Threat and adaptation: The maternal lived experience of continuing pregnancy after receiving a prenatal diagnosis of agenesis of the corpus callosum.

One stated objective of prenatal screening and diagnosis is the preparation for delivering a baby with medical needs or disability, however, psychosocial outcomes of parents who received a prenatal diagnosis suggest that this objective is not yet realised. Preparation may be complicated by diagnostic and prognostic uncertainty. A prenatal diagnosis that includes significant uncertainty due to the heterogeneous presentations, classifications, causes and outcomes is agenesis of the corpus callosum. As a neuroanatomical anomaly identified in the second or third trimesters, the diagnosis is likely to cause distress for expectant mothers, yet there is limited guidance for holistic support. To begin to address the paucity of research, this hermeneutic phenomenological study sought to explore, and provide a telling of the maternal experience of continuing pregnancy after a prenatal diagnosis of agenesis of the corpus callosum. Through interviews and a series of online, asynchronous and facilitated focus groups, lived experiences during pregnancy from the time of diagnosis to birth were explored with 26 mothers who participated in this international study. Themes were constructed through reflexive thematic analysis to describe the experience of the lived phenomenon. The first theme, Under Threat, included subthemes of The Threat to the Life of the Baby and Threatened Image of the Expected Family. The second theme, Day to Day Toward Adaptation, included subthemes of Holding it Together and Falling Apart, and More Than Information, Searching for Meaning, Hope and Control. To realise the commonly stated objective of prenatal diagnosis, to support maternal preparation, healthcare professionals require awareness of the profound, yet individual experience of prenatal diagnosis to adequately respond and support mothers through their continued pregnancies. Healthcare services should be designed to flexibly respond in a woman- and family-centred manner to reduce the threat and support maternal adaptation after a prenatal diagnosis.

Scoping Review of the Prenatal Diagnosis of Agenesis of the Corpus Callosum.

OBJECTIVE: To map and summarize the literature related to the prenatal diagnosis of agenesis of the corpus callosum (ACC) to inform nursing practice. DATA SOURCES: We searched MEDLINE, CINAHL, PyscINFO, and Academic Search Complete with the use of strings of curated terms to cover the broad ACC nomenclature. Documents were published in English between 2009 and June 1, 2020. We also hand searched the reference lists of included documents. STUDY SELECTION: We screened 582 abstracts and retrieved the full texts of primary research articles, reviews, discussion papers, and peer-reviewed book chapters if the abstracts specifically mentioned ACC and the prenatal period. We excluded case reports, conference and poster abstracts, papers on broader anomalies, and animal studies. We reviewed 84 full-text documents and identified 61 for inclusion. DATA EXTRACTION: We charted the data through an iterative process under headings for location, article type, study design, participant age, ACC type, recruitment, method, tools/assessments, results, key recommendations, gestational age at diagnosis, termination of pregnancy rate, the definition of isolated ACC, and our notes of critique of the document. DATA SYNTHESIS: We constructed a narrative synthesis from thematically arranged data. In the included documents, ACC was diagnosed between 17 and 38 weeks gestation and was frequently described as heterogeneous because of different causes, presentations, and outcomes. Whether the ACC was isolated as the only anomaly or present with other anomalies was considered the key factor for prenatal counseling. However, the definition of isolated ACC was inconsistent. CONCLUSION: The inconsistent nomenclature and definitions of an isolated presentation of ACC increase the ambiguity in the prenatal diagnosis and must be considered when the outcome and diagnostic efficacy studies are interpreted. There is an absence of research on parents' experiences of prenatal diagnoses of ACC to inform holistic nursing interventions and the provision of psychosocial support.

Music, Movement, and Mind: Use of Drumming to Improve Strength, Balance, Proprioception, Stamina, Coordination, and Emotional Status in a 12-Year-Old With Agenesis of the Corpus Callosum: A Case Study.

The purpose of this article is to report a case study of the effect of therapeutic drumming on motor, communication skills, and behavior of a preteen diagnosed with agenesis of the corpus callosum. This 12-year-old participated in 30- to 45-minute weekly sessions over a 12-month period in which rudimentary drumming exercises were used to analyze and then measure any changes in equilibrium reactions, postural transfers, and trunk control. Measurable documentation evidenced marked improvement in motor skills while suggesting communication and behavioral improvement. The findings support the theory that therapeutic drumming would benefit preteens with agenesis of the corpus callosum, which provides promising evidence to other neurologic developmental diagnoses and therefore indicates a need for further research. While the therapeutic nature of music is well documented, how the listener participates can influence the effect of the music. For example, passive music listening can improve pain or anxiety, however, active music listening with expected intentional action may improve physical, mental, behavioral, and spiritual healing. Active music listening could be a valuable holistic nursing intervention.

Ambiguous Genitalia Associated with an Extremely Rare Syndrome: A Case Report of XLAG Syndrome and Review of the Literature.

X-linked lissencephaly, absent corpus callosum, and epilepsy of neonatal onset with ambiguous genitalia comprises the XLAG syndrome and only 15 cases have been reported in literature. Due to its rarity, the exact clinical course and outcome are not known. Exact associations of this disease are also elusive. Hereby we are reporting this extremely rare entity and we searched the English literature extensively to get consolidated knowledge regarding this entity that would help the readers. Pre-natal radiological work-up can detect these malformations, which should be followed by medical termination, counseling and karyotyping. Till date the longest survival noted was 4 years only.

Early asymmetric inter-hemispheric transfer in the auditory network: insights from infants with corpus callosum agenesis.

The left hemisphere specialization for language is a well-established asymmetry in the human brain. Structural and functional asymmetries are observed as early as the prenatal period suggesting genetically determined differences between both hemispheres. The corpus callosum is a large tract connecting mostly homologous areas; some have proposed that it might participate in an enhancement of the left-hemispheric advantage to process speech. To investigate its role in early development, we compared 13 3-4-month-old infants with an agenesis of the corpus callosum ("AgCC") with 18 typical infants using high-density electroencephalography in an auditory task. We recorded event-related potentials for speech stimuli (syllables and babbling noise), presented binaurally (same syllable in both ears), monaurally (babbling noise in one ear) and dichotically (syllable in one ear and babbling noise in the other ear). In response to these stimuli, both groups developed an anterior positivity synchronous with a posterior negativity, yet the topography significantly differed between groups likely due to the atypical gyration of the medial surface in AgCC. In particular, the anterior positivity was lateral in AgCC infants while it covered the midline in typical infants. We then measured the latencies of the main auditory response (P2 at this age) for the different conditions on the symmetrical left and right clusters. The main difference between groups was a ~ 60 ms delay in typical infants relative to AgCC, for the ipsilateral response (i.e. left hemisphere) to babbling noise presented in the left ear, whereas no difference was observed in the case of right-ear stimulation. We suggest that our results highlight an asymmetrical callosal connectivity favoring the right-to-left hemisphere direction in typical infants. This asymmetry, similar to recent descriptions in adults, might contribute to an enhancement of left lateralization for language processing beyond the initial cortical left-hemisphere advantage.

The Contribution of the Corpus Callosum to Language Lateralization.

The development of hemispheric lateralization for language is poorly understood. In one hypothesis, early asymmetric gene expression assigns language to the left hemisphere. In an alternate view, language is represented a priori in both hemispheres and lateralization emerges via cross-hemispheric communication through the corpus callosum. To address this second hypothesis, we capitalized on the high temporal and spatial resolution of magnetoencephalographic imaging to measure cortical activity during language processing, speech preparation, and speech execution in 25 participants with agenesis of the corpus callosum (AgCC) and 21 matched neurotypical individuals. In contrast to strongly lateralized left hemisphere activations for language in neurotypical controls, participants with complete or partial AgCC exhibited bilateral hemispheric activations in both auditory or visually driven language tasks, with complete AgCC participants showing significantly more right hemisphere activations than controls or than individuals with partial AgCC. In AgCC individuals, language laterality positively correlated with verbal IQ. These findings suggest that the corpus callosum helps to drive language lateralization. SIGNIFICANCE STATEMENT: The role that corpus callosum development has on the hemispheric specialization of language is poorly understood. Here, we used magnetoencephalographic imaging during linguistic tests (verb generation, picture naming) to test for hemispheric dominance in patients with agenesis of the corpus callosum (AgCC) and found reduced laterality (i.e., greater likelihood of bilaterality or right hemisphere dominance) in this cohort compared with controls, especially in patients with complete agenesis. Laterality was positively correlated with behavioral measures of verbal intelligence. These findings provide support for the hypothesis that the callosum aids in functional specialization throughout neural development and that the loss of this mechanism correlates with impairments in verbal performance.

Altered functional connectivity networks in acallosal and socially impaired BTBR mice.

Agenesis of the corpus callosum (AgCC) is a congenital condition associated with wide-ranging emotional and social impairments often overlapping with the diagnostic criteria for autism. Mapping functional connectivity in the acallosal brain can help identify neural correlates of the deficits associated with this condition, and elucidate how congenital white matter alterations shape the topology of large-scale functional networks. By using resting-state BOLD functional magnetic resonance imaging (rsfMRI), here we show that acallosal BTBR T+tpr3tf/J (BTBR) mice, an idiopathic model of autism, exhibit impaired intra-hemispheric connectivity in fronto-cortical, but not in posterior sensory cortical areas. We also document profoundly altered subcortical and intra-hemispheric connectivity networks, with evidence of marked fronto-thalamic and striatal disconnectivity, along with aberrant spatial extension and strength of ipsilateral and local connectivity. Importantly, inter-hemispheric tracing of monosynaptic connections in the primary visual cortex using recombinant rabies virus confirmed the absence of direct homotopic pathways between posterior cortical areas of BTBR mice, suggesting a polysynaptic origin for the synchronous rsfMRI signal observed in these regions. Collectively, the observed long-range connectivity impairments recapitulate hallmark neuroimaging findings in autism, and are consistent with the behavioral phenotype of BTBR mice. In contrast to recent rsfMRI studies in high functioning AgCC individuals, the profound fronto-cortical and subcortical disconnectivity mapped suggest that compensatory mechanism may not necessarily restore the full connectional topology of the brain, resulting in residual connectivity alterations that serve as plausible substrates for the cognitive and emotional deficits often associated with AgCC.

Bilateral subcortical heterotopia with partial callosal agenesis in a mouse mutant.

Cognition and behavior depend on the precise placement and interconnection of complex ensembles of neurons in cerebral cortex. Mutations that disrupt migration of immature neurons from the ventricular zone to the cortical plate have provided major insight into mechanisms of brain development and disease. We have discovered a new and highly penetrant spontaneous mutation that leads to large nodular bilateral subcortical heterotopias with partial callosal agenesis. The mutant phenotype was first detected in a colony of fully inbred BXD29 mice already known to harbor a mutation in Tlr4. Neurons confined to the heterotopias are mainly born in midgestation to late gestation and would normally have migrated into layers 2-4 of overlying neocortex. Callosal cross-sectional area and fiber number are reduced up to 50% compared with coisogenic wildtype BXD29 substrain controls. Mutants have a pronounced and highly selective defect in rapid auditory processing. The segregation pattern of the mutant phenotype is most consistent with a two-locus autosomal recessive model, and selective genotyping definitively rules out the Tlr4 mutation as a cause. The discovery of a novel mutation with strong pleiotropic anatomical and behavioral effects provides an important new resource for dissecting molecular mechanisms and functional consequences of errors of neuronal migration.

Diverticulum of the third ventricle and absence of the interthalamic adhesion in a dog.

A 10-month-old male Pomeranian dog was examined for neurological abnormalities consistent with diffuse forebrain and cerebellar disease. Based on ultrasound and magnetic resonance imaging (MRI) a diagnosis of diverticulum of the third ventricle, partial agenesis of the corpus callosum, and absence of the interthalamic adhesion was made. As conservative treatment was unsuccessful, a ventriculoperitoneal shunt was placed.

Diffusion-weighted imaging in fetuses with severe congenital heart defects.

Fetal diffusion MR imaging was performed in 3 fetuses with CHD. ADC values in the periatrial WM, thalamus, and basal ganglia were compared with those in a control population of fetuses. Diffusivity in the periatrial WM and thalamus was higher for the fetuses with CHD compared with controls. These observations support the finding of abnormal in utero brain development in fetuses with CHD.

Spontaneous endogenous hypermelatoninemia: a new disease?

Melatonin, a major photoperiod-dependent hormone, regulates circadian rhythms and biological rhythms and acts as a prominent sleep promoter. Symptoms related to hypermelatoninemia have been reported in individuals supplemented with melatonin. However, spontaneous endogenous hypermelatoninemia has not been reported previously. A 6-year-old girl previously diagnosed with Shapiro's syndrome was admitted to our hospital on several occasions during a 1-year period with complaints of altered consciousness, syncope, hypothermia and episodes of sweating. The episodes occurred daily and during sleep and lasted for 1-6 h. During these episodes, she sweated profusely and felt faint and her skin was pale and cool. Other complaints included recurrent abdominal pain, urge incontinence and myopia. She was shown to have hypermelatoninemia (>1,000 pg/ml, normal range 0-150 pg/ml) during these episodes. The duration of her attacks decreased with phototherapy and she was successfully treated with propranolol. To our knowledge, this is the first case of hypermelatoninemia without any detectable organic pathology. We did not determine the exact mechanism of hypermelatoninemia in this patient; however, it might have been related to irregular control of pinealocytes by the suprachiasmatic nucleus or related pathways. Hypermelatoninemia should be considered in patients with spontaneous periodic hypothermia and hyperhidrosis, and also in patients with Shapiro's syndrome.

Functional reorganization of the auditory pathways (or lack thereof) in callosal agenesis is predicted by monaural sound localization performance.

Neuroimaging studies show that permanent peripheral lesions such as unilateral deafness cause functional reorganization in the auditory pathways. However, functional reorganization of the auditory pathways as a result of higher-level damage or abnormalities remains poorly investigated. A relatively recent behavioural study points to functional changes in the auditory pathways in some, but interestingly not in all, of the acallosal individuals that were tested. The present study uses fMRI to investigate auditory activities in both cerebral hemispheres in those same acallosal subjects in order to directly investigate the contributions of ipsilateral and contralateral functional pathways reorganization. Predictions were made that functional reorganization could be predicted from behavioural performance. As reported previously in a number of neuroimaging studies, results showed that in neurologically intact subjects, binaural stimulation induced balanced activities between both hemispheres, while monaural stimulation induced strong contralateral activities and weak ipsilateral activities. In accordance with behavioural predictions, some acallosal subjects showed patterns of auditory cortical activities that were similar to those observed in neurologically intact subjects while others showed functional reorganization of the auditory pathways. Essentially they showed a significant increase and a significant decrease of neural activities in the contralateral and/or ipsilateral pathways, respectively. These findings indicate that at least in some acallosal subjects, functional reorganization inside the auditory pathways does contribute to compensate for the absence of the corpus callosum.

SPG11 compound mutations in spastic paraparesis with thin corpus callosum.

BACKGROUND: Autosomal recessive hereditary spastic paraparesis with thin corpus callosum (ARHSP-TCC) is being increasingly recognized as a variety of spastic paraplegia with mental retardation. SPG11 gene mutations have been reported to be associated with ARHSP-TCC. METHODS: As an independent group, we investigated SPG11 gene involvement in four individuals not previously described with either recessive or sporadic HSP-TCC presentation. RESULTS: Chromosome 15q13-15 segregating autosomal disease haplotypes were different across the kindreds and sequencing of SPG11 identified four novel frameshift/nonsense segregating mutations and the R2034X mutation, which were in heterozygous compound status. The affected examined had decreased thalamic and bilateral paracentral frontal lobe metabolism on (18)F-flurodeoxyglucose PET. CONCLUSIONS: Loss-of-function SPG11 mutations are the major cause of autosomal recessive hereditary spastic paraparesis with thin corpus callosum in Southern Europe, even in apparently sporadic cases. Decreased thalamic metabolism was consistently a phenotypical SPG11 mutation hallmark.

Enhancement of sound motion detection in acallosal individuals.

It has been proposed that the corpus callosum may play an important role in spectral cue processing that allows vertical auditory movement perception. The purpose of the present study was to assess the contribution of the corpus callosum to this type of auditory processing. Noise bursts were presented to 10 control and two callosal agenesis individuals from different positions located within midsagittal and coronal planes. Although acallosal participants were comparable with controls in their ability to correctly identify the trajectory direction or its length, they showed greater capability in detecting motion per se when the task was difficult. These results suggest that in the absence of the corpus callosum, compensatory reorganization of the brain allowed for superior auditory spectral cue processing.

The requirement for Phr1 in CNS axon tract formation reveals the corticostriatal boundary as a choice point for cortical axons.

Phr1 is the single well-conserved murine ortholog of the invertebrate ubiquitin ligase genes highwire (in Drosophila) and rpm-1 (in Caenorhabditis elegans). The function and mechanism of action of highwire and rpm-1 are similar--both cell-autonomously regulate synaptogenesis by down-regulating the ortholog of the mitogen-activated protein kinase kinase kinase dual leucine zipper kinase (MAPKKK DLK). Here, using a targeted conditional mutant, we demonstrate that Phr1 also plays essential roles in mammalian neural development. As in invertebrates, Phr1 functions cell-autonomously to sculpt motor nerve terminals. In addition, Phr1 plays essential roles in the formation of major CNS axon tracts including those of the internal capsule, in part via cell-nonautonomous mechanisms, and these results reveal a choice point for cortical axons at the corticostriatal boundary. Furthermore, whereas the neurite morphology phenotypes of highwire and rpm-1 are suppressed by loss of DLK in flies and worms, Phr1-dependent CNS defects persist in Phr1, DLK double mutants. Thus, in the mammalian nervous system Phr1 is required for formation of major CNS axon tracts via a mechanism that is both cell-nonautonomous and independent of DLK.

Sound lateralization in subjects with callosotomy, callosal agenesis, or hemispherectomy.

The question of whether there is a right-hemisphere dominance in the processing of auditory spatial information in human cortex as well as the role of the corpus callosum in spatial hearing functions is still a matter of debate. Here, we approached this issue by investigating two late-callosotomized subjects and one subject with agenesis of the corpus callosum, using a task of sound lateralization with variable interaural time differences. For comparison, three subjects with left or right hemispherectomy were also tested by employing identical methods. Besides a significant reduction in their acuity, subjects with total or partial section of the corpus callosum exhibited a considerable leftward bias of sound lateralization compared to normal controls. No such bias was found in the subject with callosal agenesis, but merely a marginal reduction of general acuity. Also, one subject with complete resection of the left cerebral cortex showed virtually normal performance, whereas another subject with left hemispherectomy and one subject with right hemispherectomy exhibited severe deficits, with almost total loss of sound-lateralization ability. The results obtained in subjects with callosotomy indicate that the integrity of the corpus callosum is not indispensable for preservation of sound-lateralization ability. On the other hand, transcallosal interhemispheric transfer of auditory information obviously plays a significant role in spatial hearing functions that depend on binaural cues. Moreover, these data are compatible with the general view of a dominance of the right cortical hemisphere in auditory space perception.

Schizophrenia, neurodevelopment and corpus callosum.

The Zeitgeist favors an interpretation of schizophrenia as a condition of abnormal connectivity of cortical neurons, particularly in the prefrontal and temporal cortex. The available evidence points to reduced connectivity, a possible consequence of excessive synaptic pruning in development. A decreased thalamic input to the cerebral cortex appears likely, and developmental studies predict that this decrease should entail a secondary loss of both long- and short-range cortico-cortical connections, including connections between the hemispheres. Indeed, morphological, electrophysiological and neuropsychological studies over the last two decades suggest that the callosal connections are altered in schizophrenics. However, the alterations are subtle and sometimes inconsistent across studies, and need to be investigated further with new methodologies.

Impact of in utero exposure to EtOH on corpus callosum development and paw preference in rats: protective effects of silymarin.

BACKGROUND: Using a rat model we have found that the bioflavonoid silymarin (SY) ameliorates some of the negative consequences of in utero exposure to ethanol (EtOH). In the current study our aim was to determine if laterality preference and corpus callosum development were altered in rat offspring whose mothers were provided with a concomitant administration of SY with EtOH throughout gestation. METHODS: We provided pregnant Fisher/344 rats with liquid diets containing 35% ethanol derived calories (EDC) throughout the gestational period. A silymarin/phospholipid compound containing 29.8% silybin was co administered with EtOH to a separate experimental group. We tested the offspring for laterality preference at age 12 weeks. After testing the rats were sacrificed and their brains perfused for later corpus callosum extraction. RESULTS: We observed incomplete development of the splenium in the EtOH-only offspring. Callosal development was complete in all other treatment groups. Rats from the EtOH-only group displayed a left paw preference; whereas control rats were evenly divided between right and left paw preference. Inexplicably both SY groups were largely right paw preferring. CONCLUSIONS: The addition of SY to the EtOH liquid diet did confer some ameliorative effects upon the developing fetal rat brain.

Abnormal distributions of callosal commissural and corticothalamic neurons in the cerebral neocortex of Shaking Rat Kawasaki.

Shaking Rat Kawasaki (SRK) is an autosomal recessive mutant rat recognized by unstable gait and tremor and by early death around the time of weaning. We previously reported that corticospinal tract neurons are malpositioned in the motor cortex of the SRK rat [Ikeda and Terashima (1997) J. Comp. Neurol. 383, 370-380]. In the present study, we examined the distribution pattern of callosal commissural (CC) and corticothalamic (CT) neurons of SRK and normal rats with the injection of horseradish peroxidase (HRP) into the contralateral hemisphere or wheat germ agglutinin-conjugated HRP into the ventral lateral thalamic nucleus. The intracortical distribution pattern of retrogradely labeled CC and CT neurons in the motor cortex of SRK rat was abnormal: CC neurons were more deeply situated and CT neurons were more superficially situated in the SRK cortex than the corresponding components in the normal cortex. Most of labeled CC and CT neurons had abnormal dendritic configurations. Statistical analysis revealed that the difference of the mean intracortical position of CC and CT neurons of the SRK was significantly different from the normal counterparts (Student's t-test, P<0.01). Taken together with previous findings, our data demonstrate that the abnormal cytoarchitecture of SRK cortex resembles the reeler cortex.