Dissertations / Theses on the topic 'Corpus callosum'

In general, highly hypnotizable individuals ("highs") have exhibited greater abilities to focus attention and inhibit pain than low hypnotizable individuals ("lows"). Furthermore, highs appear to have faster neural processing than lows. The present study investigated differences between lows and highs in morphological volume of some brain structures associated with inhibitory and excitatory neural processing, particularly the corpus callosum (CC). Participants were 18 healthy university students, aged 18 to 29, with no history of concussion or medical disorders. They were in a functional Magnetic Resonance Image (fMRI) study examining the neurophysiology of pain and hypnotic analgesia (Crawford, Horton, Harrington, et al., 1998; Downs et al., 1998). As assessed by the group version (Crawford & Allen, 1982) of the Stanford Hypnotic Susceptibility Scale, Form C (SHSS:C; Weitzenhoffer & Hilgard, 1962), there were eight highs (four women and four men; SHSS:C M = 11.0) and 10 lows (five men and five women; SHSS:C M = 2.1). Highs were able to successfully eliminate perception of pain and distress to experimental noxious stimuli. Their anatomical MRIs were measured to assess relationships between brain structure volume (CC, medial cortex, anterior brain regions) and hypnotizability. In comparison to lows, highs had a significantly larger CC volume in the rostrum and isthmus, inferred to reflect larger transcallosal axon diameter or greater axon myelination. For highs, but not lows, there were significant relationships between forebrain volume and the total CC, rostrum, and splenium. Findings provide support for the neuropsychophysiological model of Crawford and her associates (e.g. Crawford, 1994a, 1994b; Crawford & Gruzelier, 1992) proposing a more effective attentional system of inhibitory processes in highs than lows. Furthermore, the data suggest that the more effective systems of attentional and inhibitory processes enhanced neural processing speed, and interhemispheric transfer times seen in highs than lows, may be associated with morphological differences in certain anterior and posterior CC regions. These regions are known to be involved in the allocation of inhibitory and excitatory transfer of information between hemispheres.
Ph. D.

The corpus callosum has a distinct topographical organisation along its length, with different cortical areas connecting through different regions of the callosum. This has led to a number of different ways to divide the callosum along its length. The aim of this thesis was to apply a relatively novel method of callosal sub~ivision to look for meaningful brain/behaviour correlations in bimanual coordination and dichotic listening tasks. Measurements of the corpus callosum were obtained from a cohort of healthy adults who underwent magnetic resonance (MR) imaging. The same method was also applied to examine differences in callosal size in adults with Neurofibromatosis type I (NFl), a disease in which a larger callosum has been found in children with NFL In addition, diffusion tensor imaging was also obtained to examine underlying microstructural differences in regions of size difference. Chapter one provides an overview of normal callosal development, topographical arrangement and differences in fibre composition across the length and a discussion of methods of callosal subdivision. Finally, a basic MR physics section and more specifically diffusion tensor imaging is provided. Chapter two is a generic methods section discussing how the callosal measures used to produce brain/behaviour correlations in the subsequent two chapters were obtained. Chapters three and four discuss the brain/behaviour relationships derived from the bimanual coordination (chapter three) and dichotic listening (chapter four) tasks. Chapter five is the examination of callosal size in adults with NFl and mat~hed healthy controls and subsequent diffusion tensor imaging investigation. Finally, chapter six reviews the results of the brain/behaviour correlations, their place in the literature and possible future investigations. The results of chapter five are also discussed with possible future investigations of brain/behaviour relationships. Finally, future methods of callosal divisions based on better understanding of the underlying cortical connections are theorised.

Background. Resilience is the capacity of individuals to resist mental disorders despite exposure to stress. Little is known about its neural underpinnings. The putative variation of white-matter microstructure with resilience in adolescence, a critical period for brain maturation and onset of high-prevalence mental disorders, has not been assessed by diffusion tensor imaging (DTI). Lower fractional anisotropy (FA) though, has been reported in the corpus callosum (CC), the brain’s largest white-matter structure, in psychiatric and stress-related conditions. We hypothesized that higher FA in the CC would characterize stress-resilient adolescents. Method. Three groups of adolescents recruited from the community were compared: resilient with low risk of mental disorder despite high exposure to lifetime stress (n = 55), at-risk of mental disorder exposed to the same level of stress (n = 68), and controls (n = 123). Personality was assessed by the NEO-Five Factor Inventory (NEO-FFI). Voxelwise statistics of DTI values in CC were obtained using tract-based spatial statistics. Regional projections were identified by probabilistic tractography. Results. Higher FA values were detected in the anterior CC of resilient compared to both non-resilient and control adolescents. FA values varied according to resilience capacity. Seed regional changes in anterior CC projected onto anterior cingulate and frontal cortex. Neuroticism and three other NEO-FFI factor scores differentiated non-resilient participants from the other two groups. Conclusion. High FA was detected in resilient adolescents in an anterior CC region projecting to frontal areas subserving cognitive resources. Psychiatric risk was associated with personality characteristics. Resilience in adolescence may be related to white-matter microstructure.

Thesis advisor: Ellen Winner
Recent studies have shown differences between several structures in the brains of professional level musicians and non-musicians. Professional musicians form an ideal group to study changes in the human brain due to the unique abilities required of them. Since many musicians begin training at a young age, it is assumed that these differences are attributable to intense, early experience brought on by the cognitive and motor demands of music training. However, it remains to be seen whether these structural differences are due to changes brought on by experience or preexisting ones which draw children to music lessons. Using magnetic resonance images, I compared the size of the corpus callosums in two groups of children who ranged between the ages of five and seven, one just beginning music lessons and another not beginning music lessons. I also compared the groups in terms of their performance on a finger tapping test for differences in speed and accuracy. A second set of comparisons of callosal size was conducted between nine-to-eleven-year-olds who had been taking music lessons for at least a year and those who had not. Differences in the five-to-seven-year-olds were seen in the anterior corpus callosum corrected for brain volume between the musician and non-musician groups. Differences in accuracy of finger tapping were seen between the musicians and non musicians, as well as between those in the musician group who had received less than sixteen or twenty-five weeks of training versus those who had received less. These findings indicate that while musicians start out with at least one slightly larger measure of corpus callosum size, differences in finger skill tend to develop slowly
Thesis (BA) — Boston College, 2004
Submitted to: Boston College. College of Arts and Sciences
Discipline: Psychology
Discipline: College Honors Program

Background: There is little published research on the wide variation of corpus callosum (CC) morphology in children, the assessment of which is made difficult by the complex alteration of its appearance in childhood. Objective: The purpose of our study was to assess the morphology of the CC on mid-sagittal T1- weighted magnetic resonance imaging (MRI) in a large number of children and correlate the findings with demographic and clinical criteria. Materials and methods: We reviewed all brain mid-sagittal T1-weighted MRI’s performed from July to December 2015 and obtained relevant demographic and clinical information from the accompanying report and laboratory system. The CC morphology was analysed by three radiologists and compared using cross tabulation with the chi-square test and ANOVA. Interobserver correlation was assessed using Kappa coefficient of conformance. Results: 257 patients with mean age 72±60 months were included, 142 were male (55%). In abnormal MRI’s the CC was less likely to have an identifiable isthmus and was more likely to be convex, thin and have separation of the fornix insertion (all p<0.01). In young children (< 5 years) the CC was also less likely to have an identifiable isthmus (p=0.01) and was more likely to be convex (p=0.04) but the fornix was more likely to insert normally (p<0.01). Children with tuberous sclerosis had significantly thinner splenia (p=0.02). Conclusion: There is a distinct pathological appearance of the CC. The immature appearance of the corpus callosum can mirror this but is distinguished by normal insertion of the fornix and normal quantitative measurements. Splenial thinning in children with tuberous sclerosis warrants further investigation.

Studies of sexual dimorphism in the corpus callosum (CC) have employed a variety of methodologies for measurement and normalization but have yielded disparate results. The present work demonstrates how in some cases different manipulations of the same raw data, corresponding to different commonly used methodologies, produce discordant results. Midsagittal CC area was measured from magnetic resonance images (MRIs) of 137 young normal volunteers. Three strategies intended to normalize for average differences in brain size between the sexes, as well as five different normalization variables, were contrasted and evaluated. The stereotaxic method normalizes for inter-subject differences in overall brain size by scaling MRIs into a standardized space. The ratio method uses one of five different indices of brain size and divides it into CC area. The covariate method uses one of these indices as a covariate in statistical analyses. Male subjects show significantly larger absolute total area, as well as anterior third and posterior midbody. However, in 2 of 3 normalization strategies, namely the stereotaxic and ratio methods, females show relatively larger total area, anterior midbody and splenium. The covariate method did not show any significant differences at the .05 level. Results suggest that different approaches to normalization and analysis are not necessarily equivalent and interchangeable.

L’obbiettivo del nostro studio è stato quello di comprendere il meccanismo che controlla la regolazione del flusso sanguigno cerebrale nel corpo calloso (CC) umano con il fine di spiegare l’effetto BOLD, precedentemente scoperto da Fabri e collaboratori nel 2011. Le analisi per determinare la presenza, il numero, la distribuzione e la morfologia delle cellule immunopositive all’enzima ossido nitrico sintetasi neuronale (nNOS) sono eseguite sul corpo calloso e sul’indusium griseum (IG). L’Ossido nitrico (NO) è un neurotrasmettitore gassoso largamente diffuso nel cervello umano ed ha, tra le altre funzioni, un potente effetto vasodilatante e perciò contribuisce a regolare il flusso sanguigno cerebrale. Sezioni seriali sagittali ottenute da blocchetti in paraffina e da taglio del tessuto in congelato sono state utilizzate per l’analisi immunoistochimica sul CC e sul IG. L’intensa marcatura che si è ottenuta ha dimostrato la presenza di cellule immunopositive al nNOS, e grazie alla microscopia a fluorescenza ne è stata confermata la loro natura neuronale e astrocitaria. Cellule neuronali immunopositive all’nNOS sono state osservate sia nel CC che nell’IG mentre gli astrociti che lo esprimono erano solo presenti nel CC. I neuroni nNOS positivi hanno mostrato diverse morfologie e risultavano essere piu abbondanti a 1mm a partire dalla linea mediana, per l’IG e a 4mm per il CC con un picco di massima abbondanza nel corpo del CC. In alcuni casi questi nueroni erano localizzati principalmente nell’interfaccia tra IG e CC e piu specificatamente in prossimita delle arterie piali, arteriole che originano dall’arteria sopracallosale che poi si affosano nel corpo calloso. La presenza di neuroni nNOS positivi in prossimità di vasi sanguigni, in questi due tessuti suggeriscono un loro plausibile ruolo nella regolazione neurovascolare del CC che potrebbero quindi ipoteticamente spiegare l’effetto BOLD osservato in risonanza. l’IG inoltre potrebbe giocare un ruolo attivo nel controllo della vascolarizzazione del CC, ed è quindi probabile e che non sia solo un tessuto di rimanenza embrionale come precedentemente si riteneva ma un tessuto con un sua funzione specifica. Infine è stata osservata per la prima volta la presenza di astrociti nNOS positivi nel corpo calloso umano. Queste cellule variavano nella presenza, nel numero e nelle loro distribuzione in base a diverse condizioni di ossigenazione sistemica che avvenivano nel momento del decesso. Infatti nei soggetti deceduti dopo una breve ipossia gli astrociti nNOS positivi erano assenti, mentre risultavano essere molto abbondanti nei soggetti deceduti con un ipossia prolungata. L’immunopositività degli astrociti sembrerebbe quindi essere correlata alla durata dell’ipossia cerebrale al momento della morte.
The aim of the present study is to investigate the possible mechanism for the control of cerebral blood flow in the corpus callosum (CC), that could explain the BOLD effect previously found (Fabri et al., 2011). The presence, number, distribution and morphology of neuronal Nitric Oxyde Sinthase (nNOS) positive cells was investigated in the corpus callosum (CC) and indusium griseum (IG). Nitric Oxyde (NO) is a gaseous neurotransmitter largely diffused in the brain, whichexerts a powerful vasodilatory effect, and therefore it can contribute to regulate the cerebral blood flow. Sagittal serial sections from paraffin or frozen autoptic specimens of human adult CC and overlying IG were processed for immunohistochemistry and immunofluorescence analysis, using an antibody against the neuronal form of the enzyme Nitric Oxyde Synthase (nNOS). The stainings revealed the presence of many nNOS immunopositive cells. By double labeling technique with immunofluorescence at confocal microscopy, it has been shown that in the CC both neurons and astrocytes positive to nNOS antibody were present, and their number varied in different conditions, as detailed below. In the IG, only neurons nNOS positive were found. Neurons showed different morphologies, were more numerous 1 mm apart from the medial line in IG and 4 mm in CC, with a peak over the body of the CC. In some cases, they were located at the boundary between IG and CC, more densely packed in proximity to the pial arteries penetrating into the CC. The significant presence of nNOS immunopositive neurons in these two structures suggests that they might have a role in the neurovascular regulation of CC, moreover the IG could plays a functional role in the adult brain. The presence of nNOS positive astrocytes in the human CC has been here demostrated for the first time. As previously mentioned, their number and distribution varied in different conditions: nNOS positive astrocytes were absent in samples from subjects deceased after a short hypoxia; their number and labeling intensity increased with the hypoxia prolongation. Neuronal NOS immunopositivity of CC astrocytes seems thus related to the hypoxia duration and the consequent brain damage.

Anatomical research of the morphology of the corpus callosum (CC) has provided a baseline for normal development of the CC. Although a large extent of variation amongst individuals has been reported, there are certain asymmetries that are consistently found in the size and shape of the CC on a midsagittal view of the brain. As the CC is the major commissural tract in the brain, it is acceptable to assume that structural variation in the CC may give clues towards the diagnosis of specific diseases. Studies relating alterations in the size and shape of the CC to the diagnosis of disorders have been done in individuals with schizophrenia, bipolar disorder (and depression. Thus, knowledge of CC anatomy in association with sex and age related changes can be helpful in providing a baseline for the diagnosis and progression of a specific disease. Morphological changes with regard to sex and age have been the topic of an extensive amount of research. However, there still remains considerable controversy as some studies report significant differences and others report none. The aim of this study was to provide a detailed description of the anatomy and variations of the corpus callosum morphology in a South African population. A primary data set was compiled using a cadaveric population, and these results were compared to a secondary data set, using a healthy living population. Lastly, the results from both data sets were then compared with a third data set, comprising of a mental disorder population, and results gained from previous studies in order to determine possible diagnoses of certain mental disorders based on CC morphology. In this study, there was no sexual dimorphism observed in the thickness of the genu, splenium and trunk in all three samples. In the cadaver sample there was no difference in the length of the CC. In the mental disorder sample there was no sexual dimorphism in the length of the CC and cerebrum. However, in the cadaver sample there was a significant difference in the length of the cerebrum between the sexes. In the healthy MRI scan there was a statistically significant difference observed in the length of the CC and the length of the cerebrum. It was found that there was no statistically significant difference in the thickness of the genu, trunk, and length of the CC and length of the cerebrum with age in all three samples measured. There was a statistically significant difference observed in the thickness of the splenium in the healthy MRI scan sample in individuals over the age of 60 years of age. This difference was not observed in the cadaver or mental disorder sample. There were no statistically significant differences in the various CC parameters measured in the various mental disorders measured. With the exception of two parameters, no differences in measurements were observed between the cadaver and healthy MRI sample. The two exceptions were the thickness of the trunk and the length of the cerebrum. Therefore, with the exception of the above mentioned cases, measurements between cadavers and living samples can be used interchangeably. Thus, the concerns about shrinkage in cadaver studies are negligible. However, when comparing the cadaver and healthy MRI scan sample with the mental disorder CT scan sample there was a statistically significant difference observed in every CC parameter measured. Thus, there is a rather noticeable difference in the anatomical structure of the CC in individuals suffering from mental disorders. Data on normal CC morphology is under represented in the South African population. Observations of variations from normal CC morphology can be used as an indicator for the possibility of a mental disorder.
Dissertation (MSc)--University of Pretoria, 2017.
Anatomy
MSc
Unrestricted

Disorders of the corpus callosum (ADCC) present developmental challenges to children and adults. These disorders are characterized by symptoms of abnormal behaviors and/or thinking patterns. Because ADCC may exist in combination with other disabilities, individual IQs and the severity and problems vary from individual to individual. Using the double ABCx model of family adaptation to stress related to a family member with a disability, the purpose of this cross-sectional study was to provide the first evaluation of parental adaptation among parents of children with ADCC. The final sample, 265 mothers of children with ADCC, was recruited through online support groups for ADCC parents. Parent adaptation was operationally defined as quality of life and operationalized by scores on the World Health Organization (WHO) Quality of Life Questionnaire (QOL). The predictors were measured by the Questionnaire on Resources and Stress (QRS), Family Empowerment Scale (FES), Sense of Coherence Scale (SOC), and Coping Health Inventory for Parents (CHIP). Linear regressions were used to evaluate the predictors in the 4-factor double ABCx prediction model of parent adaptation. Except for parent stress level, family empowerment, sense of coherence, and coping styles were statistically significant predictors of parental quality of life. That is, mothers who reported experiences of empowerment, coherence, and positive coping also have high self-reported quality of life. The findings, the first for experiences of parents of children with ADCC, provide valuable information for further research, but also for other parents and those who may be instrumental in the development of supportive services for this population.

This thesis describes a novel voxel‐based analysis of the transverse (T₂) relaxation decay curve to quantify myelin water fraction (MWF). Multi‐echo T₂ relaxation decay data was acquired for 5 preadolescent males (age range 9 – 12 years). A novel signal to noise filter appropriate for multi‐exponential T₂ analysis was then applied to remove voxels which did not accurately fit the modelled curve. The remaining voxels were designated “highly myelinated” if their MWF was greater than a certain critical value. A range of signal to noise filter cut‐off values and highly myelinated critical values were investigated. This thesis demonstrates, for the first time, a very strong and significant correlation (r = 0.990, p = 0.001) between verbal intelligence quotient scores on the Wechsler Intelligence Scale for Children – Revised and myelination in the corpus callosum of developing children. This relationship is supported by a growing number of studies showing a correlation between white matter development and cognitive ability. In addition, due to the restricted age range of our subjects, this work is able to show the individual variations in myelin maturation rates.

Peripheral neuropathy associated with agenesis of the corpus callosum (ACCPN or HMSN/ACC) is a severe polyneuropathy affecting both the peripheral nervous system and the central nervous system. It is transmitted as an autosomal recessive trait and is particularly frequent in the French Canadian population of Quebec (Canada). The disease was linked to chromosome 15 in 1996 by Dr. Rouleau's team.
We genotyped polymorphic markers in the ACCPN candidate region on chromosome 15 in over 67 patients and 200 control individuals. Observation of affected haplotypes confirmed the presence of a founder effect in the French Canadian population. Recombination analysis reduced the candidate interval to approximately 2 cM between markers D15S1040 and ACTC on chromosome 15. Linkage disequilibrium analysis suggested the gene resides nearest marker D15S1232. A physical map of the newly refined candidate region was constructed using YAC, BAC and PAC clones. These clones were used to confirm the position of candidate ESTs and genes as being either within or outside the ACCPN candidate region.
The connexin 36 gene, which was confirmed to reside within the region, was excluded as the gene responsible for ACCPN using SSCP analysis. The SLC12A6 gene was also confirmed to reside within the candidate interval and was tested for mutations using SSCP, dHPLC and sequence analyses. We found a total of four disease-specific mutations in SLC12A6, all of which are expected to truncate the KCC3 protein (the protein produced by the SLC12A6 gene). Two of the four mutations were identified in the French Canadian population; 80 French Canadian ACCPN patients are homozygous for the c.2436delG in exon 18 and one French Canadian patient is a compound heterozygote, having the c.2436delG mutation as well as the 1584_1585delCTinsG mutation in exon 11. Two additional mutations were identified in one Turkish and one Italian family in exons 22 and 15 respectively. The effects of the c.2436delG mutation on KCC3 function was studied in X. laevis oocytes and the truncated protein is not functional. Finally, collaborators at Vanderbilt University disrupted the slc12a6 gene in the mouse and found a phenotype similar to the human disease.
Identification of SLC12A6 as the gene mutated in ACCPN will allow for accurate molecular diagnosis as well as carrier testing in the French Canadian population. It is also the first step in understanding the molecular mechanism leading to the disease.

OBJECTIVE This thesis examines sex differences in the structural properties of the corpus callosum (CC) during adolescence and investigates the possible role of sex hormones in the development of these sex differences, as well as hormonal effects on the inter-individual variations in the structure of the CC in young women. DESIGN This thesis is conducted on three separate study samples: 1) the Saguenay Youth Study (SYS) sample (n=737); 2) the IMAGEN Study sample (n=1,979); and 3) the Cycle Study sample (n=26). The SYS and IMAGEN studies are large-scale studies carried out with magnetic resonance imaging (MRI) in typically developing adolescents from Canada (12 to 18 years) and Europe (13 to 15 years), respectively. In these studies, the “sex hormone-CC” relationship is explored by examining the association between the CC and: testosterone level, duration of sex hormone exposure (since menarche), puberty stage and contraceptive use. The Cycle study examines the CC of 13 freely cycling and 13 oral contraceptives (OCP) using young women (18 to 30 years) scanned using MRI across four separate phases of their menstrual cycle. Freesurfer-based computational anatomy is used to estimate the volume of the total corpus callosum and its segments in all three studies. Magnetization transfer imaging (MTI) is used to assess microstructural properties of the corpus callosum in the Cycle study. RESULTS The relative volume of the corpus callosum is seen to be sexually dimorphic in both the SYS and IMAGEN adolescents with a female versus male advantage that is particularly significant for the anterior, central and posterior segment of the corpus callosum; the mid-anterior segment is larger in males versus females. Pubertal stage of adolescent boys (SYS) demonstrates a negative correlation with the relative volume of the anterior CC and a positive correlation with the relative volume of the mid-anterior CC. These associations are consistent with the sex differences observed (anterior: F>M; mid-anterior: M>F), thus suggesting that male sex hormones that are responsible for inducing pubertal development of boys may play a role in generating the sexually dimorphic volume of the corpus callosum in a region-specific manner. Contraceptive use in adolescent girls (SYS and IMAGEN) is negatively associated with the relative volume of the corpus callosum. In addition, the Cycle study demonstrates a trend for lower MTR values in women using contraceptives versus freely cycling women, thus suggesting that the natural sex steroids suppressed by use of oral contraceptives may exert a positive effect on the volume of the CC, possibly by increasing the degree of myelination. The Cycle study demonstrates an increase in the relative volume of the total corpus callosum of freely cycling women from the ovulatory to the luteal phase with corresponding decreases in the MTR value of the total CC. This finding suggests that increased production of progesterone during the luteal phase may cause an increase in the relative volume of the CC, possibly by increasing the axonal calibre. CONCLUSION Sex steroids influence the structure (relative volume and MTR) of the corpus callosum.

Heparan sulphate proteoglycans (HSPGs) are a family of molecules that are found on the surface of cells or in the extracellular matrix, where they are involved in regulating key signalling events required for normal mammalian brain development. It is thought that specificity of HSPGs for particular signalling processes is encoded by their heparan sulphate (HS) sugar side chains, which can be modified post-translationally to yield huge variation in HS structure. Different sulphation patterns are generated by the action of the heparan sulphate sulfotransferases (HSTs) and sulfatase enzymes, which add or remove sulphate groups to specific positions on residues of the HS side chains. Depending on the expression of these enzymes and the resulting heparan sulphate ‘code’, it is proposed that cells are then able to regulate signals they receive and send in the ligand rich extracellular environment of the developing forebrain. Hs6st1 and Hs2st catalyse 6-O and 2-O HS sulphation, respectively. Following loss of either of these two HSTs, commissural tracts including the corpus callosum fail to develop normally during late mouse embryogenesis. The telencephalic midline environment is perturbed, with a striking mis-positioning of glial cell populations that normally act to guide axons towards the contralateral hemisphere. Too many radial glial cells at the glial wedge (GW) migrate towards the indusium griseum (IG) in mutant embryos. The running hypothesis to explain this phenotype is a change in critical signalling pathways required to set up the correct midline glia environment, such as Fgf8/ERK signalling which has already been identified as up-regulated at the Hs6st1-/- corticoseptal boundary (CSB). In order to further study what changes are occurring at the developing midline of HST-/- embryos compared to WT, we took a hypothesis free approach using RNA-sequencing analysis. RNA extracted from dissected midline regions of WT, Hs2st-/- and Hs6st1-/- mouse embryos at E16.5 was sent for sequencing, and a list of differentially expressed genes obtained. Overall we find few differentially expressed genes at the Hs6st1-/- midline compared to WT. At the Hs2st- /- midline there are a larger number of differentially expressed genes. Following validation studies, we find a significant and specific increase in Fgf17 protein distribution at the CSB of Hs2st-/- embryos compared to WT at E14.5. The results suggest the hypothesis that Hs2st’s normal role is to regulate Fgf17 protein distribution to limit exposure of GW radial glia cells to this translocation signal. When 2-O HS sulphation is lost then in Hs2st-/- embryos, ectopic Fgf17 signalling induces aberrant glia migration which ultimately prevents callosal axons from crossing the telencephalic midline to form the corpus callosum. To test this hypothesis, we used ex vivo slice culture experiments and showed ectopic Fgf17 protein expression is sufficient to trigger precocious translocation of midline glia in WT CSB, phenocopying the glia behaviour of Hs2st-/- embryos. Also consistent with the hypothesis, the Hs2st-/- glia phenotype can be rescued by addition of an FgfR1 inhibitor which reduces number of translocated glia cells. From these results we find for the first time that 2-O sulphated HS plays a remarkably specific role in regulating Fgf17-mediated translocation of midline glia cells at the developing mammalian telencephalic midline.

Temperament is thought to be the foundation for normative personality and subsequent behaviors later in life. To assess the relationship of early temperament with variation in structural brain development, this study examined rhesus macaque mother-infant behavior, and then three years later, used MRI to assess neurostructural differences. Individual differences in mother-infant interactions and emotionality were then linked to brain differences. Extensive behavioral data obtained over the first year of life under both resting and stressful conditions was used to assess the quality of mother-infant interactions and emotionality. The MRI focused on brain volume in areas thought to be related to emotional regulation and such as the cingulate gyrus and corpus callosum structures. These structures are often mentioned as areas that modulate emotions, temperament and general social behavior. The methods involved in this research include behavior coded from group-housed infant rhesus macaques (Macaca mulatta). The subjects were 15 mother-reared subjects, each housed in a social group of 12-20 subjects, living in social settings with their mothers, other adult females, two adult males, and other same-aged subjects; conditions that approximate the social composition of the natural setting. Behaviors related to temperament and mother-infant interactions were assessed using an objective behavioral scoring system. Behavior was coded under three conditions, and each behavioral coding session was 5-minute long. Homecage: Two behavioral coding sessions were recorded weekly for each subject as it interacted naturally with its mother and peers over the first six-months of life. Preseparation (month 6): Two weeks before four, sequential, 4-day social separations, behavioral data were collected once each day. Reunion with mother: Following each of the social separations, data were collected twice immediately following return to mother and again on the morning before the separation. Subjects underwent MRIs 1-2 years later when they were 2-3 years of age. The result of this research was that during pre-separation interactions, anterior cingulate size to brain ratio showed a positive correlation with mutual ventral contact (being cradled and held closely), a measure of the use of mother as a secure base to calm anxiety and fear.

The cerebral cortex is the largest subdivision of the human brain and is associated with higher cognitive functions. These functions are based on the interconnections between the neurons that form pre- and postnatally in the different telencephalic regions. The processes of neurons with similar functions and connectivity follow the same course and form axon tracts. There are three main axons tracts analysed in this thesis the corpus callosum, the corticothalamic/thalamocortical tracts and the lateral olfactory tract that transfers olfactory information to the telencephalon. In the mouse, these tracts are generated during embryogenesis as axons project to their target area. The mechanisms by which axons navigate still need to be elucidated. Studies of a number of mutant mice have shown that axon pathfinding is under the control of genes. Gli3 is a zinc finger transcription factor with known roles in axon pathfinding. Gli3 is widely expressed in progenitor cells of the dorsal and ventral telencephalon complicating the elucidation of the molecular mechanisms by which Gli3 controls axon tract formation. My aim here is to investigate the spatial and temporal requirements for Gli3 in axon pathfinding in the forebrain using Gli3 conditional mutants as a tool. Regarding the corpus callosum, my findings demonstrated a crucial role for Gli3 in the dorsal telencephalon, but not in the septum or medial ganglionic eminence, to control corpus callosum formation and indicated that defects in the formation of the corticoseptal boundary affect the positioning of callosal guidepost cells. Moreover, conditional inactivation of Gli3 in dorsal telencephalic progenitors led to few corticothalamic axons leaving the cortex in a restricted lateral neocortical domain. This restricted entry is at least partially caused by an expansion of the piriform cortex, which forms from an enlarged progenitor domain of the ventral pallium. Transplantation experiments showed that the expanded piriform cortex repels corticofugal axons. Moreover, expression of Sema5B, a chemorepellent for corticofugal axons produced by the piriform cortex, is similarly expanded. Hence, control of lateral cortical development by Gli3 at the progenitor level is crucial for corticothalamic pathfinding. Finally, by using Emx1Cre;Gli3fl/fl mutants I analysed the consequences of the expansion of the piriform cortex on the formation of the lateral olfactory tract (LOT). This analysis showed that LOT axons also appear to be medially shifted with LOT collaterals aberrantly colonising the expanded piriform cortex. Time course analysis confirmed an expansion of the paleocortical primordium from E13.5 onwards, coinciding with the arrival of the LOT axons. Hence, it is possible that the expanded piriform cortex contributed to the medial shift of the LOT. In conclusion, these findings support a strong link between Gli3 controlled early patterning defects and axon pathfinding defects and form the basis for future analysis of the molecular mechanisms by which Gli3 controls axon pathfinding in the forebrain. My findings also reveal how alterations in GLI3 function may contribute to connectivity defects in human patients with mutations in GLI3.

This study served as a pilot study of cingulate gyrus surface areas and their relation to intelligence in individuals with hydrocephalus. Surface areas of the corpus callosum and cingulate gyrus regions were compared between individuals with early hydrocephalus (n = 9) and controls (n = 7). Subsequently, the surface areas were correlated with full-scale intelligence scores and the verbal and nonverbal discrepancy scores. Corpus collosum surface areas were significantly smaller in participants with hydrocephalus. These areas also robustly correlated with full-scale intelligence scores. Although the cingulate gyrus did not differ significantly between the groups, the cingulate gyrus regions were increasingly divergent the more posterior the region. Additionally, the caudal anterior and the posterior cingulate gyrus regions had only moderate positive correlations with full-scale intelligence scores. Although the participants with hydrocephalus had a significantly lower mean performance IQ compared to verbal IQ, the discrepancy scores did not correlate significantly with any of the regions of interest.

Studies on split-brain cases have helped elucidate a crucial role of the corpus callosum (CC), that is information transfer between the two cerebral hemispheres (Gazzaniga, 2000). Comparative psychology studies suggested that CC plays a role in the acquisition of hemispheric specialisation. The relation between information integration in higher cognitive functions and specialisation development has to be unravelled yet. The contribution of the corpus callosum (CC) to the development of cognitive functions and the concurrent hemispheric specialisation has been relatively neglected until recently. This study examines the developmental trajectories in different domains in callosal agenesis (ACC), a pathology in which the corpus callosum (CC) is absent since birth. When ACC is isolated, children may develop normal intelligence. These extremely rare cases might help understand how the CC contributes to cognitive and linguistic functions epigenesis. Differently from adult split-brains, ACC children can transfer simple tactile and visual information across hemispheres, attesting to neuronal plasticity. Nevertheless, in tasks demanding more of efficient callosal integration (e.g. BFA Banich, 1990), their performance appears quantitatively and qualitatively different from controls. ACC individuals show early motor coordination difficulties, and no patent language impairments in routine clinical tests. At later ages, simple motor coordination problems are overcome, but bimanual coordination difficulties are distinctively reported, alongside with clearer impairments in communication abilities. While in childhood comprehension of language - literal and non-literal - is suboptimal, only in adolescence, metaphors and idioms comprehension, requiring fast inter-hemispheric integration of language skills, reveal frank difficulties. A very similar developmental trajectory emerges from a double single case of complete AgCC, examined experimentally at 8 and 12 years of age. Extent and limits of neuronal plasticity in congenital absence of CC is discussed on the background of the Dennis’ and neuroconstructivist theories. Post Scriptum. As the present work concerns only two participants and other participants are about to be recruited, anybody interested in being updated should contact me at P_de_fabritiis@yahoo.co.uk or pdefabritiis@hotmail.com, Or the Italian Forum about AgCC: agenesiacorpocalloso@hotmail.it

1. INTRODUCCIÓN

La definición de prematuro es la de recién nacido de edad gestacional inferior a 37 semanas (American Academy of Pediatrics y American College of Obstetrics and Gynecology, 2002). En relación al peso se utilizan con frecuencia las categorías: bajo peso (< 2500g), muy bajo peso (< 1500g) y extremadamente bajo peso (< 1000g) (Picard et al. 2000).

En la actualidad, la tasa de partos prematuros en España se sitúa entorno al 8% (Instituto Nacional de Estadística de España: www.se-neonatal.es), existiendo un incremento del 13% de los niños prematuros o de bajo peso en los últimos cuatro años (Sociedad Española de Neonatología: www.se-neonatal.es).

Siguiendo a Picard et al. (2000), las complicaciones médicas que pueden tener un mayor impacto sobre el desarrollo cerebral de los niños prematuros, son aquellas relacionadas con la inmadurez de sus sistemas respiratorio y cardiovascular, lo cual puede producir hipoxia. Además, y debido a la vulnerabilidad de la matriz germinal, pueden aparecer lesiones hemorrágicas peri/intraventriculares.

La mayoría de estudios neuropsicológicos acerca del rendimiento cognitivo general en sujetos prematuros indican una valoración significativamente más baja en esta población respecto al grupo control. Concretamente estos resultados se han obtenido en niños de muy bajo peso (Korkman et al. 1996; Böhm et al. 2002), así como en niños prematuros (Olsén et al. 1998; Pasman et al. 1998; Wolke & Meyer 1999; Burguet et al. 2000; Peterson et al. 2000; Foulder-Hughes & Cooke 2003; Hopkins-Golightly & Raz 2003; Youngmei Peng et al. 2005).

En cuanto a los adolescentes, la literatura es más escasa. Sin embargo, algunos estudios también muestran un coeficiente de inteligencia (CI) significativamente más bajo en adolescentes de muy bajo peso al nacer (Taylor et al. 2000, 2004; Hack et al. 2002) ó con antecedentes de prematuridad (Stewart et al. 1999, Roth et al. 2001). Asimismo, en relación a las funciones cognitivas específicas frecuentemente los estudios muestran que los sujetos prematuros rinden peor que los controles.

Específicamente, en niños de muy bajo peso ó prematuros se han obtenido estos resultados para percepción y funciones constructivas (Korkman et al. 1996; Olsén et al. 1998; Pasman et al. 1998; Briscoe & Gathercole 2001; Foulder-Hughes & Cooke 2003), funciones verbales y lenguaje (Korkman et al. 1996; Wolke & Meyer 1999; Briscoe & Gathercole 2001), aprendizaje y memoria (Olsén et al. 1998; Pasman et al. 1998), y para las funciones frontales (Pasman et al. 1998; Böhm et al. 2002; Saavalainen et al. 2006).

En estas dos últimas funciones se ha observado también un rendimiento significativamente más bajo en adolescentes con antecedentes de prematuridad (Allin et al. 2001; Giménez et al. 2004; Giménez et al. 2006b). Por último, en relación a los adolescentes con muy bajo peso al nacer, Taylor et al. (2000, 2004) han demostrado que éstos rinden peor que los nacidos a término en todas las funciones específicas anteriormente citadas

Tanto en el rendimiento cognitivo general, como en el de funciones específicas, la valoración de los prematuros suele situarse dentro del rango considerado como normal, exceptuando el CI y algunas funciones lingüísticas de aquellos individuos con un peso < 750g al nacer (Taylor et al. 2000).

En referencia al posible sustrato estructural de estas disfunciones neuropsicológicas, las técnicas cuantitativas de neuroimagen han evidenciado, en sujetos de bajo peso al nacer ó prematuros, anomalías estructurales ya presentes durante el período perinatal (Inder et al. 1999; Peterson et al. 2003), que pueden persistir tanto en la niñez (Peterson et al. 2000, Kesler et al. 2004; Reiss et al. 2004), como en la adolescencia (Nosarti et al. 2002, 2004; Giménez et al. 2006a,b) y etapa adulta (Fearon et al. 2004; Allin et al. 2004).

En relación a los adolescentes con antecedentes de prematuridad, nuestro grupo de investigación (Giménez et al. 2000a,b), ha observado lesiones periventriculares, así como un descenso del volumen de la sustancia blanca en diversas regiones cerebrales. Nosarti et al. (2004) ha observado una disminución del tamaño total del cuerpo calloso (CC), especialmente de algunas de sus subregiones.

Finalmente, varios estudios han aportado datos acerca de reducciones de la sustancia gris cerebral total, (Nosarti et al. 2002; Isaacs et al. 2003), y de diversas estructuras subcorticales como: el hipocampo (Isaacs et al. 2000; Abernethy et al. 2002; Giménez et al. 2004) y el núcleo caudado (Abernethy et al. 2002), además del cerebelo (Allin et al. 2005).

2. OBJETIVOS

En síntesis, los objetivos de los estudios realizados en esta tesis son:

1. Explorar los déficits de memoria en adolescentes con bajo peso al nacer y el papel que pueda desempeñar el coeficiente de inteligencia en relación a los mismos.

2. Estudiar las anormalidades del cuerpo calloso y el rendimiento en diversas funciones cognitivas, en adolescentes con antecedentes de prematuridad, correlacionando ambos tipos de datos.

3. Explorar la influencia específica de la edad gestacional al nacer sobre las anomalías del cuerpo calloso así como sobre el rendimiento cognitivo general, en los mismos sujetos antes citados.

3. METODOLOGIA

Los sujetos que componen la muestra total de estudio (N = 83), fueron seleccionados de la población de prematuros nacidos en el Hospital Clinic y el Hospital de la Vall d'Hebron, ambos en Barcelona. Los criterios de selección fueron: peso al nacer <2500g, edad gestacional < 37 semanas y edad actual entre 11 y 17 años. En cuanto a los criterios de exclusión, hemos utilizado: deficiencia mental (CIT < 70), antecedentes de traumatismo craneoencefálico, parálisis cerebral u otro diagnóstico neurológico, dishabilidades motoras y/o sensoriales que impidiesen la exploración neuropsicológica, prótesis dentales y claustrofobia o nivel de ansiedad elevado.

El grupo control se compone de familiares o conocidos de los sujetos de estudio ó de estudiantes universitarios. Estos sujetos nacidos a término y con una historia clínica normal, han sido emparejados por edad, género, nivel de educación, estado socioeconómico y origen étnico, con la muestra de estudio.

La evaluación neuropsicológica de todos los participantes ha sido llevada a cabo por un mismo explorador (A.N.) en dos sesiones de 90min cada una. Los tests utilizados para medir el rendimiento cognitivo general y específico son los siguientes: a) coeficiente de inteligencia: WISC-R (Wechsler 1974) ó WAIS-III (Wechsler 1997), dependiendo de la edad del sujeto; b) aprendizaje verbal y memoria: "Auditory Verbal Learning Test" (Rey 1958); c) funciones visuoperceptivas / visuoconstructivas y memoria visual: tarea de copia y reproducción del Test de la Figura Compleja de Rey (Rey 1980); d) memoria de la vida cotidiana: Test de Memoria Cotidiana Rivermead (Wilson 1985); e) fluencia verbal: versión modificada del Controlled Oral Word Association Test (Benton & Hamsher 1989), y mediante una tarea de fluencia semántica a través de la generación de palabras a partir de una consigna categórica (animales).
En relación al estudio de neuroimagen, se adquirieron imágenes por resonancia magnética potenciadas en T1. El cuerpo calloso se midió en el corte sagital medial en el que las comisuras anteriores y posteriores, y el fórnix, fueran claramente visibles. Se siguió el modelo de segmentación de Witelson (1989) analizando 7 subregiones ("rostrum, genu, rostral body, anterior midbody, posterior midbody, isthmus and splenium"), de forma semiautomática, a través del programa ANALYZE 5.0/6.0 (Biomedical Imaging Resource, Mayo Clinic). Además se utilizó el programa de procesamiento automático SPM2 (Wellcome Department of Cognitive Neuroscience, London, UK) para obtener los volúmenes de sustancia blanca, gris y líquido cefalorraquídeo.
El análisis estadístico se realizó a través del programa SPSS 10.0/11.0 (Statistical Package for the Social Sciences).

4. RESULTADOS

Estudio 1:
En el primer estudio se compara el rendimiento en memoria de 44 adolescentes de bajo peso al nacer con 44 sujetos nacidos a término. Los resultados muestran que los primeros presentan un rendimiento normal en aprendizaje verbal, memoria de reconocimiento y memoria visual. Por otra parte se observa una diferencia significativa en el Test de Memoria Cotidiana, que sin embargo desaparece al covariar (ANCOVA) por el coeficiente de inteligencia total (CIT). Además se observa, a través de un análisis de regresión, que no es el peso al nacer, sino la edad gestacional, la variable clínica que mejor predice el CIT.

Estudio 2:
En este estudio se seleccionan 25 sujetos con una edad gestacional < 33 semanas y 25 sujetos control. El análisis de neuroimagen muestra una diferencia significativa entre los grupos en el cuerpo calloso total, así como en varias subregiones (genu, posterior midbody y splenium). Asimismo aparece una diferencia significativa en el CI, aprendizaje verbal, memoria de la vida cotidiana y fluencia verbal semántica. Todos estos datos muestran un rendimiento más bajo del grupo prematuro. Por otro lado, se observa una correlación estadísticamente significativa de la edad gestacional con el tamaño del cuerpo calloso total y con el rendimiento cognitivo del sujeto. Por último, el análisis de regresión muestra que la edad gestacional es la variable que mejor predice el tamaño del cuerpo calloso.

Estudio 3:
Para este estudio se seleccionan 64 prematuros con una edad gestacional (EG) <37 semanas, clasificados en 4 grupos atendiendo a su EG. El grupo control se compone de 53 sujetos nacidos a término. Los resultados muestran que los sujetos nacidos antes de la semana 27 presentan un adelgazamiento del cuerpo calloso total, así como de 5 subregiones (genu, anterior midbody, posterior midbody, isthmus and splenium), y un CI bajo. Los sujetos que nacen entre la semana 28 y 30, también presentan un bajo CI, pero únicamente presentan una reducción del tamaño del splenium. Los prematuros que nacen con una EG entre 31 y 33 semanas, no muestran diferencias con los controles en cuanto al cuerpo calloso, pero sí en relación al CI, que es inferior en los prematuros.

Finalmente, aquellos sujetos nacidos con 34 ó más semanas de gestación, no muestran ninguna diferencia con los nacidos a término. Además existe una correlación significativa de la EG con el cuerpo calloso y con el CI.

5. DISCUSIÓN GENERAL

Los resultados neuropsicológicos indican que nuestra muestra de prematuros tiene un rendimiento significativamente más bajo que los controles en el CI y en memoria de la vida cotidiana, aprendizaje verbal y fluencia verbal semántica. Sin embargo, cabe destacar que sus puntuaciones se sitúan dentro del rango considerado normal.

Por otra parte, no se observan diferencias significativas entre los grupos de estudio en: memoria verbal y visual, funciones visuoperceptivas y visuoconstructivas, y fluencia verbal fonética). Estos resultados son comparables a los obtenidos por Rushe et al (2001) en un amplio estudio neuropsicológico, que concluye sugiriendo que los déficits cognitivos a largo plazo en sujetos prematuros son leves.

Las diferencias observadas en las funciones específicas, están por un lado, relacionadas con el CI (memoria de la vida cotidiana, estudio 1). Por otro lado, con la posible afectación de la sustancia blanca, que ocasionaría una disminución en la velocidad de procesamiento de la información y un bajo rendimiento cognitivo, evidente en las funciones prefrontales citadas (aprendizaje verbal y fluencia verbal semántica, estudio 2). Cabe destacar que todos los prematuros de este estudio presentan un riesgo de hipoxia)

En relación a los estudios de neuroimagen, la presente tesis muestra que existe una correlación significativa entre el CI y el tamaño del cuerpo calloso en adolescentes con antecedentes de prematuridad. Estudios previos obtienen este resultado en niños (Peterson 2000) y adolescentes -si bien el CI empleado es el de los 8 años- (Nosarti et al. 2004).

Específicamente, nosotros encontramos un adelgazamiento del cuerpo calloso total así como de su parte anterior (genu) y posterior (posterior midbody y splenium). Este hallazgo diferente al de Nosarti et al. (2004), que sólo aporta una disminución de la parte posterior en prematuros de 14-15 años, puede deberse a que nuestra muestra se compone también de sujetos menores de 14 años, llegando incluso a los 10. En este sentido, Peterson et al. (2000) observó una afectación de todas las partes del cuerpo calloso analizadas en niños de 8 años.

Ante estos resultados, podría decirse que las dimensiones del cuerpo calloso se recuperan de forma diferente a lo largo de la ontogenia; empezando por la parte anterior, y siendo la posterior la última en compensarse, tal y como sugirieron Giedd et al. (1996).

En cuanto a la relación entre edad gestacional (EG), cuerpo calloso y rendimiento cognitivo, nuestro estudio 3 muestra que los adolescentes que nacen con una EG menor o igual a 27 semanas son el grupo de mayor riesgo para presentar anormalidades estructurales así como déficits cognitivos. Este resultado puede relacionarse con la interrupción de los procesos normales de mielinización, cuyas consecuencias parecerían más acusadas de ocurrir en este período precoz del desarrollo. Entre las semanas 18-27 de gestación predominan los progenitores tardíos de la oligodendroglia, y entre las semanas 28-41 se esperaría un aumento del número de oligodendrocitos inmaduros, así como un aumento progresivo de las capas de mielina (Back et al. 2001).

Los sujetos que nacen entre las semanas 28 y 30 presentan únicamente una reducción del splenium, y a partir de la semana 31 ya no se observan alteraciones estructurales. Es de destacar sin embargo que los sujetos entre 28 y 33 semanas presentan un CI significativamente más bajo que los controles; lo cual no ocurre en los prematuros de más de 33 semanas de gestación.

No podemos excluir que los sujetos de nuestra muestra presenten además otras anormalidades cerebrales más sutiles no detectables en nuestros análisis de resonancia magnética. Nuevas modalidades de neuroimagen como la que utiliza tensores de difusión (DTI-en inglés-), podrían detectar alteraciones de la microestructura de la sustancia blanca, como ha sido efectivamente observado en recién nacidos prematuros con una EG entre 24-36 semanas (Partridge et al. 2004).

6. CONCLUSIONES

1. Adolescentes con antecedentes de prematuridad presentan dificultades cognitivas y anormalidades estructurales a largo plazo, que podrían estar más relacionadas con la edad gestacional que con el peso al nacer.

2. Adolescentes que nacieron prematuramente tienen déficits de memoria que pueden explicarse parcialmente por sus disfunciones en el rendimiento cognitivo general.

3. Inteligencia, memoria de la vida cotidiana, aprendizaje verbal y fluencia verbal semántica, son las funciones cognitivas más sensibles a la prematuridad.

4. Aún en el caso de observarse diferencias estadísticas significativas entre los grupos de estudio, la media de las puntuaciones de los sujetos prematuros se sitúa en el rango normal.

5. La reducción de tamaño del cuerpo calloso, observada con anterioridad en prematuros recién nacidos, se mantiene como mínimo después de 16 años de reorganización cerebral.
6. El genu, posterior midbody y splenium, son las subregiones más afectadas por la prematuridad.

7. La edad gestacional al nacer presenta una clara relación con las anormalidades del cuerpo calloso y con el bajo rendimiento cognitivo general. Los sujetos que nacen con una edad gestacional inferior o igual a 27 semanas, presentan una reducción del cuerpo calloso total, genu, anterior midbody, posterior midbody, isthmnus y splenium. Aquellos sujetos que nacen entre las semanas 28-30 sólo presentan una reducción del splenium. Después de esta edad, el cuerpo calloso y el coeficiente de inteligencia es similar a los sujetos nacidos a término.

Le cerveau des mammifères est composé de deux hémisphères. Bien qu'anatomiquement séparés, ceux-ci coopèrent l'un avec l'autre par l'intermédiaire de faisceaux de fibres qui constituent les commissures cérébrales. Parmi ces commissures, le corps calleux est la plus importante, tout au moins par le nombre de fibres qui la constitue (200 à 800 millions suivant les espèces). Bien que le rôle de cette commissure soit resté longtemps inconnu, il est maintenant bien établi qu'elle transporte des messages aussi divers que des messages visuels, limbiques, auditifs, somesthésiques et moteurs d'un hémisphère à l'autre. En conséquence, le corps calleux s'est révélé être impliqué dans des fonctions cognitives supérieures telles la perception sensorielle, l'apprentissage, la mémoire et la motricité. En dépit de l'établissement de ces concepts importants, la connaissance du corps calleux et de son rôle dans les fonctions cognitives supérieures restent encore extrêmement incomplètes que ce soit au cours du développement ou chez l'adulte. Or, ces questions sont essentielles puisqu'elles posent directement le problème du rôle de l'intégration interhémisphérique dans l'élaboration des fonctions cognitives dans les conditions normales; elles touchent également le problème du rôle de cette même intégration dans les processus de réorganisation et de compensation qui peuvent se développer dans les conditions pathologiques, conduisant à une restructuration des fonctions cognitives. Ce travail de thèse a été réalisé dans le contexte expérimental de C. Milleret et de ses collaborateurs qui étudient les caractéristiques anatomo-fonctionnelles et topographiques des cartes corticales calleuses localisées au niveau des aires visuelles corticales primaires 17 et 18 de chaque hémisphère chez le mammifère et qui sont associées au traitement de la région médiane verticale centrale du champ visuel. Cette région centrale du champ visuel est des plus stratégiques d'un point de vue perceptif puisqu'elle participe à la fusion des deux hémichamps visuels. En utilisant les techniques d'électrophysiologies in vivo et anatomiques (reconstructions 3D d'axones marqués à la biocytine), il a déjà été montré que ces connexions interhémisphériques sont presque exclusivement limitées à la bordure de transition entre les aires visuelle primaires A17 et A18. De plus, les neurones des aires visuels primaires qui sont activés par les axones interhémisphériques présentent des caractéristiques fonctionnelles bien précises. Certaines caractéristiques anatomo-fonctionnelles et topographiques des cartes corticales calleuses sont déjà bien identifiées mais elle se révèlent encore insuffisantes pour préciser le rôle du corps calleux dans les processus d'intégration visuelle interhémisphérique, en particulier en l'absence de données précises des caractéristiques dans les domaines temporels et spatiaux et la façon dont elles sont modifiées dans des conditions de développent visuel asymétriques. Ceci résulte aussi du faible nombre de travaux faisant appel à une approche computationnelle et la modélisation pour aborder ces questions. En particulier, les relations entre les caractéristiques morphologiques des axones calleux et les propriétés spatiales (cartes fonctionnelles) et temporelles (latences de transfert et propriétés spectrales) des populations neurales qu'elle mettent en relation sont encore très imprécises. Caractérisation quantitative des distributions des terminaisons d'axones calleux. Dans sa première partie, notre étude propose de préciser les extensions spatiales et les caractéristiques morphologiques des arborisations d'axones calleux obtenus dans les conditions de développement visuel normal (NR) et dans les conditions de déprivation monoculaire précoces (MD) afin de les différentier quantitativement. Dans cet objectif, deux groupes d'axones reconstruits en 3D sont tout d'abord décrits qualitativement par les méthodes conventionnelles d'anatomie. Cette méthode rencontre néanmoins des difficultés pour caractériser précisément les morphologies des axones, en particulier l'extension de leur terminaisons sur la surface du cortex, leur orientation et leur degré de fragmentation. Pour répondre à ces questions, deux méthodes computationnelles complémentaires et de complexité croissante ont été développées pour caractériser les distributions de terminaison axonales calleuses et mettre en évidences les différences entre les deux groupes. Celles-ci nous ont permis de montrer les plus grandes extensions spatiales ainsi que le plus grand degré de fragmentation des distributions des terminaisons des axones calleux du groupe MD. Dans un dernier chapitre, la simulation de propagation de potentiel d'action dans les structures axonales a permis de montrer que les différences morphologiques constatées dans le groupe MD, ne semblent pas se répercuter sur la dispersion temporelle du signal entre les terminaisons. Ainsi, la distribution temporelle du signal controlatéral demeure pour la grande majorité confinée dans un intervalle inférieur à 2ms, dispersion compatible avec des hypothèses de synchronisation. Développement de la technique d'imagerie optique par colorant sensibles au potentiels Avec la perspective d'explorer expérimentalement les propriétés spatio-temporelles de l'intégration visuelle interhémisphérique et afin de corroborer les résultats présenté dans la première partie de la thèse, la mise en place d'un poste expérimental d'imagerie optique au sein de notre laboratoire est présentée dans la deuxième partie. Cette méthode permet de visualiser in vivo les domaines d'activation spécifique à différents attributs au sein des cartes corticales calleuses et d'approcher certaines caractéristiques temporelles de l'activité neuronale. Réalisé en parallèle avec les travaux de modélisation des axones calleux, le montage complet du poste a montré d'abord permis de cerner les limitations du système initial. Dans un deuxième temps l'adaptation du système à la problématique interhémisphérique, réalisée au fils des mois, a montré d'importants progrès après plusieurs modifications spécifiques. La mise en place du poste expérimental a pu bénéficier de l'expertise en imagerie optique de l'équipe de recherche du Dr. S. Tanaka au RIKEN Brain Science Institute au Japon, où l'auteur a effectué plusieurs séjours au cours desquelles ont pu être initiées un certain nombres d'adaptation importantes comme le développement du protocole d'enregistrement en Voltage Sensitive Dye (VSD), permettant l'enregistrement de l'activité neurale avec un grande précision temporelle, ainsi que le développement de techniques de traitement des signaux appropriées. La mise en place du poste expérimental dans les locaux parisiens a pu être achevée fin 2006 avec l'obtention de données prometteuses pour la poursuite du programme expérimental, comme l'enregistrement à 3 ms/image de l'activation corticale bilatérale et ainsi que celle du transfert interhémisphérique. Ces résultats ouvrent les perspectives de recherche visant la combinaison des données anatomiques morphologiques avec les données d'enregistrement d'activations spatio-temporelles in vivo de l'intégration visuelle hémisphérique au sein des cortex visuels primaires.

Large scale functional brain networks, defined by synchronized spontaneous oscillations between spatially distinct anatomical regions, are essential to brain function and have been implicated in disease states, cognitive capacity, and many sensing and motor processes. In this work, we sever the corpus callosum in the rodent model to determine if structural connectivity (specifically the primary interhemispheric pathway) organizes and influences bilateral functional connectivity and brain-wide spatiotemporal dynamic activity patterns. Prior to the callosotomy work, resting state brain networks were evaluated using blood oxygen level dependent (BOLD) and cerebral blood volume (CBV) magnetic resonance imaging contrast mechanisms, and revealed that BOLD and CBV provide highly similar spatial maps of functional connectivity; however, the amplitude of BOLD connectivity was generally stronger. The effects of extended anesthetic durations on functional connectivity were also evaluated revealing extended isoflurane anesthetic periods prior to the switch to dexmedetomidine attenuates functional activity for a longer duration as compared to a shorter isoflurane paradigm. We also observed a secondary significant evolution of functional metrics occurring during long durations of dexmedetomidine use under the currently accepted and refined dexmedetomidine sedation paradigm. Taking these previous findings into account, we moved forward with the callosotomy study. Functional network integrity was evaluated in sham and full callosotomy groups using BOLD and electrophysiology. Functional connectivity analysis indicated a similar significant reduction in bilateral connectivity in the full callosotomy group as compared to the sham group across both recording modalities. Spatiotemporal dynamic analysis revealed bilaterally symmetric propagating waves of activity in the sham data, but none were present in the full callosotomy data; however, the emergence of unilateral spatiotemporal patterns became prominent following the callosotomy. This finding suggests that the corpus callosum could be largely responsible for maintaining bilateral network integrity, but non-bilaterally symmetric propagating waves occur in the absence of the corpus callosum, suggesting a possible subcortical driver of the dynamic cascading event. This work represents a robust finding indicating the corpus callosum's influence on maintaining integrity in bilateral functional networks.

The ankyrins comprise a family of proteins serving as components of the membrane cytoskeleton, and participate in a diverse set of associations with multiple binding partners including the cytoplasmic domains of transporters, ion channels, some classes of receptors, and cell adhesion proteins. Moreover, evidence is accumulating that ankyrin participates in defining functionally distinct subcellular regions. The complex functional and structural roles of ankyrins indicate they are likely to play essential roles in the pathology of traumatic axonal injury. The current study examined changes in ankyrin-G expression following a moderate central fluid percussion injury administered to adult rats. At 1d, 3d, and 7d postinjury (or following a sham control injury), protein levels of ankyrin-G in the corpus callosum and cerebral cortex were assessed using Western Blot analysis. Three immunopositive bands were identified in both brain regions as 220,212, and 75 kD forms of ankyrin-G. Time-dependent changes in ankyrin-G were observed in the corpus callosum. At 1d injury-induced elevations were observed in the callosal 220 kD (+147% relative to sham levels) and in the 212 kD (+73%) forms of ankyrin-G, but in both cases the expression decreased to control levels by 3d and 7d. In contrast, the 75 kD form showed moderate increases at 1d postinjury, but was significantly below control levels at 3d (-54%) and at 7d (-41%). Ankyrin-G expression in the cerebral cortex was only slightly affected by the injury, with a significant decrease in the `220 kD form occurring between 1d and 3d. These data suggest that the 220 and 212 kD changes probably represent postinjury proteolytic fragments derived from intact ankyrin-G isoforms of 480 andor 270 kD, while the 75 kD effects are likely breakdown products of intact 190 kD ankyrin-G. These results were discussed as they relate to prior findings of differential vulnerabilities of callosal myelinated and unmyelinated axons to injury. In this context, the 220,212 kD changes may reflect pathology within myelinated axons, and alterations to the 75 kD form may reflect more persistent pathology affecting unmyelinated callosal fibers.

Thesis (Ph. D.)--University of California, San Diego, 2008.
Title from first page of PDF file (viewed November 10, 2008). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.

Atrophy of the corpus callosum (CC) is a documented consequence of moderate-to-severe traumatic brain injury (TBI), which has been expressed as volume loss using quantitative magnetic resonance imaging (MRI). Other advanced imaging modalities such as diffusion tensor imaging (DTI) have also detected white matter microstructural alteration following TBI in the CC. The manner and degree to which macrostructural changes such as volume and microstructural changes develop over time following pediatric TBI and their relation to a measure of processing speed is the focus of this longitudinal investigation. As such, DTI and volumetric changes of the CC in participants with TBI and a comparison group at approximately three and 18 months post injury and their relation to processing speed were determined.

1. INTRODUCTION Intrauterine growth restriction (IUGR) is diagnosed at the presence of an estimated fetal weight below the 10th centile and is a frequent condition in perinatal medicine, reaching a prevalence of 5-8% in live newborn babies being a major contributor of perinatal and long term morbidity, such as neurological deficits. We hypothesized that these neurological impairement are related to brain microstructural changes which might be characterized by fetal neuroimaging, either MRI or ultrasonography. Identifying fetuses at risk for abnormal neurodevelopment in fetal medicine lays the basis to perform specific strategies to potentially improve both pre and postnatal management, such as timely delivery, careful support for breastfeeding and a thoughtful use of this window of opportunity to improve their neurocognitive outcome through specific strategies. So the objective of this thesis was to identify brain imaging biomarkers that could predict an adverse neurological outcome in small for gestational age fetuses. 2. METHODS This is a prospective cohort study which included 2 study groups: AGA (adequeate for gestational age fetuses) with an estimated fetal weight >10th centile and, SGA (small for gestational age fetuses) with an estimated fetal weight <10th centile. A fetal ultrasound was performed to establish clinical group membership and Doppler evaluation. Then, either a MRI at 37 weeks was performed or a neurosonography during the 3rd trimester in order to assess cortical development, insular and corpus callosum morphometry. Once these babies were born, they underwent a neurobehavioral assessment during the neonatal period (NBAS) and a neurodevelopmental test at 2 years (Bayley-III). The analysis was focused on the evaluation of differences among study groups. As secondary analysis, linear regression was used to evaluate the relationship between brain development and postnatal neurological outcome adjusting by potentially confounders. Statistical anlyses were performed using the SPSS for Windows version 17.0 statistical software. 3. RESULTS The thesis led to five articles which are published in international journals. Maternal characteristics did not differ between the study groups. We found that late-onset IUGR fetuses showed a different pattern of brain development assessed by fetal MRI, expressed by deeper fissures, smaller brain volumes and a more pronounced right asymmetry. They also presented thinner cortex with lower fractional anisotropy values wich was significantly associated to worse NBAS test. Small fetuses presented smaller corpus callosum assessed by MRI and US, particularly in its posterior portion which was associated to worse neurobehavioral outcome. When we explored the correlation between brain structure and neurodevelopment at 2 years, we found that smaller measurements were associated to worse Bayley-III scores. 7. DISCUSSION Although previous studies have shown poorer neurodevelopmental outcome in term, none of them have provided information about their brain developmental status before birth. Our findings support a microstructural/functional association. Interestingly, we found that small-born babies had lower cognitive, motor and language competencies. All of these functions are closely related to the insula and callosal functionality. Indeed, Geva et al. proposed that thinner cortex found in severe IUGR born children could be responsible for their lower IQ scores. The importance of this study relais in the high prevalence of late-onset IUGR, therefore they represent a significant public health problem and its impact on the adverse neurodevelopment outcome of this population cannot be overestimated. Therefore findings applicable imaging biomarkers in fetal medicine can identify those fetuses at risk in this and other clinical scenarios. Finally, our study suggests that brain alterations at term could constitute the first step in the cascade of functional impairments underlying neurodevelopmental pathologies.
“EVALUACIÓN DEL DESARROLLO CORTICAL Y CUERPO CALLOSO COMO MARCADORES PREDICTIVOS DE NEURODESARROLLO EN FETOS PEQUEÑOS PARA LA EDAD GESTACIONAL “ INTRODUCCION: la restricción del crecimiento intrauterino (RCIU) afecta alrededor del 8% de los recién nacidos vivos y se asocia a morbilidad a corto y a largo plazo, dentro de los cuales se encuentran los déficits neurológicos. Nuestra hipótesis es que dichos déficits se asocian a una reprogramación cerebral durante la vida intrauterina gatillada por la RCIU. Por lo que el objetivo de esta tesis fue detectar biomarcadores cerebrales que puedan predecir un resultado neurológico adverso en los fetos con RCIU. MÉTODOS: incluimos dos grupos de estudio: AGA (fetos adecuados para la edad gestacional) y SGA (fetos pequeños para la edad gestacional definidos por un percentil de crecimiento