Obesity status and obesity-associated gut dysbiosis effects on hypothalamic structural covariance.

BACKGROUND: Functional connectivity alterations in the lateral and medial hypothalamic networks have been associated with the development and maintenance of obesity, but the possible impact on the structural properties of these networks remains largely unexplored. Also, obesity-related gut dysbiosis may delineate specific hypothalamic alterations within obese conditions. We aim to assess the effects of obesity, and obesity and gut-dysbiosis on the structural covariance differences in hypothalamic networks, executive functioning, and depressive symptoms. METHODS: Medial (MH) and lateral (LH) hypothalamic structural covariance alterations were identified in 57 subjects with obesity compared to 47 subjects without obesity. Gut dysbiosis in the subjects with obesity was defined by the presence of high (n = 28) and low (n = 29) values in a BMI-associated microbial signature, and posthoc comparisons between these groups were used as a proxy to explore the role of obesity-related gut dysbiosis on the hypothalamic measurements, executive function, and depressive symptoms. RESULTS: Structural covariance alterations between the MH and the striatum, lateral prefrontal, cingulate, insula, and temporal cortices are congruent with previously functional connectivity disruptions in obesity conditions. MH structural covariance decreases encompassed postcentral parietal cortices in the subjects with obesity and gut-dysbiosis, but increases with subcortical nuclei involved in the coding food-related hedonic information in the subjects with obesity without gut-dysbiosis. Alterations for the structural covariance of the LH in the subjects with obesity and gut-dysbiosis encompassed increases with frontolimbic networks, but decreases with the lateral orbitofrontal cortex in the subjects with obesity without gut-dysbiosis. Subjects with obesity and gut dysbiosis showed higher executive dysfunction and depressive symptoms. CONCLUSIONS: Obesity-related gut dysbiosis is linked to specific structural covariance alterations in hypothalamic networks relevant to the integration of somatic-visceral information, and emotion regulation.

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.

Mapping the molecular and cellular complexity of cortical malformations.

The cerebral cortex is an intricate structure that controls human features such as language and cognition. Cortical functions rely on specialized neurons that emerge during development from complex molecular and cellular interactions. Neurodevelopmental disorders occur when one or several of these steps is incorrectly executed. Although a number of causal genes and disease phenotypes have been identified, the sequence of events linking molecular disruption to clinical expression mostly remains obscure. Here, focusing on human malformations of cortical development, we illustrate how complex interactions at the genetic, cellular, and circuit levels together contribute to diversity and variability in disease phenotypes. Using specific examples and an online resource, we propose that a multilevel assessment of disease processes is key to identifying points of vulnerability and developing new therapeutic strategies.

Global white matter microstructural abnormalities associated with addiction liability score in drug naïve youth.

Abnormalities in brain white matter (WM) structure have been reported in youths having a family history of substance use disorders (SUDs). It was hypothesized that these abnormalities constitute features of the liability for SUDs transmitted across generations. The association between severity of intergenerational risk for SUD, measured by the Transmissible Liability Index (TLI), and white matter microstructure was examined. Diffusion tensor imaging (DTI) measured WM microstructure in forty-four drug-naïve 10-14 year-olds (N = 19 with parental SUD). Metrics of WM microstructure (i.e., fractional anisotropy, radial diffusivity, mean diffusivity and axial diffusivity) were quantified across the whole brain and in four tracts of interest: anterior corona radiata, superior and inferior longitudinal fasciculi and superior fronto-occipital fasciculi. The TLI was completed by the youths, their parents and, when available, their teachers. The relationship between WM structure and TLI score across the entire group was evaluated using linear multiple regression and between group comparisons were also examined. Fractional anisotropy and radial diffusivity in multiple tracts across the brain were significantly associated with TLI scores. Confirming and extending prior research, the findings indicate that global atypicality in WM tracts was linearly related to liability for eventual SUD development in drug naïve youths.

A rare case of cerebellar agenesis: a probabilistic Constrained Spherical Deconvolution tractographic study.

Aim of this study is to show the potential of probabilistic tractographic techniques, based on the Constrained Spherical Deconvolution (CSD) algorithms, in recognizing white matter fiber bundle anomalies in patients with complex cerebral malformations, such as cerebellar agenesis. The morphological and tractographic study of a 17-year-old male patient affected by cerebellar agenesis was performed by using a 3Tesla MRI scanner. Genetic and neuropsychological tests were carried out. An MRI morphological study showed the absence of both cerebellar hemispheres and the flattening of the anterior side of the pons. Moreover, it showed a severe vermian hypoplasia with a minimal vermian residual. The study recognized two thin cerebellar remnants, medially in contact with the small vermian residual, at the pontine level. The third ventricle, morphologically normal, communicated with a permagna cerebello-medullary cistern. Probabilistic CSD tractography identified some abnormal and aberrant infratentorial tracts, symmetrical on both sides. In particular, the transverse pontine fibers were absent and the following tracts with aberrant trajectories have been identified: "cerebello-thalamic" tracts; "fronto-cerebellar" tracts; and ipsilateral and contralateral "spino-cerebellar" tracts. Abnormal tracts connecting the two thin cerebellar remnants have also been detected. There were no visible alterations in the main supratentorial tracts in either side. Neuropsychiatric evaluation showed moderate cognitive-motor impairment with discrete adaptive compensation. Probabilistic CSD tractography is a promising technique that overcome reconstruction biases of other diffusion tensor-based approaches and allowed us to recognize, in a patient with cerebellar agenesis, abnormal tracts and aberrant trajectories of normally existing tracts.

Learning to live without the cerebellum.

The near-total absence of the cerebellum is a rare congenital condition with a wide phenotypic heterogeneity ranging from a severe to mild impairment of motor, cognitive, and behavioral functions. In this study, the case of a 48-year-old right-handed man with a near-total absence of the cerebellum was examined with the aim of understanding the long-term reorganization of a brain developed without a cerebellum. Clinical, neuropsychological evaluation and a neuroimaging study on a 3-T scanner were carried out. Both conventional structural diffusion tensor imaging (DTI) and functional (resting-state fMRI) data were acquired. A severe neuropsychomotor delay in infancy and adolescence involving motor skills, cognitive, and affective competencies was observed, which improved over the years. Conventional MRI findings confirmed the complete absence of the cerebellum. Analysis of DTI and resting-state fMRI data showed an impairment of the executive-control network, involving areas strongly connected with the cerebellum through the frontopontine fibers. The neuroimaging findings excluded the involvement of the extracerebellar structure. In conclusion, our data support the vascular genesis hypothesis for this rare pathology, consistent with an acquired embryonic cerebellar insult. This case also shows that it is possible to learn to live without the cerebellum over time.

Aberrant Executive and Frontoparietal Functional Connectivity in Very Preterm Infants With Diffuse White Matter Abnormalities.

BACKGROUND: Diffuse white matter abnormalities are identified in up to 80% of very preterm infants on magnetic resonance imaging at 40 weeks' postmenstrual age. Several studies have observed an association between diffuse white matter abnormalities and cognitive deficits. We hypothesized that very preterm infants (gestational age ≤32 weeks) with diffuse white matter abnormalities will exhibit reduced executive control and frontoparietal functional connectivity compared with infants without diffuse white matter abnormalities measured using resting state functional magnetic resonance imaging at term-equivalent age. METHODS: We quantified diffuse white matter abnormality volume objectively using an automated segmentation approach and defined diffuse white matter abnormality severity as no-mild (volume ≤50th percentile; N = 13) and moderate-severe (N = 14). Resting state networks of interests were identified using probabilistic independent component analysis. Within network functional connectivity was calculated between the different pair of nodes in a given network using partial correlation coefficients. RESULTS: We studied 27 very preterm infants born at a mean (standard deviation) gestational age of 26.9 (2.0) weeks and imaged at 39.6 (1.4) weeks' postmenstrual age. Within-network connectivity was significantly reduced in the moderate-severe diffuse white matter abnormalities group than in the no-mild diffuse white matter abnormalities group for the executive control (P < 0.001) and frontoparietal (P = 0.02) networks. As expected, connectivity in three control resting state networks was similar: visual (P = 0.17), motor (P = 0.89), and somatosensory (P = 0.69) networks. CONCLUSIONS: Very preterm infants with moderate or severe diffuse white matter abnormalities exhibited reduced functional connectivity in important cognitive and attention networks. This aberrant connectivity may be the early life antecedent to the cognitive deficits reported at 2 years of age or later in such infants.

Syngap1 haploinsufficiency damages a postnatal critical period of pyramidal cell structural maturation linked to cortical circuit assembly.

BACKGROUND: Genetic haploinsufficiency of SYNGAP1/Syngap1 commonly occurs in developmental brain disorders, such as intellectual disability, epilepsy, schizophrenia, and autism spectrum disorder. Thus, studying mouse models of Syngap1 haploinsufficiency may uncover pathologic developmental processes common among distinct brain disorders. METHODS: A Syngap1 haploinsufficiency model was used to explore the relationship between critical period dendritic spine abnormalities, cortical circuit assembly, and the window for genetic rescue to understand how damaging mutations disrupt key substrates of mouse brain development. RESULTS: Syngap1 mutations broadly disrupted a developmentally sensitive period that corresponded to the period of heightened postnatal cortical synaptogenesis. Pathogenic Syngap1 mutations caused a coordinated acceleration of dendrite elongation and spine morphogenesis and pruning of these structures in neonatal cortical pyramidal neurons. These mutations also prevented a form of developmental structural plasticity associated with experience-dependent reorganization of brain circuits. Consistent with these findings, Syngap1 mutant mice displayed an altered pattern of long-distance synaptic inputs into a cortical area important for cognition. Interestingly, the ability to genetically improve the behavioral endophenotype of Syngap1 mice decreased slowly over postnatal development and mapped onto the developmental period of coordinated dendritic insults. CONCLUSIONS: Pathogenic Syngap1 mutations have a profound impact on the dynamics and structural integrity of pyramidal cell postsynaptic structures known to guide the de novo wiring of nascent cortical circuits. These findings support the idea that disrupted critical periods of dendritic growth and spine plasticity may be a common pathologic process in developmental brain disorders.

Bilateral agenesis of arcuate fasciculus demonstrated by fiber tractography in congenital bilateral perisylvian syndrome.

Congenital bilateral perisylvian syndrome (CBPS) is a type of cortical developmental abnormality associated with distinctive clinical and imaging features. Clinical spectrum of this syndrome is quite heterogeneous, with different degrees of neurological impairment in affected individuals. High-definition magnetic resonance imaging (MRI) has a great importance in revealing the presence of CBPS, but is limited in elucidating the heterogeneous clinical spectrum. The arcuate fasciculus (AF) is a prominent language tract in the perisylvian region interconnecting Broca and Wernicke areas, and has a high probability of being affected developmentally in CBPS. Herein, we report a case of CBPS with investigation of AF using diffusion tensor imaging (DTI) and fiber tractography in relation to clinical findings. We postulated that proven absence of AF on DTI and fiber tractography would correlate with a severe phenotype of CBPS.

Low-intensity repetitive transcranial magnetic stimulation improves abnormal visual cortical circuit topography and upregulates BDNF in mice.

Repetitive transcranial magnetic stimulation (rTMS) is increasingly used as a treatment for neurological and psychiatric disorders. Although the induced field is focused on a target region during rTMS, adjacent areas also receive stimulation at a lower intensity and the contribution of this perifocal stimulation to network-wide effects is poorly defined. Here, we examined low-intensity rTMS (LI-rTMS)-induced changes on a model neural network using the visual systems of normal (C57Bl/6J wild-type, n = 22) and ephrin-A2A5(-/-) (n = 22) mice, the latter possessing visuotopic anomalies. Mice were treated with LI-rTMS or sham (handling control) daily for 14 d, then fluorojade and fluororuby were injected into visual cortex. The distribution of dorsal LGN (dLGN) neurons and corticotectal terminal zones (TZs) was mapped and disorder defined by comparing their actual location with that predicted by injection sites. In the afferent geniculocortical projection, LI-rTMS decreased the abnormally high dispersion of retrogradely labeled neurons in the dLGN of ephrin-A2A5(-/-) mice, indicating geniculocortical map refinement. In the corticotectal efferents, LI-rTMS improved topography of the most abnormal TZs in ephrin-A2A5(-/-) mice without altering topographically normal TZs. To investigate a possible molecular mechanism for LI-rTMS-induced structural plasticity, we measured brain derived neurotrophic factor (BDNF) in the visual cortex and superior colliculus after single and multiple stimulations. BDNF was upregulated after a single stimulation for all groups, but only sustained in the superior colliculus of ephrin-A2A5(-/-) mice. Our results show that LI-rTMS upregulates BDNF, promoting a plastic environment conducive to beneficial reorganization of abnormal cortical circuits, information that has important implications for clinical rTMS.

Pattern of structural and functional brain abnormalities in asymptomatic granulin mutation carriers.

BACKGROUND: To investigate the patterns of brain atrophy, white matter (WM) tract changes, and functional connectivity (FC) abnormalities in asymptomatic granulin (GRN) mutation carriers. METHODS: Ten cognitively normal subjects (five mutation carriers, GRN+; years to estimated disease onset: 12±7; five mutation noncarriers, GRN-) underwent a clinical and imaging (structural, diffusion tensor, and resting-state functional magnetic resonance imaging) assessment. Brain atrophy was measured with cortical thickness analysis, WM abnormalities with tract-based spatial statistics, and FC with independent component analysis. RESULTS: GRN+ showed smaller cortical thickness than GRN- in the right orbitofrontal and precentral gyrus and left rostral middle frontal gyrus. WM tracts abnormalities were limited to increased axial diffusivity in the right cingulum, superior longitudinal fasciculus, and corticospinal tract. There were no differences in FC of resting-state networks. CONCLUSION: Brain atrophy and WM tract abnormalities in frontal-parietal circuits can be detected at least a decade before the estimated symptom onset in asymptomatic mutation carriers.

Microstructural abnormalities in language and limbic pathways in orphanage-reared children: a diffusion tensor imaging study.

This study utilized diffusion tensor imaging fiber tractography to examine the miscrostructural integrity of limbic and paralimbic white matter tracts in 36 children (age M = 124 months) with histories of early deprivation, raised from birth in orphanages and subsequently adopted into the United States, compared to 16 age-matched typically developing children. We found increased mean diffusivity bilaterally in the arcuate fasciculus and increased mean diffusivity and reduced fractional anisotropy bilaterally in the uncinate fasciculus and cingulum in children with early deprivation. Microstructural integrity of the left arcuate fasciculus and right cingulum was related to language and behavioral functioning, respectively. White matter abnormalities were also associated with length of deprivation and time in the adoptive home. Our findings suggest that white matter pathways, connecting limbic and paralimbic brain regions is abnormal in children with histories of early deprivation, with some pathways appearing more susceptible to early deprivation than others.

Mutation of the BiP/GRP78 gene causes axon outgrowth and fasciculation defects in the thalamocortical connections of the mammalian forebrain.

Proper development of axonal connections is essential for brain function. A forward genetic screen for mice with defects in thalamocortical development previously isolated a mutant called baffled. Here we describe the axonal defects of baffled in further detail and identify a point mutation in the Hspa5 gene, encoding the endoplasmic reticulum chaperone BiP/GRP78. This hypomorphic mutation of BiP disrupts proper development of the thalamocortical axon projection and other forebrain axon tracts, as well as cortical lamination. In baffled mutant brains, a reduced number of thalamic axons innervate the cortex by the time of birth. Thalamocortical and corticothalamic axons are delayed, overfasciculated, and disorganized along their pathway through the ventral telencephalon. Furthermore, dissociated mutant neurons show reduced axon extension in vitro. Together, these findings demonstrate a sensitive requirement for the endoplasmic reticulum chaperone BiP/GRP78 during axon outgrowth and pathfinding in the developing mammalian brain.

[Endophenotypes and autism spectrum disorders]. / Endophénotypes et tro ubles du spectre autistique.

Genetic factors of ASD stay unknown after 30 years of research. The concept of "endophenotype" seems an interesting approach toward these factors. "Enlarged phenotypes" in families of ASD persons could lead to the definition of ASD endophenotypes. "Enlarged phenotypes" include clinical symptoms, morphological and functional brain anomalies enlightening ASD physiopathology and brain physiology. Knowledge of endophenotypes will lead to ASD genetic risk factors. This knowledge will open ethical questions about prenatal diagnosis.

Frontoparietal connectivity in substance-naïve youth with and without a family history of alcoholism.

Frontoparietal connections underlie key executive cognitive functions. Abnormalities in the frontoparietal network have been observed in chronic alcoholics and associated with alcohol-related cognitive deficits. It remains unclear whether neurobiological differences in frontoparietal circuitry exist in substance-naïve youth who are at-risk for alcohol use disorders. This study used functional connectivity magnetic resonance imaging and diffusion tensor imaging to examine frontoparietal connectivity and underlying white matter microstructure in 20 substance-naïve youth with a family history of alcohol dependence and 20 well-matched controls without familial substance use disorders. Youth with a family history of alcohol dependence showed significantly less functional connectivity between posterior parietal and dorsolateral prefrontal seed regions (ps<.05), as compared to family history negative controls; however, they did not show differences in white matter architecture within tracts subserving frontoparietal circuitry (ps>.34). Substance-naïve youth with a family history of alcohol dependence show less frontoparietal functional connectivity in the absence of white matter microstructural abnormalities as compared to youth with no familial risk. This may suggest a potential neurobiological marker for the development of substance use disorders.

Default mode network dysfunction in adults with prenatal alcohol exposure.

Prenatal alcohol exposure (PAE) is known to cause significant cognitive and attentional dysfunction. Given the relationship between default mode network (DMN) activity and task-related attentional modulation, it is possible that PAE affects activity of this network. In the present study, task-related deactivation as well as structural and resting state functional connectivity of the DMN were examined using diffusional tensor imaging and functional magnetic resonance imaging in non-dysmorphic and dysmorphic PAE populations and compared to healthy controls. The dysmorphic PAE group was found to have reduced DMN deactivation as compared to controls, indicating poorer attentional modulation during the cognitive task. Additionally, structural connectivity and baseline functional connectivity were lower in both PAE groups as compared to controls. Primarily the findings suggest that learning problems seen with PAE may be a combination of general attentional and specific cognitive deficits. A secondary implication is that DMN activity is affected to varying extents depending on the degree of PAE.

Slit-Robo signals regulate pioneer axon pathfinding of the tract of the postoptic commissure in the mammalian forebrain.

During early vertebrate forebrain development, pioneer axons establish a symmetrical scaffold descending longitudinally through the rostral forebrain, thus forming the tract of the postoptic commissure (TPOC). In mouse embryos, this tract begins to appear at embryonic day 9.5 (E9.5) as a bundle of axons tightly constrained at a specific dorsoventral level. We have characterized the participation of the Slit chemorepellants and their Robo receptors in the control of TPOC axon projection. In E9.5-E11.5 mouse embryos, Robo1 and Robo2 are expressed in the nucleus origin of the TPOC (nTPOC), and Slit expression domains flank the TPOC trajectory. These findings suggested that these proteins are important factors in the dorsoventral positioning of the TPOC axons. Consistently with this role, Slit2 inhibited TPOC axon growth in collagen gel cultures, and interfering with Robo function in cultured embryos induced projection errors in TPOC axons. Moreover, absence of both Slit1 and Slit2 or Robo1 and Robo2 in mutant mouse embryos revealed aberrant TPOC trajectories, resulting in abnormal spreading of the tract and misprojections into both ventral and dorsal tissues. These results reveal that Slit-Robo signaling regulates the dorsoventral position of this pioneer tract in the developing forebrain.

Abnormal white matter integrity in young children with autism.

This study investigated white matter integrity in young children with autism using diffusion tensor imaging (DTI). Twenty-two children with autism, mean age 3:2 years, and 32 controls, mean age 3:4 years, participated in the study. Tract-based spatial statistics (TBSS) revealed white matter abnormalities in several distinct clusters within the genu and body of the corpus callosum (CC), left superior longitudinal fasciculus (SLF) and right and left cingulum (Cg). TBSS-VOIs analysis was performed in the clusters where differences in fractional anisotropy (FA) were detected to investigate the relationship between changes in FA and diffusivity indices. In all VOIs, increase in FA was caused by a decrease in radial diffusivity (Dr), while no changes in axial diffusivity (Da) or mean diffusivity (MD) were observed. Tractography analysis was applied to further study the CC, SLF, and Cg. Witelson parcellation scheme was used for the CC. Significant increase in FA was seen in children with autism in the mid-body of the CC as well as in the left Cg. It is suggested that such abnormal white matter integrity in young children with autism may adversely affect connectivity between different brain regions and may be linked to some of the behavioral impairments apparent in autism.

Cerebellar dentate dysplasia.

Dysplasia of the cerebellar dentate nucleus is a state of apparent maturational arrest that involves the cerebellar dentate nucleus. Origins include Joubert syndrome, other disorders of axon guidance and dentato-olivary dysplasia. An overview is given, linking the diverse etiologies.

The UNC5C netrin receptor regulates dorsal guidance of mouse hindbrain axons.

The cerebellum receives its input from multiple precerebellar nuclei located in the brainstem and sends processed information to other brain structures via the deep cerebellar neurons. Guidance molecules that regulate the complex migrations of precerebellar neurons and the initial guidance of their leading processes have been identified. However, the molecules necessary for dorsal guidance of precerebellar axons to the developing cerebellum or for guidance of decussating axons of the deep nuclei are not known. To determine whether Unc5c plays a role in the dorsal guidance of precerebellar and deep cerebellar axons, we studied axonal trajectories of these neurons in Unc5c(-/-) mice. Our results show that Unc5c is expressed broadly in the precerebellar and deep cerebellar neurons. Unc5c deletion disrupted long-range dorsal guidance of inferior olivary and pontine axons after crossing the midline. In addition, dorsal guidance of the axons from the medial deep cerebellar and external cuneate neurons was affected in Unc5c(-/-) mice, as were anterior migrations of pontine neurons. Coincident with the guidance defects of their axons, degeneration of neurons in the external cuneate nucleus and subdivisions of the inferior olivary nucleus was observed in Unc5c(-/-) mice. Lastly, transgenic expression of Unc5c in deep neurons and pontine neurons by the Atoh1 promoter rescued defects of the medial deep cerebellar and pontine axons observed in Unc5c(-/-) embryos, demonstrating that Unc5c acts cell autonomously in the guidance of these axons. Our results suggest that Unc5c plays a broad role in dorsal guidance of axons in the developing hindbrain.