Genetic ablation of the Rho GTPase Rnd3 triggers developmental defects in internal capsule and the globus pallidus formation.

The forebrain includes the cerebral cortex, the thalamus, and the striatum and globus pallidus (GP) in the subpallium. The formation of these structures and their interconnections by specific axonal tracts take place in a precise and orchestrated time and spatial-dependent manner during development. However, the knowledge of the molecular and cellular mechanisms that are involved is rather limited. Moreover, while many extracellular cues and specific receptors have been shown to play a role in different aspects of nervous system development, including neuron migration and axon guidance, examples of intracellular signaling effectors involved in these processes are sparse. In the present work, we have shown that the atypical RhoGTPase, Rnd3, is expressed very early during brain development and keeps a dynamic expression in several brain regions including the cortex, the thalamus, and the subpallium. By using a gene-trap allele (Rnd3gt ) and immunological techniques, we have shown that Rnd3gt/gt embryos display severe defects in striatal and thalamocortical axonal projections (SAs and TCAs, respectively) and defects in GP formation already at early stages. Surprisingly, the corridor, an important intermediate target for TCAs is still present in these mutants. Mechanistically, a conditional genetic deletion approach revealed that Rnd3 is primarily required for the normal development of Medial Ganglionic Eminence-derived structures, such as the GP, and therefore acts non-cell autonomously in SAs and TCAs. In conclusion, we have demonstrated the important role of Rnd3 as an early regulator of subpallium development in vivo and revealed new insights about SAs and TCAs development.

Surgical Treatment of Cavernous Malformations Involving the Posterior Limb of the Internal Capsule: Utility and Predictive Value of Preoperative Diffusion Tensor Imaging.

OBJECTIVE: The surgical treatment of cavernous malformations involving the posterior limb of the internal capsule (PLIC-CMs) is challenging. The aim of this study was to determine the utility and predictive value of preoperative diffusion tensor imaging (DTI) in the surgical treatment of PLIC-CMs. METHODS: Patients with PLIC-CMs who were surgically treated between September 2012 and June 2015 were reviewed. All patients underwent preoperative DTI. Three major fiber tracts were selected for evaluation: 1) corticospinal tract (CST); 2) arcuate fasciculus (AF); and 3) optic radiation (OR). The utility of preoperative DTI for surgical approach selection and intraoperative navigation was documented. An involvement grading system of the major fibers was applied to determine the predictive value of preoperative DTI. A last modified Rankin Scale (mRS) score of 0-2 was considered a good outcome, and a last mRS >2 was considered a poor outcome. RESULTS: Thirteen patients with 13 PLIC-CMs were reviewed in this study. All the lesions were radically resected via the corridor formed by CST, AF, and OR. None of the patents suffered from mRS >3, and 7 patients (53.8%) got good outcomes at the last clinic visit. The difference between the preoperative mRS scores and last mRS scores was not significant (P = 0.673). The involvement grade of the fiber tracts was significantly associated with the surgical outcome (P = 0.011). CONCLUSIONS: Preoperative DTI may be a promising tool to determine the surgical approach and predict the surgical outcomes in patients with PLIC-CMs.

Thalamocortical pathfinding defects precede degeneration of the reticular thalamic nucleus in polysialic acid-deficient mice.

The modification of the neural cell adhesion molecule (NCAM) with polysialic acid (polySia) is tightly linked to neural development. Genetic ablation of the polySia-synthesizing enzymes ST8SiaII and ST8SiaIV generates polySia-negative but NCAM-positive (II(-/-)IV(-/-)) mice characterized by severe defects of major brain axon tracts, including internal capsule hypoplasia. Here, we demonstrate that misguidance of thalamocortical fibers and deficiencies of corticothalamic connections contribute to internal capsule defects in II(-/-)IV(-/-) mice. Thalamocortical fibers cross the primordium of the reticular thalamic nucleus (Rt) at embryonic day 14.5, before they fail to turn into the ventral telencephalon, thus deviating from their normal trajectory without passing through the internal capsule. At postnatal day 1, a reduction and massive disorganization of fibers traversing the Rt was observed, whereas terminal deoxynucleotidyl transferase dUTP nick end labeling and cleaved caspase-3 staining indicated abundant apoptotic cell death of Rt neurons at postnatal day 5. Furthermore, during postnatal development, the number of Rt neurons was drastically reduced in 4-week-old II(-/-)IV(-/-) mice, but not in the NCAM-deficient N(-/-) or II(-/-)IV(-/-)N(-/-) triple knock-out animals displaying no internal capsule defects. Thus, degeneration of the Rt in II(-/-)IV(-/-) mice may be a consequence of malformation of thalamocortical and corticothalamic fibers providing major excitatory input into the Rt. Indeed, apoptotic death of Rt neurons could be induced by lesioning corticothalamic fibers on whole-brain slice cultures. We therefore propose that anterograde transneuronal degeneration of the Rt in polysialylation-deficient, NCAM-positive mice is caused by defective afferent innervation attributable to thalamocortical pathfinding defects.

Imaging studies in congenital anophthalmia reveal preservation of brain architecture in 'visual' cortex.

The functional specialization of the human brain means that many regions are dedicated to processing a single sensory modality. When a modality is absent, as in congenital total blindness, 'visual' regions can be reliably activated by non-visual stimuli. The connections underlying this functional adaptation, however, remain elusive. In this study, using structural and diffusion-weighted magnetic resonance imaging, we investigated the structural differences in the brains of six bilaterally anophthalmic subjects compared with sighted subjects. Surprisingly, the gross structural differences in the brains were small, even in the occipital lobe where only a small region of the primary visual cortex showed a bilateral reduction in grey matter volume in the anophthalmic subjects compared with controls. Regions of increased cortical thickness were apparent on the banks of the Calcarine sulcus, but not in the fundus. Subcortically, the white matter volume around the optic tract and internal capsule in anophthalmic subjects showed a large decrease, yet the optic radiation volume did not differ significantly. However, the white matter integrity, as measured with fractional anisotropy showed an extensive reduction throughout the brain in the anophthalmic subjects, with the greatest difference in the optic radiations. In apparent contradiction to the latter finding, the connectivity between the lateral geniculate nucleus and primary visual cortex measured with diffusion tractography did not differ between the two populations. However, these findings can be reconciled by a demonstration that at least some of the reduction in fractional anisotropy in the optic radiation is due to an increase in the strength of fibres crossing the radiations. In summary, the major changes in the 'visual' brain in anophthalmic subjects may be subcortical, although the evidence of decreased fractional anisotropy and increased crossing fibres could indicate considerable re-organization.

Volume reduction of the right anterior limb of the internal capsule in patients with schizotypal disorder.

We have previously reported bilateral volume reductions in the anterior limb of the internal capsule (ALIC) in patients with schizophrenia. The purpose of this study was to extend the volumetric measurements of ALIC to subjects with schizotypal features to explore the neurobiology underlying schizophrenia-spectrum disorders in view of the fronto-thalamic connectivity. Three-dimensional magnetic resonance images were acquired from 24 patients with schizotypal disorder (ICD-10) and 47 healthy volunteers matched for age, gender, handedness, and parental education. Volumetric analyses of the ALIC and anterior parts of the caudate and lentiform nuclei were conducted using consecutive 1-mm thick coronal slices rostral to the anterior commissure. Compared with the comparison subjects, the schizotypal patients had significantly decreased volume in the right ALIC, but there was no significant group difference in the left ALIC volume. Volumes of the anterior part of the caudate or lentiform nucleus did not differ between groups. Volume deficit confined to the right ALIC suggests that limited involvement of the fronto-thalamic connectivity may have some relevance to the sparing of schizotypal patients from the development of overt psychosis.

Abnormal thalamocortical pathfinding and terminal arbors lead to enlarged barrels in neonatal GAP-43 heterozygous mice.

GAP-43 has been implicated in axonal pathfinding and sprouting, synaptic plasticity, and neurotransmitter release. However, its effect on cortical development in vivo is poorly understood. We have previously shown that GAP-43 knockout (-/-) mice fail to develop whisker-related barrels or an ordered whisker map in the cortex. Here we used cytochrome oxidase (CO) histochemistry to demonstrate that GAP-43 heterozygous (+/-) mice develop larger than normal barrels at postnatal day 7 (P7), despite normal body and brain weight. Using serotonin transporter (5HT-T) histochemistry to label thalamocortical afferents (TCAs), we found no obvious abnormalities in other somatosensory areas or primary visual cortex of GAP-43 (+/-) mice. However, TCA projections to (+/-) primary auditory cortex were not as clearly defined. To clarify the mechanism underlying the large-barrel phenotype, we used lipophilic (DiI) axon labeling. We found evidence for multiple pathfinding abnormalities among GAP-43 (+/-) TCAs. These axons show increased fasciculation within the internal capsule, as well as abnormal turning and branching in the subcortical white matter. These pathfinding errors most likely reflect failures of signal recognition and/or transduction by ingrowing TCAs. In addition, many DiI-labeled (+/-) TCAs exhibit widespread, sparsely branched terminal arbors in layer IV, reflecting the large-barrel phenotype. They also resemble those found in rat barrel cortex deprived of whisker inputs from birth, suggesting a failure of activity-dependent synaptogenesis and/or synaptic stabilization in (+/-) cortex. Our findings suggest that reduced GAP-43 expression can alter the fine-tuning of a cortical map through a combination of pathfinding and synaptic plasticity mechanisms.

Asymmetrical myelination of the posterior limb of the internal capsule in infants with periventricular haemorrhagic infarction: an early predictor of hemiplegia.

AIM: To prospectively assess the predictive value of asymmetrical myelination on MRI of the posterior limb of the internal capsule (PLIC) in newborn infants with an intraventricular haemorrhage (IVH) associated with unilateral haemorrhagic parenchymal involvement (PI), for subsequent development of a hemiplegia. METHODS: 12 preterm infants (GA 25-36 wks) and 4 full-term infants were studied. Using cranial ultrasound (US), the pre-term infants were diagnosed to have an IVH with unilateral PI. The term infants presented with a porencephalic cyst (PC) on the first postnatal US, following an antenatal IVH with PI. MRI was performed at 40 wks postmenstrual age in the pre-term infants and during the first 2 weeks of life in the full-term infants, using a 1.5T magnet. Using an inversion recovery sequence, the myelination of the internal capsule was recorded as normal, abnormal or equivocal. Neurological assessment > or = 12 months disclosed the presence of a hemiplegia or asymmetry in tone pattern. RESULTS: All 4 cases with a normal internal capsule had a normal outcome in spite of the development of a PC. All 9 cases with an abnormal PLIC developed a hemiplegia, while 1 of the 3 cases with an equivocal PLIC is normal on neurological assessment, one developed a mild asymmetry in tone and 1 a mild hemiplegia. CONCLUSION: While a symmetrical signal intensity within the internal capsule on MRI, performed at 40 weeks PMA, in infants with an IVH and unilateral PI appears to be strongly related to a normal outcome, an asymmetrical PLIC is an early predictor of future hemiplegia.