Temporal control of Wnt signaling is required for habenular neuron diversity and brain asymmetry.

Precise temporal coordination of signaling processes is pivotal for cellular differentiation during embryonic development. A vast number of secreted molecules are produced and released by cells and tissues, and travel in the extracellular space. Whether they induce a signaling pathway and instruct cell fate, however, depends on a complex network of regulatory mechanisms, which are often not well understood. The conserved bilateral left-right asymmetrically formed habenulae of the zebrafish are an excellent model for investigating how signaling control facilitates the generation of defined neuronal populations. Wnt signaling is required for habenular neuron type specification, asymmetry and axonal connectivity. The temporal regulation of this pathway and the players involved have, however, have remained unclear. We find that tightly regulated temporal restriction of Wnt signaling activity in habenular precursor cells is crucial for the diversity and asymmetry of habenular neuron populations. We suggest a feedback mechanism whereby the tumor suppressor Wnt inhibitory factor Wif1 controls the Wnt dynamics in the environment of habenular precursor cells. This mechanism might be common to other cell types, including tumor cells.

The changes of c-Fos expression by motor cortex stimulation in the deafferentation pain model.

The effect of motor cortex stimulation (MCS) therapy for deafferentation pain was evaluated based on c-Fos, a known pain marker. Nineteen mature cats weighing 1.5-3.5 kg were used. Cats were divided into three groups: a deafferentation pain group in which the left trigeminal ganglion was destroyed, an MCS group in which MCS was used following destruction of the trigeminal ganglion, and a control group. Sites and levels of c-Fos expression were examined immunohistochemically. The percentage of c-Fos-positive cells in the left spinal nucleus of the trigeminus, the bilateral insula, and the bilateral operculum increased in both the deafferentation pain and the MCS groups. There were no statistically significant differences between these groups. In the cingulate gyrus, the percentage of c-Fos-positive cells increased bilaterally in the deafferentation pain group and the MCS group, but the increase was greater in the MCS group. The increase in c-Fos-positive cells in the left spinal nucleus of the trigeminus in the deafferentation group may reflect reported electrical hyperactivity. The cingulate gyrus, insula, and parietal operculum were activated after deafferentation. This change (increase in c-Fos positive cells) is related to the development of deafferentation pain. Pain relief due to MCS is not dependent on the suppression of the activated left spinal nucleus of the trigeminus or the descending analgesic mechanism of the brain stem. Activation of the cingulate gyrus appears to be a factor in the analgesic mechanism of MCS.

Breast cancer predisposition and brain hemispheric laterality specification likely share a common genetic cause.

The majority of breast cancer cases seen in women remain unexplained by simple Mendelian genetics. It is generally hypothesized that such non-familial, so-called sporadic cases, result from exposure of the affected individuals to a cancer-causing environment and/or from stochastic cell biological errors. Clearly, adverse environment exposure can cause disease, but is that necessarily the cause of most sporadic cases? Curiously, female breast cancer patients who were selected to prefer right-hand-use reportedly exhibited a higher incidence of reversed-brain hemispheric laterality when compared to that of the public at large. Notably, such a higher level of hemispheric reversal is also found in healthy, left-handed or ambidextrous persons. Based on the association between these disparate traits, a new hypothesis for the etiology of sporadic breast cancer cases is advanced here; breast cancer predisposition and brain laterality development likely share a common genetic cause.

Effects of skilled training on sleep slow wave activity and cortical gene expression in the rat.

STUDY OBJECTIVE: The best characterized marker of sleep homeostasis is the amount of slow wave activity (SWA, 0.5-4 Hz) during NREM sleep. SWA increases as a function of previous waking time and declines during sleep, but the underlying mechanisms remain unclear. We have suggested that SWA homeostasis is linked to synaptic potentiation associated with learning during wakefulness. Indeed, studies in rodents and humans found that SWA increases after manipulations that presumably enhance synaptic strength, but the evidence remains indirect. Here we trained rats in skilled reaching, a task known to elicit long-term potentiation in the trained motor cortex, and immediately after learning measured SWA and cortical protein levels of c-fos and Arc, 2 activity-dependent genes involved in motor learning. DESIGN: Intracortical local field potential recordings and training on reaching task. SETTING: Basic sleep research laboratory. PATIENTS OR PARTICIPANTS: Long Evans adult male rats. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: SWA increased post-training in the trained cortex (the frontal cortex contralateral to the limb used to learn the task), with smaller or no increase in other cortical areas. This increase was reversible within 1 hour, specific to NREM sleep, and positively correlated with changes in performance during the prior training session, suggesting that it reflects plasticity and not just motor activity. Fos and Arc levels were higher in the trained relative to untrained motor cortex immediately after training, but this asymmetry was no longer present after 1 hour of sleep. CONCLUSION: Learning to reach specifically affects gene expression in the trained motor cortex and, in the same area, increases sleep need as measured by a local change in SWA.

Association of a polymorphism near CREB1 with differential aversion processing in the insula of healthy participants.

CONTEXT: Previous functional neuroimaging studies have identified a network of brain regions that process aversive stimuli, including anger. A polymorphism near the cyclic adenosine monophosphate response element binding protein gene (CREB1) has recently been associated with greater self-reported effort at anger control as well as risk for antidepressant treatment-emergent suicidality in men with major depressive disorder, but its functional effects have not been studied. OBJECTIVE: To determine whether this genetic variant is associated with altered brain processing of and behavioral avoidance responses to angry facial expressions. DESIGN AND PARTICIPANTS: A total of 28 white participants (mean age, 29.2 years; 13 women) were screened using the Structured Clinical Interview for DSM-IV to exclude any lifetime Axis I psychiatric disorder and were genotyped for rs4675690, a single-nucleotide polymorphism near CREB1. MAIN OUTCOME MEASURES: Blood oxygenation level-dependent signal by functional magnetic resonance imaging in the amygdala, insula, anterior cingulate, and orbitofrontal cortex during passive viewing of photographs of faces with emotional expressions. To measure approach and avoidance responses to anger, an off-line key-press task that traded effort for viewing time assessed valuation of angry faces compared with other expressions. RESULTS: The CREB1-linked single-nucleotide polymorphism was associated with significant differential activation in an extended neural network responding to angry and other facial expressions. The CREB1-associated insular activation was coincident with activation associated with behavioral avoidance of angry faces. CONCLUSIONS: A polymorphism near CREB1 is associated with responsiveness to angry faces in a brain network implicated in processing aversion. Coincident activation in the left insula is further associated with behavioral avoidance of these stimuli.

Sporadic rapid-onset dystonia-parkinsonism presenting as Parkinson's disease.

We report on a 38-year-old patient with rapid-onset dystonia-parkinsonism (RDP) with a missense mutation in the Na/K-ATPase alpha3 subunit (ATP1A3). Asymmetrical parkinsonian symptoms evolved over a year. After a stable episode of another 2.5 years, overnight he developed oromandibular dystonia and more severe parkinsonian symptoms. We conclude that RDP should be considered as a rare cause of levodopa-unresponsive parkinsonism even if there is no family history and the classic presentation is lacking.

Hereditary porencephaly: clinical and MRI findings in two Dutch families.

Familial porencephaly is a rare disorder causing motor impairment, hemiplegia, mental retardation and epilepsy in variable degrees. Two families with porencephaly and apparently dominant inheritance are reported. Brain MRI findings are reviewed and described in seven affected individuals. Most patients also show white matter abnormalities in the cerebral hemisphere, also contralateral to the cystic lesion. In the first family an obligate carrier was identified who did not have a cystic lesion but clear abnormalities of the white matter. Although a predisposition for thrombophilia has previously been reported, we did not observe any genetic, environmental or epigenetic predisposition for the porencephaly. The lesions are most compatible with a deep venous thrombosis/ischemic event occurring in a late stage of pregnancy, not necessarily aggravated by perinatal asphyxia.

Unsuspected atypical hemispheric dominance for language as determined by fMRI.

PURPOSE: We sought to illustrate the value of functional magnetic resonance imaging (fMRI) in the presurgical assessment of hemispheric dominance for language by means of an illustrative case report. METHODS: fMRI with two language paradigms was performed in a right-handed patient without familial sinistrality suffering from a left frontal focal epilepsy. RESULTS: Both fMRI paradigms revealed unequivocally lateralized right hemispheric activation. Atypical language representation was confirmed by Wada test. The further presurgical workup could be restricted to subdural strip recordings instead of the initially intended grid implantation. After resective surgery, no language deficits were apparent. CONCLUSIONS: Hemispheric dominance for language should be assessed by fMRI in all patients before surgery in areas potentially relevant for language in either cerebral hemisphere. fMRI may influence the further diagnostic workup and should be performed before other invasive diagnostic procedures.

Immunohistochemical expression of cell adhesion molecule L1 in hemimegalencephaly.

We demonstrated immunohistochemically an abnormal expression of the neural cell adhesion molecule L1 in 10 developing brains of children with hemimegalencephaly (HM) aged from 36 weeks gestation to 10 years of age, comparing them with 23 controls aged from 13 weeks of gestation to 14 years. There was dense L1 expression in focal regions of the molecular layer beneath leptomeningeal glioneuronal heterotopia, in areas of cerebral cortex with large neurons, and in the disorganized or neuronal heterotopic sites in the white matter in HM. L1 was also heterogeneously enhanced in the abnormal cortex after 1 year of age, suggesting that axonal growth was delayed. These changes persisted into the older age group in the abnormal areas of cortex in HM. The cell bodies of many enlarged neurons in HM were immunopositive for L1, whereas L1 was usually localized to the processes of normal neurons. The delayed L1 immunoreactivity and enlarged L1-immunopositive neurons may be closely related to the pathogenesis of unilateral megalencephaly with cortical dysplasia and heterotopia.

Schizencephaly: surgical features and new molecular genetic results.

Schizencephaly is a rare developmental disorder characterized by a full thickness cleft within the cerebral hemispheres. Large portions of the cerebral hemispheres may be missing and are replaced by cerebrospinal fluid (CSF). The walls of the clefts are lined by polymicrogyric grey matter and are covered by the so-called "pialependymal seam". The cleft may be unilateral or bilateral, and if bilateral are fairly symmetrical. Their dimensions can be small or large. The clinical features may vary from a normal to a severe development delay. 13 patients with this anomaly have been evaluated. Using SSCP (single strand conformation polymorphism) analysis, as previously described (2), they were found to have a mutant homeobox gene, Emx2.

Optic gliomas in neurofibromatosis type 1: role of visual evoked potentials.

Optic gliomas occur in 15% of patients with neurofibromatosis type 1 (NF 1) and are a significant cause of morbidity. Of these tumors, 20-30% become symptomatic, usually before age 10 years. Previous studies have suggested that visual evoked potentials (VEPs) are a sensitive method for the detection of asymptomatic optic gliomas. Because routine neuroimaging of children with NF 1 is currently not recommended, the role of pattern-shift VEPs (PS VEPs) as a screening test for optic gliomas was evaluated. PS VEPs were performed on 10 children with NF 1 and optic gliomas and 20 children with NF 1 and normal visual pathways (as defined on MRI). PS VEPs had 90% sensitivity for detecting optic gliomas, with an increase in sensitivity to 100% when hemifield stimulation was used. The specificity of the test was 60%. Four of 20 children without optic gliomas had thickened optic nerves on computed tomography which represented dural ectasia with normal visual pathways on MRI; PS VEPs were normal in these patients. The efficacy of PS VEPs as a routine screen for optic gliomas is limited by the age at which children will cooperate with the test procedure and the high incidence of false-positive results; however, VEPs do provide a useful adjunct to routine clinical ophthalmologic assessment in the detection of optic gliomas in children with NF 1. Abnormal test results provide a stronger indication for neuroimaging. The early detection of optic gliomas allows for close monitoring of tumor progression and earlier intervention prior to significant visual loss.

Unilateral stimulation or removal of rat vibrissae: analysis of nerve growth factor and tyrosine hydroxylase mRNA in the brain.

Previous work has shown that unilateral manipulation of vibrissae in the rat can lead to behavioral asymmetries and to neuronal changes in the basal ganglia: in brief, vibrissae stimulation led to increases in neostriatal dopamine release, whereas unilateral removal of vibrissae led to asymmetries in striatal afferents and to bilateral changes in mesencephalic dopamine mechanisms which were related to the occurrence of behavioral asymmetries and the later recovery therefrom. In the present study, the analysis of neuronal mechanisms possibly affected by vibrissae manipulation was extended to the nerve growth factor and the expression of tyrosine hydroxylase mRNA. Unilateral stimulation or removal of the vibrissae did not lead to significant changes in tissue levels of nerve growth factor in the neostriatum, parietal cortex (including the barrel cortex) or the hippocampus. In contrast, tyrosine hydroxylase mRNA in the substantia nigra and ventral tegmental area was affected by vibrissae removal but not by stimulation, as a bilateral increase in labeling was observed on the level of individual neurons. This effect was only observed in animals tested 4 h after vibrissae removal but not after 10 days. The results are discussed with respect to the interaction of vibrissae function with the basal ganglia, the neurotransmitter dopamine and mechanism of functional recovery.

Hypopigmentation, anomalous cerebral dominance and seasonality.

This paper proposes a prenatal seasonal hypopigmentation influence associated with anomalous cerebral dominance that occurs during the winter or early spring. A possible mechanism would be seasonal changes in sex hormone levels that affect the activation and inactivation of DNA by reversible methylation. The proposed prenatal seasonal hypopigmentation effect might be relevant to dyslexia, Prader-Willi syndrome, breast cancer, Alzheimer's and Parkinson's disease. Putative chromosomal loci associated with the proposed seasonal mechanism would be 15q11-13 (dyslexia and Prader-Willi syndrome), 21q region (breast cancer and Alzheimer's disease) and 19p region (pigmentation gene).