Neuregulin-1 (NRG1) polymorphisms linked with psychosis transition are associated with enlarged lateral ventricles and white matter disruption in schizophrenia.

BACKGROUND: Two single-nucleotide polymorphisms (SNPs) (rs4281084 and rs12155594) within the neuregulin-1 (NRG1) gene have been associated with psychosis transition. However, the neurobiological changes associated with these SNPs remain unclear. We aimed to determine what relationship these two SNPs have on lateral ventricular volume and white matter integrity, as abnormalities in these brain structures are some of the most consistent in schizophrenia. METHODS: Structural (n = 370) and diffusion (n = 465) magnetic resonance imaging data were obtained from affected and unaffected individuals predominantly of European descent. The SNPs rs4281084, rs12155594, and their combined allelic load were examined for their effects on lateral ventricular volume, fractional anisotropy (FA) as well as axial (AD) and radial (RD) diffusivity. Additional exploratory analyses assessed NRG1 effects on gray matter volume, cortical thickness, and surface area throughout the brain. RESULTS: Individuals with a schizophrenia age of onset ⩽25 and a combined allelic load ⩾3 NRG1 risk alleles had significantly larger right (up to 50%, p adj = 0.01) and left (up to 45%, p adj = 0.05) lateral ventricle volumes compared with those with allelic loads of less than three. Furthermore, carriers of three or more risk alleles, regardless of age of onset and case status, had significantly reduced FA and elevated RD but stable AD in the frontal cortex compared with those carrying fewer than three risk alleles. CONCLUSIONS: Our findings build on a growing body of research supporting the functional importance of genetic variation within the NRG1 gene and complement previous findings implicating the rs4281084 and rs12155594 SNPs as markers for psychosis transition.

Neuroprotection after a first episode of mania: a randomized controlled maintenance trial comparing the effects of lithium and quetiapine on grey and white matter volume.

Lithium and quetiapine are effective treatments for bipolar disorder, but their potential neuroprotective effects in humans remain unclear. A single blinded equivalence randomized controlled maintenance trial was conducted in a prospective cohort of first-episode mania (FEM) patients (n=26) to longitudinally compare the putative protective effects of lithium and quetapine on grey and white matter volume. A healthy control sample was also collected (n=20). Using structural MRI scans, voxel-wise grey and white matter volumes at baseline and changes over time in response to treatment were investigated. Patients were assessed at three time points (baseline, 3 and 12-month follow-up), whereas healthy controls were assessed at two time points (baseline and 12-month follow-up). Patients were randomized to lithium (serum level 0.6 mmol l-1, n=20) or quetiapine (flexibly dosed up to 800 mg per day, n=19) monotherapy. At baseline, compared with healthy control subjects, patients with FEM showed reduced grey matter in the orbitofrontal cortex, anterior cingulate, inferior frontal gyrus and cerebellum. In addition, patients had reduced internal capsule white matter volume bilaterally (t1,66>3.20, P<0.01). Longitudinally, there was a significant treatment × time effect only in the white matter of the left internal capsule (F2,112=8.54, P<0.01). Post hoc testing showed that, compared with baseline, lithium was more effective than quetiapine in slowing the progression of white matter volume reduction after 12 months (t1,24=3.76, P<0.01). Our data support the role of lithium but not quetiapine therapy in limiting white matter reduction early in the illness course after FEM.

[Scientific research in family medicine: practitioners' experience, barriers and needs]. / Recherche scientifique en médecine de famille: expériences, barrières et besoins des praticiens.

Scientific data from family medicine are relevant for the majority of the population. They are therefore essential from an ethical and public health perspective. We need to promote quality research in family medicine despite methodological, financial and logistic barriers. To highlight the strengths and weaknesses of research in family medicine in the French-speaking part of Switzerland we asked practitioners from this region to share their experience, critics and needs in relation to research. This article summarizes their contribution in light of the international literature.

Spine dynamics and synapse remodeling during LTP and memory processes.

While changes in the efficacy of synaptic transmission are believed to represent the physiological bases of learning mechanisms, other recent studies have started to highlight the possibility that a structural reorganization of synaptic networks could also be involved. Morphological changes of the shape or size of dendritic spines or of the organization of postsynaptic densities have been described in several studies, as well as the growth and formation following stimulation of new protrusions. Confocal in vivo imaging experiments have further revealed that dendritic spines undergo a continuous turnover and replacement process that may vary as a function of development, but can be markedly enhanced by sensory activation or following brain damage. The implications of these new aspects of plasticity for learning and memory mechanisms are discussed.

WITHDRAWN: Role of NCAM in Spine Dynamics and Synaptogenesis.

Increasing evidence indicates that adhesion molecules are critically involved in the regulation of mechanisms of synaptic plasticity including synapse formation, but also synaptic remodeling associated to changes in synaptic strength. Among these, the Neural Cell Adhesion Molecule (NCAM) and its polysialylated form PSA-NCAM are important candidates. Here we review recent results that point to a possible role of these two molecules in regulating the structural properties of excitatory synapses and namely the composition and stability of the postsynaptic density, thereby accounting for their contribution to mechanisms of synaptogenesis and activity-dependent synaptic plasticity.

Potentially toxic effects of anaesthetics on the developing central nervous system.

A growing body of experimental evidence suggests that anaesthetics, by influencing GABAergic and glutaminergic neural signalling, can have adverse effects on the developing central nervous system. The biological foundation for this is that gamma-aminobutyric acid and glutamate could act non-synaptically, in addition to their role in neurotransmission in the adult brain, in the regulation of neuronal development in the central nervous system. These neurotransmitters and their receptors are expressed from very early stages of central nervous system development and appear to influence neural progenitor proliferation, cell migration and neuronal differentiation. During the synaptogenetic period, pharmacological blockade of N-methyl-d-aspartate (NMDA)-type glutamate receptors as well as stimulation of GABAA receptors has been reported to be associated with increased apoptosis in the developing brain. Importantly, recent data suggest that even low, non-apoptogenic concentrations of anaesthetics can perturb neuronal dendritic development and thus could potentially lead to impairment of developing neuronal networks. The extrapolation of these experimental observations to clinical practice is of course very difficult and requires extreme caution as differences in drug concentrations and exposure times as well as interspecies variations are all important confounding variables. While clinicians should clearly not withhold anaesthesia based on current animal studies, these observations should urge more laboratory and clinical research to further elucidate this issue.

Intrathoracic neuroblastoma presenting with neonatal cardiorespiratory distress.

We report an unusual presentation of congenital intrathoracic neuroblastoma. Severe respiratory distress was present at birth and several salient clinical signs were suggestive of neonatal myocarditis. Excessive catecholamine secretions may have caused the observed cardiac dysfunction. Peculiar previously unreported cutaneous lesions were also noted in this case.