comparable to the spatial resolution of fMRI BOLD, and the temporal resolution of the modeled dynamics, importantly including activity conduction, matches the fastest known EEG phenomena. The creation of a cortical mean field model with anatomically sound geometry, extensive connectivity, and proper signal expression is an important first step towards the model-based integration of multimodal neuroimages. 01 juni 2010

Background and Purpose— White matter hyperintensities (WMH) are associated with clinically heterogeneous symptoms that cannot be explained by these lesions alone. It is hypothesized that these lesions are associated with distant cortical atrophy and cortical thickness network measures, which can result in an additional cognitive impairment. Here, we investigated the relationships between WMH, cortical thickness, and cognition in subjects with cerebral small vessel disease. Methods— A total of 426 subjects with cerebral small vessel disease were included, aged between 50 and 85 years, without dementia, and underwent MRI scanning. Cortical thickness analysis was performed, and WMH were manually segmented. Graph theory was applied to examine the relationship between network measures and WMH, and structural covariance matrices were constructed using inter-regional cortical thickness correlations. Results— Higher WMH load was related to lower cortical thickness in frontotemporal regions, whereas in paracentral regions, this was related to higher cortical thickness. Network analyses revealed that measures of network disruption were associated with WMH and cognitive performance. Furthermore, WMH in specific white matter tracts were related to regional-specific cortical thickness and network measures. Cognitive performances were related to cortical thickness in frontotemporal regions and network measures, and not to WMH, while controlling for cortical thickness. Conclusions— These cross-sectional results suggest that cortical changes (regional-specific damage and network breakdown), mediated (in)directly by WMH (tract-specific damage) and other factors (eg, vascular risk factors), might lead to cognitive decline. These findings have implications in understanding the relationship between WMH, cortical morphology, and the possible attendant cognitive decline and eventually dementia.

Item does not contain fulltext Key nodes of neural networks for ocular motor control and visual motion processing have been localized using saccades, smooth pursuit, and optokinetic nystagmus (OKN). Within the context of an independent fMRI study using OKN, 9 bilateral network nodes were localized comprising cortical eye fields in frontal (FEF), supplementary motor (SEF), cingulate (CEF) and parietal cortex (PEF), visual motion centers MT+ and V6, the superior colliculus (SC), the lateral geniculate nucleus (LGN) and the globus pallidus (GP). Here, we examined the network's functional hierarchy as present in the structural co-variation (SCoV) and resting-state (RS) fMRI, and the effect of RS condition (eyes open/closed) on its' functional connectivity (FC). Two publicly available samples were analyzed consisting of the enhanced NKI sample with RS (TR 1.4s) and structural MR data (n = 124; age 46.7 ± 17.6; 40 male) and the "Beijing: eyes open eyes closed sample" measuring RS (TR 2s; n = 48; age 22.5 ± 2.2; 24 male). For the FC analysis, ICA-based denoising (FSL) was applied before spatial preprocessing (SPM) and band-pass filtering. Each bilateral ROI was represented by the first eigenvariate of the respective voxels' time-series and partial correlation were computed using FSLNets. One group t-tests were computed over Fisher's z transformed correlation coefficients. Each ROIs volume was approximated with voxel-based morphometry (VBM8) using non-linearly modulated gray matter density and partial correlations were computed for SCoV. Hierarchical cluster analysis was applied to determine sub-clustering within the OKN network. Edge-wise comparisons between RS conditions were performed using permutation testing and Bonferroni correction. Both FC and SCoV revealed two major subcluster. MT+ and V6 were similar to LGN and SC. The cortical eye fields clustered together with the GP. As effect of RS condition, with eyes closed the CEF switched to the visual subcluster. The edge-wise comparison revealed generally higher FC with eyes open and in particular a decrease of FC between MT+ and PEF, FEF and SEF as well as between V6 and SEF. Hierarchical clustering based on RS and structural data revealed a task-independent sub-division of the network for ocular-motor control and visual motion processing into two streams either involved in top-down (efferent voluntary) ocular-motor control (FEF, PEF, SEF, GP) and in more bottom-up visual target tracking (MT+, V6, LGN, SC) streams. This general network hierarchy was equally present in the RS with eyes open and eyes closed, with the CEF fulfilling a condition specific role in the network. The edge-wise comparison between RS conditions strengthens the evidence for a specific influence of MT+ on the ocular-motor control subcluster. These findings indicate a systematic influence of the resting condition not only on FC of the visual system, but on the state of the whole OKN network, while a general system hierarchy is omnipresent independent of RS condition. 2 p.

Item does not contain fulltext The assessment of motor and executive functions following stroke or traumatic brain injury is a key aspect of impairment evaluation and used to guide further therapy. In clinical routine such assessments are largely dominated by pen-and-paper tests. While these provide standardized, reliable and ecologically valid measures of the individual level of functioning, rather little is yet known about their neurobiological underpinnings. Therefore, the aim of this study was to investigate brain regions and their associated networks that are related to upper extremity motor function, as quantified by the Motor Speed subtest of the Trail Making Test (TMT-MS) (Delis et al., 2001). Whole brain voxel-based morphometry (Ashburner and Friston, 2000) and whole brain tract-based spatial statistics (Smith et al., 2006) were used to investigate the association between TMT-MS performance with gray matter volume (GMV) and white matter integrity respectively. While results demonstrated no relationship to local white-matter properties, we found a significant correlation between TMT-MS performance and GMV of the lower bank of the inferior frontal sulcus, a region associated with cognitive processing, as indicated by assessing its functional profile by the BrainMap database (Laird et al., 2011). Using this finding as a seed region, we further examined and compared networks as reflected by resting state connectivity (Fox and Raichle, 2007), meta-analytic-connectivity modeling (Eickhoff et al., 2011), structural covariance (Albaugh et al., 2013) and probabilistic tractography (Behrens et al., 2003). While differences between the different approaches were observed, all approaches converged on a network comprising regions that overlap with the multiple-demand network. Our data therefore indicates that performance may primarily depend on executive function, thus suggesting that motor speed in a more naturalistic setting should be more associated with executive rather than primary motor function. Moreover, results showed that while there were differences between the approaches, a convergence indicated that common networks can be revealed across highly divergent methods. 2 p.

The dynamin family of GTPases has been implicated as novel regulators of the acrosome reaction, a unique exocytotic event that is essential for fertilization. Dynamin activity during the acrosome reaction is accompanied by phosphorylation of key serine residues. We now tested the hypothesis that glycogen synthase kinase 3 (GSK3) is the protein kinase responsible for dynamin phosphorylation at these phosphosites in mouse spermatozoa. Pharmacologic inhibition of GSK3 in mature mouse spermatozoa (CHIR99021: IC50 = 6.7 nM) led to a significant reduction in dynamin phosphorylation (10.3% vs. 27.3%; P0.001), acrosomal exocytosis (9.7% vs. 25.7%; P0.01), and in vitro fertilization (53% vs. 100%; P0.01). GSK3 was shown to be present in developing germ cells where it colocalized with dynamin in the peri-acrosomal domain. However, additional GSK3 was acquired by maturing mouse spermatozoa within the male reproductive tract, via a novel mechanism involving direct interaction of sperm heads with extracellular structures known as epididymal dense bodies. These data reveal a novel mode for the cellular acquisition of a protein kinase and identify a key role for GSK3 in the regulation of sperm maturation and acrosomal exocytosis.

It is now well established that regional indices of brain structure such as cortical thickness, surface area or grey matter volume exhibit spatially variable patterns of heritability. However, a recent study found these patterns to change with age during development, a result supported by gene expression studies. Changes in heritability have not been investigated in adulthood so far and could have important implications in the study of heritability and genetic correlations in the brain as well as in the discovery of specific genes explaining them. Herein, we tested for genotype by age (G × A) interactions, an extension of genotype by environment interactions, through adulthood and healthy aging in 902 subjects from the Genetics of Brain Structure (GOBS) study. A “jackknife” based method for the analysis of stable cortical thickness clusters (JASC) and scale selection is also introduced. Although additive genetic variance remained constant throughout adulthood, we found evidence for incomplete pleiotropy across age in the cortical thickness of paralimbic and parieto-temporal areas. This suggests that different genetic factors account for cortical thickness heritability at different ages in these regions.

Item does not contain fulltext Previous studies have shown that males and females differ in personality. In particular, gender differences have been reported for neuroticism and agreeableness (Costa et al., 2001), with women scoring higher on these two traits than men. Although gender has also been shown to influence brain structure, effects of gender on personality ? brain relationships have hardly been investigated. Indeed, most studies treated gender as a covariate of no interest. (Hu et al., 2011). In this study, we used whole brain voxel-based morphometry (Ashburner and Friston, 2000) to investigate the influence of gender on associations between personality traits (assessed by the NEO FFI) and grey matter volume (GMV) in a large sample of 182 males and 182 females. Personality-GMV relationships were, on the one hand, assessed across the entire sample, and on the other hand, separately for males and females, with the aim of detecting associations both dependent on and independent of gender. Results revealed no significant correlations between any personality scale and GMV in the analyses across the entire sample. In contrast, when the sample was split by gender, significant positive associations between extraversion and GMV were observed in males, but not females, in precuneues/cuneus (Prc/Cun), left fusiform gyrus extending into cerebellum (lFFG/Cb), left thalamus and right cerebellum. Similarly, positive associations between conscientiousness and GMV were found only for males in lPrc/Cun. In addition, negative associations were found between neuroticism and GMV in cuneus/calcarine sulcus (Cun/CaS), lFFG/Cb and rFFG/Cb, again only in males. Interestingly, GMV in lPrc/Cun correlated with all three traits. Functional characterization (Laird et al., 2011) of this region revealed an association with perception of vision motion, explicit memory and action inhibition. Our finding suggests that men who tend to be more extroverted, conscientious, and emotionally stable, display higher GMV in lPrc/Cun, which might indicate that higher scores in those traits also go along with better abilities in these cognitive functions. In conclusion, our study demonstrated that neural correlates of personality are highly dependent on gender, which might be due to hormonal interplays or differences in brain organization between males and females. Furthermore, our results extend previous investigations, which focus on relationships between personality traits and performance in specific tasks, by providing possible neural substrates of those personality-behavior relationships. 1 p.

Alzheimer's disease (AD) appears to be a uniquely human condition, which is possibly attributable to our expanded longevity and peculiar capacity for episodic memory. Due to a lack of naturally-occurring animal model for investigating AD pathogenesis, our knowledge about the disease must be derived from correlational observation of humans, or from animal models produced by genetic manipulation of known risk factors in humans. Advances in neuroimaging, cellular and molecular science, and computational methods have proven useful for the improvement of such techniques, but the general limitation persists; as a result we remain without clear answers to some of the fundamental questions posed by AD. On the other hand, much progress has been made in characterizing the longitudinal progression of AD pathology, which includes the formation of "plaques and tangles", a distinct topological pattern of atrophy of grey and white matter, and the concurrent decline of specific cognitive functions, beginning with mild memory impairments and ending with general debilitating dementia. In this review, we first discuss the existing literature which characterizes AD etiology, pathology, and pathogenesis, with the intention of framing the disease as primarily a "disconnection syndrome". We next describe methodologies for investigating the topological properties of human brain networks, using graph theoretical techniques and connectivity information derived from anatomical and diffusion-weighted MR imaging. Finally, we discuss how these methodologies have been applied to systems-level analyses of AD, to help characterize the network changes underlying the disease process, and how these patterns relate to specific cognitive outcome measures.

Contains fulltext : 89824.pdf (Publisher’s version ) (Closed access) Emerging noninvasive neuroimaging techniques allow for the morphometric analysis of patterns of gray and white matter degeneration in vivo, which may help explain and predict the occurrence of cognitive impairment and Alzheimer's disease. A single center prospective follow-up study (Radboud University Nijmegen Diffusion tensor and Magnetic resonance imaging Cohort study (RUN DMC)) was performed involving 503 nondemented elderly individuals (50-85 years) with a history of symptomatic cerebral small vessel disease (SVD). Age was associated with a global reduction in cortical thickness, and this relationship was strongest for ventrolateral prefrontal cortex, auditory cortex, Wernicke's area, superior temporal lobe, and primary visual cortex. Right and left hemispheres differed in the thickness of language-related areas. White matter (WM) lesions were generally negatively correlated with cortical thickness, primarily in individuals over the age of 60, with the notable exception of Brodmann areas 4 and 5, which were positively correlated in age groups 50-60 and 60-70, respectively. The observed pattern of age-related decline may explain problems in memory and executive functions, which are already well documented in individuals with SVD. The additional gray matter loss affecting visual and auditory cortex, and specifically the head region of primary motor cortex, may indicate morphological correlates of impaired sensory and motor functions. The paradoxical positive relationship between WM lesion volume and cortical thickness in some areas may reflect early compensatory hypertrophy. This study raises a further interest in the mechanisms underlying cerebral gray and white matter degeneration in association with SVD, which will require further investigation with diffusion weighted and longitudinal MR studies. 01 december 2010

Contains fulltext : 87841.pdf (Publisher’s version ) (Open Access) In a recent paper (Reid et al., 2009) we introduced a method to calculate optimal hierarchies in the visual network that utilizes continuous, rather than discrete, hierarchical levels, and permits a range of acceptable values rather than attempting to fit fixed hierarchical distances. There, to obtain a hierarchy, the sum of deviations from the constraints that define the hierarchy was minimized using linear optimization. In the short time since publication of that paper we noticed that many colleagues misinterpreted the meaning of the term "optimal hierarchy". In particular, a majority of them were under the impression that there was perhaps only one optimal hierarchy, but a substantial difficulty in finding that one. However, there is not only more than one optimal hierarchy but also more than one option for defining optimality. Continuing the line of this work we look at additional options for optimizing the visual hierarchy: minimizing the number of violated constraints and minimizing the maximal size of a constraint violation using linear optimization and mixed integer programming. The implementation of both optimization criteria is explained in detail. In addition, using constraint sets based on the data from Felleman and Van Essen (1991), optimal hierarchies for the visual network are calculated for both optimization methods. 8 p.

Contains fulltext : 88103reid.pdf (Publisher’s version ) (Closed access) Norepinephrine has been hypothesized to provide a learning and memory signal. Norepinephrine long-term potentiation of perforant path input to the dentate gyrus of the hippocampus provides a model for norepinephrine initiated memory processes. However, in vitro, the pairing of perforant path stimulation and norepinephrine is not required for the occurrence of norepinephrine-dependent long-term potentiation. Since bath application of norepinephrine induces long-term changes in 2nd messenger signalling and differs in a number of ways from physiological norepinephrine release, the present study is an in vivo test of the associative requirement for the pairing of perforant path input with norepinephrine to induce long-term potentiation. Phasic activation of the locus coeruleus is provided by glutamate infusion into the locus coeruleus to initiate transient norepinephrine release in the hippocampus of urethane-anesthetized Sprague-Dawley rats. Perforant path stimulation (0.067 Hz) was given throughout the experiment in the paired condition. In the unpaired condition perforant path stimulation was interrupted 10 min prior to locus coeruleus activation and resumed 10 min after locus coeruleus activation. Locus coeruleus-induced long-term potentiation of both EPSP slope and population spike only occurred in the pairing condition. This result argues that, in vivo, temporal proximity of locus coeruleus-associated norepinephrine release and perforant path stimulation are required to induce long-term plasticity. The associativity requirement for locus coeruleus activation and perforant path stimulation in vivo is consistent with the hypothesis that norepinephrine can initiate circuit changes supporting learning and memory. 01 januari 2010

Brain activity can be measured non-invasively with functional imaging techniques. Each pixel in such an image represents a neural mass of about 105 to 107 neurons. Mean field models (MFMs) approximate their activity by averaging out neural variability while retaining salient underlying features, like neurotransmitter kinetics. However, MFMs incorporating the regional variability, realistic geometry and connectivity of cortex have so far appeared intractable. This lack of biological realism has led to a focus on gross temporal features of the EEG. We address these impediments and showcase a "proof of principle" forward prediction of co-registered EEG/fMRI for a full-size human cortex in a realistic head model with anatomical connectivity, see figure 1. MFMs usually assume homogeneous neural masses, isotropic long-range connectivity and simplistic signal expression to allow rapid computation with partial differential equations. But these approximations are insufficient in particular for the high spatial resolution obtained with fMRI, since different cortical areas vary in their architectonic and dynamical properties, have complex connectivity, and can contribute non-trivially to the measured signal. Our code instead supports the local variation of model parameters and freely chosen connectivity for many thousand triangulation nodes spanning a cortical surface extracted from structural MRI. This allows the introduction of realistic anatomical and physiological parameters for cortical areas and their connectivity, including both intra- and inter-area connections. Proper cortical folding and conduction through a realistic head model is then added to obtain accurate signal expression for a comparison to experimental data. To showcase the synergy of these computational developments, we predict simultaneously EEG and fMRI BOLD responses by adding an established model for neurovascular coupling and convolving "Balloon-Windkessel" hemodynamics. We also incorporate regional connectivity extracted from the CoCoMac database [1]. Importantly, these extensions can be easily adapted according to future insights and data. Furthermore, while our own simulation is based on one specific MFM [2], the computational framework is general and can be applied to models favored by the user. Finally, we provide a brief outlook on improving the integration of multi-modal imaging data through iterative fits of a single underlying MFM in this realistic simulation framework.

Contains fulltext : 81553.pdf (Publisher’s version ) (Closed access) Although information flow in the neocortex has an apparent hierarchical organization, there is much ambiguity with respect to the definition of such a hierarchy, particularly in higher cortical regions. This ambiguity has been addressed by utilizing observable anatomical criteria, based upon tract tracing experiments, to constrain the definition of hierarchy [Felleman D.J. and van Essen D.C., 1991. Distributed hierarchical processing in the primate. Cereb. Cortex. 1(1), 1-47.]. There are, however, a high number of equally optimal hierarchies that fit these constraints [Hilgetag C.C., O'Neill M.A., Young M.P., 1996. Indeterminate organization of the visual system. Science. 271(5250), 776-777.]. Here, we propose a refined constraint set for optimization which utilizes continuous, rather than discrete, hierarchical levels, and permits a range of acceptable values rather than attempting to fit fixed hierarchical distances. Using linear programming to obtain hierarchies across a number of range sizes, we find a clear hierarchical pattern for both the original and refined versions of the Felleman and Van Essen [Felleman D.J. and van Essen D.C., 1991. Distributed hierarchical processing in the primate. Cereb. Cortex. 1(1), 1-47.] visual network. We also obtain an optimal hierarchy from a refined set of anatomical criteria which allows for the direct specification of hierarchical distance from the laminar distribution of labelled cells (Barone P., Batardiere A., Knoblauch K., Kennedy H., 2000. Laminar distribution of neurons in extrastriate areas projecting to visual areas V1 and V4 correlates with the hierarchical rank and indicates the operation of a distance rule. J. Neurosci. 20(9), 3263-3281.), and discuss the limitations and further possible refinements of such an approach.

Throughout sperm maturation distinct remodelling events occur that imbue the cells with both the ability to bind the zona pellucida and undergo the acrosome reaction. Of long standing interest to our laboratory is the elucidation of the molecular mechanisms that underpin the attainment of these key functional attributes. This process begins with a complex range of morphological changes that accompany spermatogenesis, and is continued through post-testicular phases of maturation in both the male (epididymal maturation) and female (capacitation) reproductive tracts. However, among these changes only those occurring during the initial stages of spermatogenesis are intrinsically driven. The fact that the majority of sperm remodelling is extrinsically stimulated, and occurs in the absence of new protein synthesis, highlights the potential importance of processes such as intracellular protein trafficking. This has directed our focus towards the dynamin family of protein traffickers. The GTPase dynamin exists in three isoforms, namely Dnm1, Dnm2 and Dnm3 and is an integral part of the molecular machinery required for vesicle mediated protein translocation. Recent research from our laboratory has demonstrated the presence of these three isoforms in distinct, cell-specific locations during murine spermatogenesis. Immunofluorescence on mouse testis revealed that both Dnm1 and 2 are present within a region corresponding to the developing acrosome in maturing sperm, whilst Dnm3 appears to reside solely within pre-meiotic germ cells. Interestingly, Dnm1 and Dnm2 are both retained within the peri-acrosomal region of the sperm head in mature spermatozoa. Additionally, upon the induction of capacitation in vitro, staining for both Dnm1 and 2 becomes significantly reduced. Collectively these data support the novel hypothesis that dynamin not only participates in sperm remodelling events during spermatogenesis but may also have a previously unappreciated role in capacitation-associated priming of the sperm surface for interaction with the oocyte.

In contrast to the histone packaging of somatic cells, spermatozoa are predominantly packaged by the protamine proteins. However, human spermatozoa retain ~15% histone packaging. Regions that are left nucleosome bound could be: either genes that are active shortly after fertilisation or genes that are transcribed late during spermatogenesis. DNA damage at histone bound loci would be of consequence to spermatogenesis and/or to a resulting embryo post-fertilisation. Western blot analysis confirmed the presence of acetylated H3 and H4 in sperm. Interestingly, we identified the presence of these modified histones in isolated good quality sperm considered to have complete packaging. This indicates that histone retention is not a consequence of aberrant chromatin remodelling. Using a combination of ChIP (chromatin immunoprecipitation) and tiling arrays we have identified regions bound by acetylated histone 3 (H3). ChIP-PCR confirmed histone retention at several of these loci. For the previously identified loci in exon 1 of the TNP-2 gene we were able to narrow the region bound to the size of one nucleosome only. Using a modified form of ChIP known as carrier ChIP we examined histone retention in individual ejaculates. We demonstrate that humans consistently retain acetylated H3 at the same loci. Retention of one nucleosome at the TNP-2 loci was maintained across ejaculates and donors. In conclusion, retention of acetylated H3 is consistently maintained during packaging of the genome in spermiogenesis.

The presence of white matter lesions in patients with cerebral small vessel disease (SVD) is among the main causes of cognitive decline. We investigated the relation between white matter hyperintensity (WMH) locations and executive and language abilities in 442 SVD patients without dementia with varying burden of WMH. We used Stroop Word Reading, Stroop Color Naming, Stroop Color‐Word Naming, and Category Fluency as language measures with varying degrees of executive demands. The Symbol Digit Modalities Test (SDMT) was used as a control task, as it measures processing speed without requiring language use or verbal output. A voxel‐based lesion–symptom mapping (VLSM) approach was used, corrected for age, sex, education, and lesion volume. VLSM analyses revealed statistically significant clusters for tests requiring language use, but not for SDMT. Worse scores on all tests were associated with WMH in forceps minor, thalamic radiations and caudate nuclei. In conclusion, an association was found between WMH in a core frontostriatal network and executive‐verbal abilities in SVD, independent of lesion volume and processing speed. This circuitry underlying executive‐language functioning might be of potential clinical importance for elderly with SVD. More detailed language testing is required in future research to elucidate the nature of language production difficulties in SVD., The manuscript describes a study of the relation between white matter hyperintensity (WMH) locations and executive and language abilities in small vessel disease patients without dementia with varying burden of WMH.