Probst Bundles Research Articles

MRI Evaluation of Corpus Callosum Malformation and Associated Anomalies: A Retrospective Cross-Sectional Study.

Objective This study aims to evaluate the MRI morphology of corpus callosum malformations and the associated anomalies frequently observed in a tertiary care center in northern India. Methods We conducted a retrospectivecross-sectional study using MRI reports, images, and clinical records fromJanuary 2020 to July 2024. A total of 19 patients with corpus callosum agenesis or hypoplasia were identified, with 17 patients included after excluding those with incomplete records. We analyzed MRI findings for agenesis type (complete or partial), commissural abnormalities, midline anomalies, cortical abnormalities, and posterior fossa abnormalities. Statistical analysis was performed using chi-square tests to compare associations between complete and partial agenesis. Results Of the 17 patients, 52.9% had complete agenesis and 47.1% had partial agenesis. Complete agenesis was associated with higher rates of commissural involvement (44.4% vs. 12.5%), midline anomalies (22.2% vs. 0%), and Probst bundle formation (88.9% vs. 37.5%). Ventricular distortion was more common in complete agenesis (88.9% vs. 40%), and cortical malformations were also more prevalent (44.4% vs. 12.5%). Other anomalies included holoprosencephaly, Dandy-Walker malformation, and hypoxic-ischemic encephalopathy changes. Conclusion Complete agenesis of the corpus callosum is significantly associated with other commissural abnormalities, midline cysts, Probst bundle formation, ventricular distortions, and cortical malformations compared to partial agenesis. This study highlights the varied imaging presentations of corpus callosum malformations and their associated anomalies.

Quantitative fetal MRI with diffusion tensor imaging in cases with 'short' corpus callosum.

It has been suggested previously that the presence of Probst bundles (PB) in cases with a short corpus callosum (SCC) on diffusion tensor imaging (DTI) may help to differentiate between corpus callosal (CC) dysplasia and a variant of normal CC development. The objectives of this study were to compare DTI parameters between cases of SCC vs normal CC and between cases of SCC with PB (SCC-PB+) vs SCC without PB (SCC-PB-). This was a retrospective study of patients referred to the Necker Hospital in Paris, France, for magnetic resonance imaging (MRI) evaluation of an apparently isolated SCC detected by sonography between November 2016 and December 2022 (IRB: 00011928). MRI was performed using a 1.5-Tesla Signa system. T2-weighted axial and sagittal sequences of the fetal brain were used to measure the length and thickness of the CC. 16-direction DTI axial brain sequences were performed to identify the presence of PB and to generate quantitative imaging parameters (fractional anisotropy (FA) and apparent diffusion coefficient (ADC)) of the entire CC, genu, body and splenium. Cases in which other associated brain abnormalities were detected on MRI were excluded. Cases were matched for fetal gender and gestational age with controls in a 1:3 ratio. Control cases were normal fetuses included in the LUMIERE on the FETUS trial (NCT04142606) that underwent the same DTI evaluation of the brain. Comparisons between SCC and normal CC cases, and between SCC-PB+ and SCC-PB- cases were performed using ANOVA and adjusted for potential confounders using ANCOVA. Twenty-two SCC cases were included and compared with 66 fetuses with a normal CC. In 10/22 (45.5%) cases of SCC, PB were identified. As expected, dimensions of the CC were significantly smaller in SCC compared with normal CC cases (all P < 0.01). In SCC-PB+ vs SCC-PB- cases, FA values were significantly lower in the entire CC (median, 0.21 (range, 0.19-0.24) vs 0.24 (range, 0.22-0.28); P < 0.01), genu (median, 0.21 (range, 0.15-0.29) vs 0.24 (range, 0.17-0.29); P = 0.04), body (median, 0.21 (range, 0.18-0.23) vs 0.23 (range, 0.21-0.27); P = 0.04) and splenium (median, 0.22 (range, 0.16-0.30) vs 0.25 (range, 0.20-0.29); P = 0.03). ADC values were significantly higher in the entire CC, genu and body in SCC-PB+ vs SCC-PB- cases (all P < 0.05). In SCC-PB+ cases, all FA values were significantly lower, and ADC values in the CC body were significantly higher compared with normal CC cases (all P < 0.05). In SCC-PB- cases, there was no significant difference in FA and ADC compared with normal CC cases (all P > 0.05). Fetal DTI evaluation of the CC showed that FA values were significantly lower and ADC values tended to be significantly higher in SCC-PB+ compared with normal CC cases. This may highlight alterations of the white matter microstructure in SCC-PB+. In contrast, isolated SCC-PB- did not demonstrate significant changes in DTI parameters, strengthening the possibility that this is a normal CC variant. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Brain plasticity following corpus callosum agenesis or loss: a review of the Probst bundles.

The corpus callosum is the largest axonal tract in the human brain, connecting the left and right cortical hemipheres. This structure is affected in myriad human neurodevelopmental disorders, and can be entirely absent as a result of congenital or surgical causes. The age when callosal loss occurs, for example via surgical section in cases of refractory epilepsy, correlates with resulting brain morphology and neuropsychological outcomes, whereby an earlier loss generally produces relatively improved interhemispheric connectivity compared to a loss in adulthood (known as the "Sperry's paradox"). However, the mechanisms behind these age-dependent differences remain unclear. Perhaps the best documented and most striking of the plastic changes that occur due to developmental, but not adult, callosal loss is the formation of large, bilateral, longitudinal ectopic tracts termed Probst bundles. Despite over 100 years of research into these ectopic tracts, which are the largest and best described stereotypical ectopic brain tracts in humans, much remains unclear about them. Here, we review the anatomy of the Probst bundles, along with evidence for their faciliatory or detrimental function, the required conditions for their formation, patterns of etiology, and mechanisms of development. We provide hypotheses for many of the remaining mysteries of the Probst bundles, including their possible relationship to preserved interhemispheric communication following corpus callosum absence. Future research into naturally occurring plastic tracts such as Probst bundles will help to inform the general rules governing axon plasticity and disorders of brain miswiring.

Feasibility and Added Value of Fetal DTI Tractography in the Evaluation of an Isolated Short Corpus Callosum: Preliminary Results.

Prognosis of isolated short corpus callosum is challenging. Our aim was to assess whether fetal DTI tractography can distinguish callosal dysplasia from variants of normal callosal development in fetuses with an isolated short corpus callosum. This was a retrospective study of 37 cases referred for fetal DTI at 30.4 weeks (range, 25-34 weeks) because of an isolated short corpus callosum less than the 5th percentile by sonography at 26 weeks (range, 22-31 weeks). Tractography quality, the presence of Probst bundles, dysmorphic frontal horns, callosal length (internal cranial occipitofrontal dimension/length of the corpus callosum ratio), and callosal thickness were assessed. Cytogenetic data and neurodevelopmental follow-up were systematically reviewed. Thirty-three of 37 fetal DTIs distinguished the 2 groups: those with Probst bundles (Probst bundles+) in 13/33 cases (40%) and without Probst bundles (Probst bundles-) in 20/33 cases (60%). Internal cranial occipitofrontal dimension/length of the corpus callosum was significantly higher in Probst bundles+ than in Probst bundles-, with a threshold value determined at 3.75 for a sensitivity of 92% (95% CI, 77%-100%) and specificity of 85% (95% CI, 63%-100%). Callosal lipomas (4/4) were all in the Probst bundles- group. More genetic anomalies were found in the Probst bundles+ than in Probst bundles- group (23% versus 10%, P = .08). Fetal DTI, combined with anatomic, cytogenetic, and clinical characteristics could suggest the possibility of classifying an isolated short corpus callosum as callosal dysplasia and a variant of normal callosal development.

Transient Probst Bundle Diffusion Restriction: An Acute Encephalopathy Equivalent to Clinically Mild Encephalopathy with a Reversible Splenial Lesion

Probst bundles are selectively seen in patients with agenesis of the corpus callosum (CC) and are thought to be homologous to the CC. We herein report a 19-year-old woman with partial agenesis of the CC. She developed acute encephalopathy during Bordetella pertussis infection. Brain magnetic resonance imaging (MRI) showed restricted diffusion of bilateral Probst bundles. She was treated with anti-epileptics and azithromycin and recovered with no neurological sequelae. Follow-up MRI showed the resolution of the diffusion abnormality. The characteristics of diffusion-weighted images on brain MRI and clinical course mimicked those in cases of clinically mild encephalopathy/encephalitis with reversible splenial lesion.

Altered structural connectivity networks in a mouse model of complete and partial dysgenesis of the corpus callosum

Corpus callosum dysgenesis (CCD) describes a collection of brain malformations in which the main fiber tract connecting the two hemispheres is either absent (complete CCD, or ‘agenesis of the corpus callosum’) or reduced in size (partial CCD). Humans with these neurodevelopmental disorders have a wide range of cognitive outcomes, including seemingly preserved features of interhemispheric communication in some cases. However, the structural substrates that could underlie this variability in outcome remain to be fully elucidated. Here, for the first time, we characterize the global brain connectivity of a mouse model of complete and partial CCD. We demonstrate features of structural brain connectivity that model those predicted in humans with CCD, including Probst bundles in complete CCD and heterotopic sigmoidal connections in partial CCD. Crucially, we also histologically validate the recently predicted ectopic sigmoid bundle present in humans with partial CCD, validating the utility of this mouse model for fine anatomical studies of this disorder. Taken together, this work describes a mouse model of altered structural connectivity in variable severity CCD and forms a foundation for future studies investigating the function and mechanisms of development of plastic tracts in developmental disorders of brain connectivity.

Council of Europe resolution to promote pharmaceutical care in Europe

<h3>BACKGROUND AND PURPOSE:</h3> Prognosis of isolated short corpus callosum is challenging. Our aim was to assess whether fetal DTI tractography can distinguish callosal dysplasia from variants of normal callosal development...

Does the superior fronto-occipital fascicle exist in the human brain? Fiber dissection and brain functional mapping in 90 patients with gliomas.

The presence of the superior fronto-occipital fascicle (SFOF) has been reported in the Rhesus monkey; however, it is a subject of controversy in humans. The aim of this study is to identify the SFOF using both in vitro and in vivo anatomo-functional analyses. This study consisted of two approaches. First, one acallosal brain and 12 normal postmortem hemispheres (five left and seven right sides) were dissected under a microscope using Klingler's fiber dissection technique. We focused on the medial subcallosal area superior to the Muratoff bundle, which has been indicated as a principal target area of the SFOF in previous studies. Second, 90 patients underwent awake craniotomy for gliomas with direct electrical stimulations. Functional examinations for visual, ataxic, and cognitive tasks were performed and 453 positive mapping sites were investigated by voxel-based morphometry analysis to establish the functions of the SFOF. The corticostriatal fibers, or the Muratoff bundle, and thalamic peduncle fibers joined in the area of the caudate nucleus, making thalamic peduncle/ corticostriatal bundles, which ran antero-posteriorly in the anterior subcallosal area and radiated from the caudate superior margin in the posterior subcallosal area. However, no SFOF fiber bundle crossed perpendicular to the thalamic peduncle/ corticostriatal bundles in the posterior subcallosal area. In the acallosal hemispheres, Probst bundles were confirmed and the subcallosal areas did not show a specific organization different from the normal brain. Hence, we could not detect a long and continuous association fascicle connecting the frontal lobe and occipital or parietal lobe in the target areas. Furthermore, in the in vivo functional mappings of awake surgery and voxel-based morphometry analysis, eight positive points on the SFOF were selected from the total 453 positive points, but their functions were not related with visual processing and spatial awareness, as has been reported in previous studies. In conclusion, in the present study we attempted to investigate the existence of the SFOF using an anatomical and functional approach. According to our results, the SFOF may not exist in the human brain.

White-matter commissures: a clinically focused anatomical review.

The objective of this review is to provide a structured approach to the main white matter commissures, their anatomic and radiological definition and disease implications. The Pubmed database and The JAMA Network were used for the literature review and the following terms were searched using Sort by: Best Match and Sort by: Most Recent: telencephalic commissure, forebrain commissure anatomy, fornix anatomy, commissure of fornix, posterior commissure, corpus callosum, commissural agenesis, Probst bundle, corpus callosum disorders review, corpus callosum diseases review, Marchiafava-Bignami, Alzheimer's disease and Forel commissure; 36 papers were selected, one excluded due to the language barrier. The interhemispheric communication in the brain is achieved via the brain commissures, bundles of white matter linking the two cerebral hemispheres. Anterior white commissure (AWC)-related with olfactory and non-visual communication, hippocampal commissure-main efferent pathway of the hippocampus, connecting the hippocampal formation to structures beyond the temporal lobe, crucial in declarative memory formation and consolidation-and the corpus callosum (CC)-from the anterior commissure to the hippocampal commissure-are the main telencephalic commissures. Supramammilary commissure, posterior commissure, supraoptic commissure and habenular commissure are diencephalic commissures-unknown function, probably related to involuntary eye movements. Commissural agenesis (AWC is absent or impossible to recognize), Alzheimer's Disease (hippocampal commissure may contribute for disease dissemination) and agenesis of corpus callosum are some of the disturbances that involve the telenchephalic commissures. A comprehensive understanding of the clinic-anatomic correlation is pivotal to understand the pathology and therefore improve our diagnostic accuracy and treatment options, in the background of all patient management.

The use of diffusion tractography to characterize a corpus callosum malformation in a dog.

IntroductionThe pathogenesis of corpus callosum malformations (CCM) is not well defined in the dog because of inherent limitations of structural magnetic resonance imaging (MRI) to evaluate the white matter. We used the advanced neuroimaging technique of tractography to virtually dissect the white matter projections in a dog with a CCM and in a normal control dog.MethodsA 9‐month‐old male Coonhound that had a previous structural MRI diagnosis of CCM and a normal control dog underwent anesthesia and 3‐Tesla MRI. Diffusion‐tensor imaging and 3D T1‐weighted and 2D T2‐weighted sequences were acquired. Diffusion data were processed before tensor reconstruction and fiber tracking. Virtual dissections were performed to dissect out the major white matter projections in each dog.ResultsIn the dog with CCM, the corpus callosum exhibited interhemispheric crossing fibers at the level of the splenium and formed longitudinal callosal fasciculi (Probst bundles). In addition, the fornix was small and the cingula enlarged and exhibited increased dorsal connectivity relative to the normal control.Conclusions and Clinical ImportanceWe used tractography to describe a white matter malformation in a dog. The results suggest that, embryologically, formed axons fail to cross midline and instead create Probst bundles.

Altered GLI3 and FGF8 signaling underlies acrocallosal syndrome phenotypes in Kif7 depleted mice.

Acrocallosal syndrome (ACLS) is a rare genetic disorder characterized by agenesis or hypoplasia of corpus callosum (CC), polydactyly, craniofacial dysmorphism and severe intellectual deficiency. We previously identified KIF7, a key ciliary component of the Sonic hedgehog (SHH) pathway, as being a causative gene for this syndrome, thus including ACLS in the group of ciliopathies. In both humans and mice, KIF7 depletion leads to abnormal GLI3 processing and over-activation of SHH target genes. To understand the pathological mechanisms involved in CC defects in this syndrome, we took advantage of a previously described Kif7-/- mouse model to demonstrate that in addition to polydactyly and neural tube closure defects, these mice present CC agenesis with characteristic Probst bundles, thus recapitulating major ACLS features. We show that CC agenesis in these mice is associated with specific patterning defects of the cortical septum boundary leading to altered distribution of guidepost cells required to guide the callosal axons through the midline. Furthermore, by crossing Kif7-/- mice with Gli3Δ699 mice exclusively producing the repressive isoform of GLI3 (GLI3R), we demonstrate that decreased GLI3R signaling is fully responsible for the ACLS features in these mice, as all phenotypes are rescued by increasing GLI3R activity. Moreover, we show that increased FGF8 signaling is responsible in part for CC defects associated to KIF7 depletion, as modulating FGF8 signaling rescued CC formation anteriorly in Kif7-/- mice. Taken together our data demonstrate that ACLS features rely on defective GLI3R and FGF8 signaling.

Balkenfehlbildungen

Agenesis of the corpus callosum is reported to have an incidence of about 1:4000 live births. In 30-45% of cases, genetic etiologies can be identified, e. g., 10% chromosomal anomalies and 20-35% genetic syndromes. Environmental factors like fetal alcohol syndrome are also known to be prone to callosal agenesis. Callosal agenesis can be complete or partial and can be isolated or associated with other central nervous system (CNS) anomalies (e. g., cortical developmental disorders, callosal lipoma, intracranial cysts) or extra-CNS anomalies (e. g., eyes, face, cardiovascular). Diagnosis is made using ultrasound, computed tomography (CT) or best with magnetic resonance imaging (MRI). Typical imaging findings in callosal agenesis are colpocephaly, high riding enlarged third ventricle, Texas Longhorn configuration of frontal horns and so-called Probst bundles parasagittal. Diffusion tensor imaging and fiber-tracking, based on diffusion-weighted techniques, can also visualize fiber/tract anomalies in the patients' brains. Clinical correlations of callosal agenesis is difficult in general because of the common association of other CNS malformations. Differential diagnosis of primary complete or partial callosal agenesis are secondary callosal changes, e. g. vascular, inflammatory or posttreatment in origin.

Structural Connectivity Analysis in Children with Segmental Callosal Agenesis.

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. 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. 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. 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.

Agenesis of the corpus callosum in Nogo receptor deficient mice.

The corpus callosum (CC) is the largest fiber tract in the mammalian brain, linking the bilateral cerebral hemispheres. CC development depends on the proper balance of axon growth cone attractive and repellent cues leading axons to the midline and then directing them to the contralateral hemisphere. Imbalance of these cues results in CC agenesis or dysgenesis. Nogo receptors (NgR1, NgR2, and NgR3) are growth cone directive molecules known for inhibiting axon regeneration after injury. We report that mice lacking Nogo receptors (NgR123-null mice) display complete CC agenesis due to axon misdirection evidenced by ectopic axons including cortical Probst bundles. Because glia and glial-derived growth cone repellent factors (especially the diffusible factor Slit2) are required for CC development, their distribution was studied. Compared with wild-type mice, NgR123-null mice had a sharp increase in the glial marker glial fibrillary acidic protein (GFAP) and in Slit2 at the glial wedge and indusium griseum, midline structures required for CC formation. NgR123-null mice displayed reduced motor coordination and hyperactivity. These data are consistent with the hypotheses that Nogo receptors are membrane-bound growth cone repellent factors required for migration of axons across the midline at the CC, and that their absence results directly or indirectly in midline gliosis, increased Slit2, and complete CC agenesis. J. Comp. Neurol. 525:291-301, 2017. © 2016 Wiley Periodicals, Inc.

Inter- and Intra-Hemispheric Fibers of Olfactory and Motor Areas in Kallmann Syndrome with Defective Corpus Callosum

Kallmann syndrome (KS) is a form of hypogonadotropic hypogonadism with variable disturbances of olfaction, with some patients having complete anosmia. In this study, we report observations of cerebral white matter connectivity in a rare patient diagnosed with KS associated with a defective corpus callosum (DCC) (KS-DCC) using non-invasive tractography-based diffusion tensor imaging (DTI). In the partial CC, two genua remnants were observed. The KS-DCC patient had a normal life without cognitive impairment and had a normal intelligence quotient, manifesting only the two common symptoms hypogonadotropic hypogonadism and anosmia. Mirror movements were not observed. Compared with normal, DTI tractography of the olfactory related area in the KS-DCC patient revealed fewer inter-hemispheric fibers between right and left olfactory areas (including olfactory tubercle and anterior commissure). Overall, the KSDCC patient had higher numbers of intra-hemispheric fibers bilaterally and fewer inter-hemispheric connecting fibers. The higher numbers of intra-hemispheric fibers connected the right thalamus and right supplementary motor area (SMA) and the left thalamus and left SMA. The fewest number of fibers observed in the KS-DCC patient were those connecting right and left SMA. The Probst bundle together with increased intra-hemispheric fibers may indicate plastic rewiring of corpus callosum connections.

Corpus callosum abnormalities: neuroradiological and clinical correlations.

To study neuroradiological features in pediatric patients with corpus callosum abnormalities, using new functional subtyping for the corpus callosum, and to correlate the features with the clinical presentation. We performed a retrospective review of 125 patients with radiologically identified abnormalities of the corpus callosum seen between 1999 and 2012. The study reviewed clinical features, genetic etiology, and chromosomal microarray (CMA) results. We used a new functional classification for callosal abnormalities based on embryological and anatomical correlations with four classes: complete agenesis, anterior agenesis (rostrum, genu, body), posterior agenesis (isthmus, splenium), and complete hypoplasia (thinning). We also studied the presence of extracallosal abnormalities. The new functional callosal subtyping did not reveal significant differences between the various subtypes in association with neurological outcome; however, the presence of cardiac disease was found more frequently in the group with complete agenesis. Thirty-seven per cent (46/125) had identifiable causes: of these, 48% (22/46) had a monogenic disorder, 30% (14/46) had a pathogenic chromosomal copy-number variant detected by CMA or karyotype, and 22% (10/46) had a recognizable clinical syndrome for which no confirmatory genetic test was available (namely Aicardi syndrome/septo-optic dysplasia and Goldenhar syndrome). The diagnostic yield for a significant CMA change was 19%. The presence of Probst bundles was found to be associated with a better neurodevelopmental outcome. The functional classification system alone 'without clinical data' cannot predict the functional outcome. The presence of extracallosal brain abnormalities and an underlying genetic diagnosis predicted a worse neurodevelopmental outcome. This study highlights the importance of CMA testing and cardiac evaluation as part of a routine screen.

Morphometric variability of neuroimaging features in children with agenesis of the corpus callosum.

BackgroundAgenesis of the corpus callosum (ACC) is a developmental brain malformation associated with a wide spectrum of structural brain abnormalities and genetic loci. To characterize the diverse callosal morphologies and malformations of brain development associated with ACC, we report on the neuroimaging findings of 201 individuals diagnosed with corpus callosal abnormalities.MethodsWe searched through medical records of individuals seen at New York Presbyterian Hospital between 2002 and 2013 and thought to have ACC. We confirmed 201 individuals meeting criteria and used magnetic resonance imaging to characterize morphological variants of the corpus callosum and associated brain malformations.ResultsThe majority of individuals displayed hypoplasia or dysplasia of the corpus callosum (N = 160, 80 %). Forty-one (20 %) displayed complete agenesis of the corpus callosum with other abnormalities, while only 18 (9 %) displayed complete agenesis without associated brain abnormalities. White matter abnormalities were more frequent in hypoplasia or dysplasia group than complete agenesis (28.2 % vs 9.8 %, p < 0.05). In contrast, hippocampal abnormalities, colpocephaly, and Probst bundles were significantly more frequent in complete agenesis compared to hypoplasia or dysplasia group.ConclusionsCollectively, our results underscore the broad diversity of morphological variants of the corpus callosum and associated brain abnormalities in individuals with ACC.

Heinrich Sachs (1863-1928).

Heinrich Sachs (1863-1928).

Organising white matter in a brain without corpus callosum fibres

Isolated corpus callosum dysgenesis (CCD) is a congenital malformation which occurs during early development of the brain. In this study, we aimed to identify and describe its consequences beyond the lack of callosal fibres, on the morphology, microstructure and asymmetries of the main white matter bundles with diffusion imaging and fibre tractography. Seven children aged between 9 and 13 years old and seven age- and gender-matched control children were studied. First, we focused on bundles within the mesial region of the cerebral hemispheres: the corpus callosum, Probst bundles and cingulum which were selected using a conventional region-based approach. We demonstrated that the Probst bundles have a wider connectivity than the previously described rostrocaudal direction, and a microstructure rather distinct from the cingulum but relatively close to callosal remnant fibres. A sigmoid bundle was found in two partial ageneses. Second, the corticospinal tract, thalamic radiations and association bundles were extracted automatically via an atlas of adult white matter bundles to overcome bias resulting from a priori knowledge of the bundles' anatomical morphology and trajectory. Despite the lack of callosal fibres and the colpocephaly observed in CCD, all major white matter bundles were identified with a relatively normal morphology, and preserved microstructure (i.e. fractional anisotropy, mean diffusivity) and asymmetries. Consequently the bundles' organisation seems well conserved in brains with CCD. These results await further investigations with functional imaging before apprehending the cognition variability in children with isolated dysgenesis.

Transcallosal Projections Require Glycoprotein M6-Dependent Neurite Growth and Guidance.

The function of mature neurons critically relies on the developmental outgrowth and projection of their cellular processes. It has long been postulated that the neuronal glycoproteins M6a and M6b are involved in axon growth because these four-transmembrane domain-proteins of the proteolipid protein family are highly enriched on growth cones, but in vivo evidence has been lacking. Here, we report that the function of M6 proteins is required for normal axonal extension and guidance in vivo. In mice lacking both M6a and M6b, a severe hypoplasia of axon tracts was manifested. Most strikingly, the corpus callosum was reduced in thickness despite normal densities of cortical projection neurons. In single neuron tracing, many axons appeared shorter and disorganized in the double-mutant cortex, and some of them were even misdirected laterally toward the subcortex. Probst bundles were not observed. Upon culturing, double-mutant cortical and cerebellar neurons displayed impaired neurite outgrowth, indicating a cell-intrinsic function of M6 proteins. A rescue experiment showed that the intracellular loop of M6a is essential for the support of neurite extension. We propose that M6 proteins are required for proper extension and guidance of callosal axons that follow one of the most complex trajectories in the mammalian nervous system.