A single low dose of valproic acid in late prenatal life alters postnatal behavior and glutamic acid decarboxylase levels in the mouse.

RATIONALE: Rodents exposed to valproic acid (VPA) in prenatal life exhibit post-natal characteristics analogous to autism spectrum disorder (ASD). Many previous studies used relatively high doses of VPA during early pregnancy, potentially confounding interpretation because the offspring are the 'survivors' of a toxic insult. Low dose or late gestation exposure has not been widely studied. OBJECTIVES: We examined the behavioral sequelae of late gestation exposure to low dose VPA in the mouse. We also examined postnatal levels of glutamic acid decarboxylase (GAD65 and GAD67) as markers for GABA neurons, because GABA pathology and subsequent excitatory/inhibitory imbalance is strongly implicated in ASD. METHODS: Pregnant C57BL/6N mice received a single subcutaneous injection of 100 or 200mg/kg on gestation day 17. The control group received a saline injection on the same day. The offspring were tested in a battery of behavioral tests in adolescence and adulthood. Six brain regions were harvested and GAD65 and GAD67 were measured by western blotting. RESULTS: Compared to saline-exposed controls, adult mice exposed to prenatal VPA had impaired novel object exploration and fear conditioning anomalies. GAD67 was decreased in midbrain, olfactory bulb, prefrontal cortex and increased in cerebellum, hippocampus and striatum; GAD65 was decreased in all 6 regions. CONCLUSIONS: Our results suggest that a low dose of VPA in late pregnancy has persistent effects on brain development, and in particular the GABA system, which may be relevant to ASD. Further attention to the impact of gestation time and dose of exposure in VPA-induced ASD models is encouraged.

Multimodal MRI of the hippocampus in Parkinson's disease with visual hallucinations.

Visual hallucinations carry poor prognosis in Parkinson's disease. Here we tested the hypothesis that the hippocampus and visuospatial memory impairment play a central role in the pathology of PD with visual hallucinations. Multimodal magnetic resonance imaging of the brain was carried out in 12 people with PD and visual hallucinations; 15 PD individuals without hallucinations; and 14 healthy controls. Age, gender, cognitive ability, and education level were matched across the three groups. PD patients were taking dopaminergic medication. Hippocampal volume, shape, mean diffusivity (MD), and functional connectivity within the whole brain were examined. Visuospatial memory was compared between groups, and correlations with hippocampal MD, functional connectivity, and the severity of hallucinations were explored. There were no macrostructural differences across groups, but individuals with hallucinations had higher diffusivity in posterior hippocampus than the other two groups. Visuospatial memory was poorer in both PD groups compared to controls, and was correlated with hallucinations. Finally, hippocampal functional connectivity in the visual cortices was lower in those with hallucinations than other groups, and this correlated with visuospatial memory impairment. In contrast, functional connectivity between the hippocampus and default mode network regions and frontal regions was greater in the PD hallucinators compared to other groups. We suggest that hippocampal pathology, which disrupts visuospatial memory, makes a key contribution to visual hallucinations in PD. These findings may pave the way for future studies of imaging biomarkers to measure treatment response in those with PD who are most at risk of poor outcomes.

The Effect of Oxytocin on Social and Non-Social Behaviour and Striatal Protein Expression in C57BL/6N Mice.

Oxytocin has been suggested as a promising new treatment for neurodevelopmental disorders. However, important gaps remain in our understanding of its mode of action, in particular, to what extent oxytocin modulates social and non-social behaviours and whether its effects are generalizable across both sexes. Here we investigated the effects of a range of oxytocin doses on social and non-social behaviours in C57BL/6N mice of both sexes. As the striatum modulates social and non-social behaviours, and is implicated in neurodevelopmental disorders, we also conducted a pilot exploration of changes in striatal protein expression elicited by oxytocin. Oxytocin increased prepulse inhibition of startle but attenuated the recognition memory in male C57BL/6N mice. It increased social interaction time and suppressed the amphetamine locomotor response in both sexes. The striatum proteome following oxytocin exposure could be clearly discriminated from saline controls. With the caveat that these results are preliminary, oxytocin appeared to alter individual protein expression in directions similar to conventional anti-psychotics. The proteins affected by oxytocin could be broadly categorized as those that modulate glutamatergic, GABAergic or dopaminergic signalling and those that mediate cytoskeleton dynamics. Our results here encourage further research into the clinical application of this peptide hormone, which may potentially extend treatment options across a spectrum of neurodevelopmental conditions.

Resting activity in visual and corticostriatal pathways in Parkinson's disease with hallucinations.

BACKGROUND: Visual hallucinations are an important non-motor complication of Parkinson's disease (PD) and carry a negative prognosis. Their biological basis is uncertain, but may relate to the activity of resting state networks in brain. We therefore aimed to investigate functional activity of brain in patients with visual hallucinations (PDVH) in resting state compared to patients without hallucinations (PDnonVH) and a healthy control group (HC). METHODS: Resting state functional MRI was acquired and the primary analysis compared the amplitude of low-frequency fluctuations (ALFF) across groups. This informed a secondary analysis, in the PD groups only, comparing functional connectivity between a 'seed' region in the occipital lobe and the rest of the brain. RESULTS: Individuals with PDVH showed lower ALFF in bilateral lingual gyrus and cuneus and greater ALFF in temporo-parietal regions, medial temporal gyrus and cerebellum than PDnonVH and HC. PDnonVH also had lower ALFF in occipitoparietal region and greater ALFF in medial temporal gyrus, temporo-parietal and cerebellum regions than HC. Functional connectivity analysis revealed that, although both PD groups had lower occipital functional connectivity relative to the HC group, occipital - corticostriatal connectivity was significantly higher in those with PDVH compared with PDnonVH. CONCLUSION: Our study reveals widespread hemodynamic alterations in PD. However, within a functionally abnormal occipital lobe, those with PDVH have even lower ALFF than non-hallucinators, but have higher occipital functional connectivity with cortical-striatal regions. These findings suggest disruption of pathways underpinning both primary visual perceptual and intrinsic visual integration may contribute to visual hallucinations in PD.

MRI predicts remission at 1 year in first-episode schizophrenia in females with larger striato-thalamic volumes.

BACKGROUND/AIMS: The Remission in Schizophrenia Working Group has defined remission as 'a low-mild symptom intensity level, maintained for a minimum of 6 months, where such symptoms do not affect an individual's behaviour' [Andreasen et al.: Am J Psychiatry 2005;162:441-449]. Since brain morphology relates to symptomatology, treatment and illness progression, MRI may assist in predicting remission. METHODS: Thirty-nine patients newly diagnosed with DSM-IV schizophrenia underwent MRI brain scan prior to antipsychotic exposure. The Global Assessment of Functioning (GAF) score was entered into a voxel-based analysis to evaluate its relationship with cerebral grey matter volume from the baseline MRI. We entered age, total intracranial volume and intake GAF score as co-variates. Males and females were analysed separately because gender is a potent determinant of outcome. RESULTS: Males had lower GAF scores than females, both at intake and at 1 year. Males comprised only 40% (12 out of 39) of the early remission group. For females only, early remission was strongly and positively correlated with bilateral lentiform and striatal volumes. For males, there was no such relationship. CONCLUSION: Larger striato-thalamic volume correlated with early remission in females only. These baseline MRI findings were unlikely to be confounded by antipsychotic treatment and chronicity. These brain morphological markers show gender dimorphism and may assist in the prediction of early remission in newly diagnosed schizophrenia.

The default mode network is disrupted in Parkinson's disease with visual hallucinations.

BACKGROUND: Visual hallucinations (VH) are one of the most striking nonmotor symptoms in Parkinson's disease (PD), and predict dementia and mortality. Aberrant default mode network (DMN) is associated with other psychoses. Here, we tested the hypothesis that DMN dysfunction contributes to VH in PD. METHODS: Resting state functional data was acquired from individuals with PD with VH (PDVH) and without VH (PDnonVH), matched for levodopa drug equivalent dose, and a healthy control group (HC). Independent component analysis was used to investigate group differences in functional connectivity within the DMN. In addition, we investigated whether the functional changes associated with hallucinations were accompanied by differences in cortical thickness. RESULTS: There were no group differences in cortical thickness but functional coactivation within components of the DMN was significantly lower in both PDVH and PDnonVH groups compared to HC. Functional coactivation within the DMN was found to be greater in PDVH group relative to PDnonVH group. CONCLUSION: Our study demonstrates, for the first time that, within a functionally abnormal DMN in PD, relatively higher "connectivity" is associated with VH. We postulate that aberrant connectivity in a large scale network affects sensory information processing and perception, and contributes to "positive" symptom generation in PD.

Frontal-subcortical protein expression following prenatal exposure to maternal inflammation.

BACKGROUND: Maternal immune activation (MIA) during prenatal life is a risk factor for neurodevelopmental disorders including schizophrenia and autism. Such conditions are associated with alterations in fronto-subcortical circuits, but their molecular basis is far from clear. METHODOLOGY/PRINCIPAL FINDINGS: Using two-dimensional differential in-gel electrophoresis (2D-DIGE) and mass spectrometry, with targeted western blot analyses for confirmation, we investigated the impact of MIA on the prefrontal and striatal proteome from an established MIA mouse model generated in C57B6 mice, by administering the viral analogue PolyI:C or saline vehicle (control) intravenously on gestation day (GD) 9. In striatum, 11 proteins were up-regulated and 4 proteins were down-regulated in the PolyI:C mice, while 10 proteins were up-regulated and 7 proteins down-regulated in prefrontal cortex (PFC). These were proteins involved in the mitogen-activated protein kinase (MAPK) signaling pathway, oxidation and auto-immune targets, including dual specificity mitogen-activated protein kinase kinase 1 (MEK), eukaryotic initiation factor (eIF) 4A-II, creatine kinase (CK)-B, L-lactate dehydrogenase (LDH)-B, WD repeat-containing protein and NADH dehydrogenase in the striatum; and guanine nucleotide-binding protein (G-protein), 14-3-3 protein, alpha-enolase, olfactory maker protein and heat shock proteins (HSP) 60, and 90-beta in the PFC. CONCLUSIONS/SIGNIFICANCE: This data fits with emerging evidence for disruption of critical converging intracellular pathways involving MAPK pathways in neurodevelopmental conditions and it shows considerable overlap with protein pathways identified by genetic modeling and clinical post-mortem studies. This has implications for understanding causality and may offer potential biomarkers and novel treatment targets for neurodevelopmental conditions.

Effects on prolongation of Bazett's corrected QT interval of seven second-generation antipsychotics in the treatment of schizophrenia: a meta-analysis.

The use of second-generation antipsychotics (SGAs) for the treatment of schizophrenia has surged worldwide. Amisulpride, aripiprazole, olanzapine, quetiapine, risperidone, sertindole and ziprasidone have now been commonly prescribed. Their effects on QT interval differ but evidence remains sparse and mostly inconclusive. Since prolongation of heart-rate corrected QT interval has been implicated as an useful surrogate marker to predict drug-related cardiac mortality and pro-arrhythmic potentials, it is timely and necessary to compare the effects of Bazett's corrected QT interval (QT(Bc)) prolongation for the commonly prescribed SGAs. A meta-analysis was conducted according to suggestions by the Quality of Reporting of Meta-analysis group with literature identified using various databases and augmented with hand-searching to assess the magnitude and risk on QT(Bc) prolongation by these seven SGAs for treatments in adult subjects with schizophrenia. Because of incomplete QT(Bc) data reporting, quetiapine could not be assessed by the meta-analytical approach in this study. Aripiprazole was the only SGA associated with both statistically significant lower risk and mean change in QT(Bc), with sertindole giving a statistically significant worsening effect on mean QT(Bc). Other analyses did not demonstrate any statistically significant pooled effects for the studied SGAs, neither on the magnitude over mean or mean change, nor the risk on QT(Bc) prolongation.

Spatiotemporal dipole source localization of face processing ERPs in adolescents: a preliminary study.

BACKGROUND: Despite extensive investigation of the neural systems for face perception and emotion recognition in adults and young children in the past, the precise temporal activation of brain sources specific to the processing of emotional facial expressions in older children and adolescents is not well known. This preliminary study aims to trace the spatiotemporal dynamics of facial emotion processing during adolescence and provide a basis for future developmental studies and comparisons with patient populations that have social-emotional deficits such as autism. METHODS: We presented pictures showing happy, angry, fearful, or neutral facial expressions to healthy adolescents (aged 10-16 years) and recorded 128-channel event-related potentials (ERPs) while they performed an emotion discrimination task. ERP components were analyzed for effects of age and emotion on amplitude and latency. The underlying cortical sources of scalp ERP activity were modeled as multiple equivalent current dipoles using Brain Electrical Source Analysis (BESA). RESULTS: Initial global/holistic processing of faces (P1) took place in the visual association cortex (lingual gyrus) around 120 ms post-stimulus. Next, structural encoding of facial features (N170) occurred between 160-200 ms in the inferior temporal/fusiform region, and perhaps early emotion processing (Vertex Positive Potential or VPP) in the amygdala and orbitofrontal cortex. Finally, cognitive analysis of facial expressions (P2) in the prefrontal cortex and emotional reactions in somatosensory areas were observed from about 230 ms onwards. The temporal sequence of cortical source activation in response to facial emotion processing was occipital, prefrontal, fusiform, parietal for young adolescents and occipital, limbic, inferior temporal, and prefrontal for older adolescents. CONCLUSION: This is a first report of high-density ERP dipole source analysis in healthy adolescents which traces the sequence of neural activity within the first 500 ms of categorizing emotion from faces. Our spatio-temporal brain source models showed the presence of adult-like cortical networks for face processing in adolescents, whose functional specificity to different emotions appear to be not yet fully mature. Age-related differences in brain activation patterns illustrate the continued development and maturation of distinct neural systems for processing facial expressions during adolescence and possible changes in emotion perception, experience, and reaction with age.