structural connectivity analysis in children with segmental callosal agenesis

BACKGROUND AND PURPOSE: Segmental callosal agenesis is characterized by the absence of the intermediate callosal portion. We aimed to evaluate the structural connectivity of segmental callosal agenesis by using constrained spherical deconvolution tractography and connectome analysis. MATERIALS AND METHODS: We reviewed the clinical-radiologic features of 8 patients (5 males; mean age, 3.9 years). Spherical deconvolution and probabilistic tractography were performed on diffusion data. Structural connectivity analysis, including summary network metrics, modularity analysis, and network consistency measures, was applied in 5 patients and 10 age-/sex-matched controls. RESULTS: We identified 3 subtypes based on the position of the hippocampal commissure: beneath the anterior callosal remnant in 3 patients (type I), beneath the posterior callosal remnant in 3 patients (type II), and between the anterior and posterior callosal remnants in 2 patients (type III). In all patients, the agenetic segment corresponded to fibers projecting to the parietal lobe, and segmental Probst bundles were found at that level. Ectopic callosal bundles were identified in 3 patients. Topology analysis revealed reduced global connectivity in patients compared with controls. The network topology of segmental callosal agenesis was more variable across patients than that of the control connectomes. Modularity analysis revealed disruption of the structural core organization in the patients. CONCLUSIONS: Three malformative subtypes of segmental callosal agenesis were identified. Even the absence of a small callosal segment may impact global brain connectivity and modularity organization. The presence of ectopic callosal bundles may explain the greater interindividual variation in the connectomes of patients with segmental callosal agenesis

Relationship between large-scale structural and functional brain connectivity in the human lifespan

The relationship between the anatomical structure of the brain and its functional organization is not straightforward and has not been elucidated yet, despite the growing interest this topic has received in the last decade. In particular, a new area of research has been defined in these years, called \u2019connectomics\u2019: this is the study of the different kinds of \u2019connections\u2019 existing among micro- and macro-areas of the brain, from structural connectivity \u2014 described by white matter fibre tracts physically linking cortical areas \u2014 to functional connectivity \u2014 defined as temporal correlation between electrical activity of different brain regions \u2014 to effective connectivity\u2014defining causal relationships between functional activity of different brain areas. Cortical areas of the brain physically linked by tracts of white matter fibres are known to exhibit a more coherent functional synchronization than areas which are not anatomically linked, but the absence of physical links between two areas does not imply a similar absence of functional correspondence. Development and ageing, but also structural modifications brought on by malformations or pathology, can modify the relation between structure and function. The aim of my PhD work has been to further investigate the existing relationship between structural and functional connectivity in the human brain at different ages of the human lifespan, in particular in healthy adults and both healthy and pathological neonates and children. These two \u2019categories\u2019 of subjects are very different in terms of the analysis techniques which can be applied for their study, due to the different characteristics of the data obtainable from them: in particular, while healthy adult data can be studied with the most advanced state-of-the-art methods, paediatric and neonatal subjects pose hard constraints to the acquisition methods applicable, and thus to the quality of the data which can be analysed. During this PhD I have studied this relation in healthy adult subjects by comparing structural connectivity from DWI data with functional connectivity from stereo-EEG recordings of epileptic patients implanted with intra-cerebral electrodes. I have then focused on the paediatric age, and in particular on the challenges posed by the paediatric clinical environment to the analysis of structural connectivity. In collaboration with the Neuroradiology Unit of the Giannina Gaslini Hospital in Genova, I have adapted and tested advanced DWI analysis methods for neonatal and paediatric data, which is commonly studied with less effective methods. We applied the same methods to the study of the effects of a specific brain malformation on the structural connectivity in 5 paediatric patients. While diffusion weighted imaging (DWI) is recognised as the best method to compute structural connectivity in the human brain, the most common methods for estimating functional connectivity data \u2014 functional MRI (fMRI) and electroencephalography (EEG) \u2014 suffer from different limitations: fMRI has good spatial resolution but low temporal resolution, while EEG has a better temporal resolution but the localisation of each signal\u2019s originating area is difficult and not always precise. Stereo-EEG (SEEG) combines strong spatial and temporal resolution with a high signal-to-noise ratio and allows to identify the source of each signal with precision, but is not used for studies on healthy subjects because of its invasiveness. Functional connectivity in children can be computed with either fMRI, EEG or SEEG, as in adult subjects. On the other hand, the study of structural connectivity in the paediatric age is met with obstacles posed by the specificity of this data, especially for the application of the advanced DWI analysis techniques commonly used in the adult age. Moreover, the clinical environment introduces even more constraints on the quality of the available data, both in children and adults, further limiting the possibility of applying advanced analysis methods for the investigation of connectivity in the paediatric age. Our results on adult subjects showed a positive correlation between structural and functional connectivity at different granularity levels, from global networks to community structures to single nodes, suggesting a correspondence between structural and functional organization which is maintained at different aggregation levels of brain units. In neonatal and paediatric subjects, we successfully adapted and applied the same advanced DWI analysis method used for the investigation in adults, obtaining white matter reconstructions more precise and anatomically plausible than with methods commonly used in paediatric clinical environments, and we were able to study the effects of a specific type of brain malformation on structural connectivity, explaining the different physical and functional manifestation of this malformation with respect to similar pathologies. This work further elucidates the relationship between structural and functional connectivity in the adult subject, and poses the basis for a corresponding work in the neonatal and paediatric subject in the clinical environment, allowing to study structural connectivity in the healthy and pathological child with clinical data

In utero diffusion tensor imaging of the fetal brain: a reproducibility study

Our purpose was to evaluate the within-subject reproducibility of in utero diffusion tensor imaging (DTI) metrics and the visibility of major white matter structures. Images for 30 fetuses (20-33. postmenstrual weeks, normal neurodevelopment: 6 cases, cerebral pathology: 24 cases) were acquired on 1.5 T or 3.0 T MRI. DTI with 15 diffusion-weighting directions was repeated three times for each case, TR/TE: 2200/63 ms, voxel size: 1 ∗ 1 mm, slice thickness: 3-5 mm, b-factor: 700 s/mm(2). Reproducibility was evaluated from structure detectability, variability of DTI measures using the coefficient of variation (CV), image correlation and structural similarity across repeated scans for six selected structures. The effect of age, scanner type, presence of pathology was determined using Wilcoxon rank sum test. White matter structures were detectable in the following percentage of fetuses in at least two of the three repeated scans: corpus callosum genu 76%, splenium 64%, internal capsule, posterior limb 60%, brainstem fibers 40% and temporooccipital association pathways 60%. The mean CV of DTI metrics ranged between 3% and 14.6% and we measured higher reproducibility in fetuses with normal brain development. Head motion was negatively correlated with reproducibility, this effect was partially ameliorated by motion-correction algorithm using image registration. Structures on 3.0 T had higher variability both with- and without motion correction. Fetal DTI is reproducible for projection and commissural bundles during mid-gestation, however, in 16-30% of the cases, data were corrupted by artifacts, resulting in impaired detection of white matter structures. To achieve robust results for the quantitative analysis of diffusivity and anisotropy values, fetal-specific image processing is recommended and repeated DTI is needed to ensure the detectability of fiber pathways

Intra- and inter-hemispheric structural connectome in agenesis of the corpus callosum

Agenesis of the corpus callosum (AgCC) is a congenital brain malformation characterized by the complete or partial failure to develop the corpus callosum. Despite missing the largest white matter bundle connecting the left and right hemispheres of the brain, studies have shown preserved inter-hemispheric communication in individuals with AgCC. It is likely that plasticity provides mechanisms for the brain to adjust in the context of AgCC, as the malformation disrupts programmed developmental brain processes very early on. A proposed candidate for neuroplastic response in individuals with AgCC is strengthening of intra-hemispheric structural connections. In the present study, we explore this hypothesis using a graph-based approach of the structural connectome, which enables intra- and inter-hemispheric analyses at multiple resolutions and quantification of structural characteristics through graph metrics. Structural graph metrics of 19 children with AgCC (13 with complete, 6 with partial AgCC) were compared to those of 29 typically developing controls (TDC). Associations between structural graph metrics and a wide range of neurobehavioral outcomes were examined using a multivariate data-driven approach (Partial Least Squares Correlation, PLSC). Our results provide new evidence suggesting structural strengthening of intra-hemispheric pathways as a neuroplastic response in the acallosal brain, and highlight regional variability in structural connectivity in children with AgCC compared to TDC. There was little evidence that structural graph properties in children with AgCC were associated with neurobehavioral outcomes. To our knowledge, this is the first report leveraging graph theory tools to explicitly characterize whole-brain intra- and inter-hemispheric structural connectivity in AgCC, opening avenues for future research on neuroplastic responses in AgCC

Multimodal anatomy of the human forniceal commissure

Ambiguity surrounds the existence and morphology of the human forniceal commissure. We combine advanced in-vivo tractography, multidirectional ex-vivo fiber dissection, and multiplanar histological analysis to characterize this structure's anatomy. Across all 178 subjects, in-vivo fiber dissection based on the Human Connectome Project 7 T MRI data identifies no interhemispheric connections between the crura fornicis. Multidirectional ex-vivo fiber dissection under the operating microscope demonstrates the psalterium as a thin soft-tissue membrane spanning between the right and left crus fornicis, but exposes no commissural fibers. Multiplanar histological analysis with myelin and Bielchowsky silver staining, however, visualizes delicate cruciform fibers extending between the crura fornicis, enclosed by connective tissue, the psalterium. The human forniceal commissure is therefore much more delicate than previously described and presented in anatomical textbooks. This finding is consistent with the observed phylogenetic trend of a reduction of the forniceal commissure in non-human primates compared to non-primate eutherian mammals

On the role of the corpus callosum in interhemispheric functional connectivity in humans

Resting state functional connectivity is defined in terms of temporal correlations between physiologic signals, most commonly studied using functional magnetic resonance imaging. Major features of functional connectivity correspond to structural (axonal) connectivity. However, this relation is not one-to-one. Interhemispheric functional connectivity in relation to the corpus callosum presents a case in point. Specifically, several reports have documented nearly intact interhemispheric functional connectivity in individuals in whom the corpus callosum (the major commissure between the hemispheres) never develops. To investigate this question, we assessed functional connectivity before and after surgical section of the corpus callosum in 22 patients with medically refractory epilepsy. Section of the corpus callosum markedly reduced interhemispheric functional connectivity. This effect was more profound in multimodal associative areas in the frontal and parietal lobe than primary regions of sensorimotor and visual function. Moreover, no evidence of recovery was observed in a limited sample in which multiyear, longitudinal follow-up was obtained. Comparison of partial vs. complete callosotomy revealed several effects implying the existence of polysynaptic functional connectivity between remote brain regions. Thus, our results demonstrate that callosal as well as extracallosal anatomical connections play a role in the maintenance of interhemispheric functional connectivity

Alien Hand, Restless Brain: Salience Network and Interhemispheric Connectivity Disruption Parallel Emergence and Extinction of Diagonistic Dyspraxia

International audienceDiagonistic dyspraxia (DD) is by far the most spectacular manifestation reported by sufferers of acute corpus callosum (CC) injury (so-called "split-brain"). In this form of alien hand syndrome, one hand acts at cross purposes with the other "against the patient's will". Although recent models view DD as a disorder of motor control, there is still little information regarding its neural underpinnings, due to widespread connectivity changes produced by CC insult, and the obstacle that non-volitional movements represent for task-based functional neuroimaging studies. Here, we studied patient AM, the first report of DD in patient with complete developmental CC agenesis. This unique case also offers the opportunity to study the resting-state connectomics of DD in the absence of diffuse changes subsequent to CC injury or surgery. AM developed DD following status epilepticus (SE) which resolved over a 2-year period. Whole brain functional connectivity (FC) was compared (Crawford-Howell [CH]) to 16 controls during the period of acute DD symptoms (Time 1) and after remission (Time 2). Whole brain graph theoretical models were also constructed and topological efficiency examined. At Time 1, disrupted FC was observed in inter-hemispheric and intra-hemispheric right edges, involving frontal superior and midline structures. Graph analysis indicated disruption of the efficiency of salience and right frontoparietal (FP) networks. At Time 2, after remission of diagnostic dyspraxia symptoms, FC and salience network changes had resolved. In sum, longitudinal analysis of connectivity in AM indicates that DD behaviors could result from disruption of systems that support the experience and control of volitional movements and the ability to generate appropriate behavioral responses to salient stimuli. This also raises the possibility that changes to large-scale functional architecture revealed by resting-state functional magnetic resonance imaging (fMRI) (rs-fMRI) may provide relevant information on the evolution of behavioral syndromes in addition to that provided by structural and task-based functional imaging