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Objectives Patients with schizophrenia have a significant risk of self-harm. We aimed to explore the dynamic relationship between symptomatology, functioning and deliberate self-harm (DSH) and evaluate the feasibility of developing a self-harm risk prediction tool for patients with first-episode schizophrenia (FES). Methods Patients with FES (n = 1234) were followed up for 36 months. Symptomatology, functioning, treatment adherence and self-harm information were obtained monthly over the follow-up period. A time-varying vector autoregressive (VAR) model was used to study the contribution of clinical variables to self-harm over the 36th month. Random forest models for self-harm were established to classify the individuals with self-harm and predict future self-harm events. Results Over a 36-month period, 187 patients with FES had one or more self-harm events. The depressive symptoms contributed the most to self-harm prediction during the first year, while the importance of positive psychotic symptoms increased from the second year onwards. The random forest model with all static information and symptom instability achieved a good area under the receiver operating characteristic curve (AUROC = 0.77 ± 0.023) for identifying patients with DSH. With a sliding window analysis, the averaged AUROC of predicting a self-event was 0.65 ± 0.102 (ranging from 0.54 to 0.78) with the best model being 6-month predicted future 6-month self-harm for month 11–23 (AUROC = 0.7). Conclusions Results highlight the importance of the dynamic relationship of depressive and positive psychotic symptoms with self-harm and the possibility of self-harm prediction in FES with longitudinal clinical data.

Supplemental material, sj-docx-1-isp-10.1177_00207640231152691 for Unpacking the mediating role of resilience in the relationship between ideal-actual self-discrepancy, stressful life events, depression and anxiety: Results from 1,144 young people in an epidemiological study in Hong Kong by Suen Yi Nam, Ling Cheuk Ying Crystal, Cheung Charlton, Hui Lai Ming Christy, Wong Ming Yin Stephanie, Wong Tak Hing Michael, Chan Kit Wa Sherry, Lee Ho Ming Edwin and Chen Yu Hai Eric in International Journal of Social Psychiatry

The underpinnings of language deviations in psychotic symptoms (eg, formal thought disorder, delusions) remain unclear. We examined whether the semantic networks underlying word associations are useful predictors of clinical outcomes in psychosis. Fifty-one patients with schizophrenia and other psychotic disorders and 51 matched healthy controls generated words in a Cantonese continued word association task. Patterns of word associations were examined using semantic similarity metrics derived from word embeddings (fastText) and the structure of individual semantic networks. A longitudinal design—baseline and 6 months later—enabled investigation of the relationship of changes in semantic associations in patients who were in an acute psychotic state at baseline compared to clinical stabilization 6 months later. The semantic similarity measure increased over time in patients, while it remained stable in controls. Moreover, the change in semantic similarity over time correlated with the changes in patients’ formal thought disorder symptoms. There were differences in individual semantic networks between the groups at both time points. Patients had less structured networks on average, as evidenced by a smaller network diameter and clustering coefficient, and smaller average shortest path lengths. The identification of several state-like semantic measures that change over time with patients’ mental states allows for nuanced comparison with clinical measures. Semantic measures are complex. Semantic similarity was a state-like measure that changed over time with mental state in psychotic disorders, whereas individual semantic network parameters were trait-like and stable over time.

Spinal cord injury (SCI) impairs mobility and often results in complications like intractable neuropathic pain. A multi-approach management of this chronic pain condition has been encouraged, but little has been explored of the field. Here, we focus on the effect and underlying mechanism of environmental enrichment (EE), which promotes voluntary social and physical activities, combined with a clinical analgesic, ketamine, on SCI-induced neuropathic pain as well as motor dysfunction. We performed T13 spinal hemisection in rats, which induced unilateral motor impairment and neuropathic pain-like behaviors in the hindlimb. Treatment regimen started a week after SCI, which consists of ketamine administration (30 mg kg–1day–1; intramuscular) for 10 days, or EE housing for 20 days, or their combination. Paw withdrawal response to mechanical and thermal stimuli, motor function, burrowing behaviors, and body weight was monitored. Spinal segments at T13 lesion and L4–L6 were collected for histopathological and protein analyses. The joint treatment of EE and ketamine provided greater relief of pain-like behaviors and locomotor recovery than did either paradigm alone. These improvements were associated with reduced cavitation area, astrogliosis, and perilesional phosphorylation of glutamateN-methyl-D-aspartate receptor (NMDAR). Concurrently, lumbar spinal analysis of NMDAR-linked excitatory markers in hypersensitization showed reduced activation of NMDAR, mitogen-activated protein kinase (MAPK) family, nuclear factor (NF)-κB, interleukin (IL)-1β signaling, and restored excitatory amino acid transporter 2 level. Our data support a better therapeutic efficacy of the combination, EE, and ketamine, in the attenuation of neuropathic pain and motor recovery by reducing spinal glutamatergic activation, signifying a potential multifaceted neurorehabilitation strategy to improve SCI patient outcome.

Additional file 1: Table 1. Moderation effects of gender on the association between mental health literacy and public stigma. Table 2. Moderation effects of age status on the association between mental health literacy and public stigma. Table 3. Moderation effects of education status on the association between mental health literacy and public stigma. Table 4. Moderation effects of retirement status on the association between mental health literacy and public stigma. Table 5. Moderation effects of housemaker status on the association between mental health literacy and public stigma. Table 6. Moderation effects of life satisfaction on the association between mental health literacy and public stigma.

Aim The preference of and potential barriers to disclosure of psychotic illness vary across cultures. Studying its patterns and correlates can guide the design of future culture-specific intervention and public education approaches to improve willingness to disclose and thereby reducing the duration of untreated psychosis (DUP). Methods A population-based, random telephone survey was conducted with a total of 1514 respondents in Hong Kong in January 2018. Cross-sectional data on willingness to disclose psychotic illness, life satisfaction, stigmatizing attitude and recent experience of stressful life events (SLEs) were analysed against age and gender using structural equation modelling (SEM). Results Unwillingness to disclose to anyone was reported by 12% of the participants. Family was reported as the preferred disclosure candidate by most respondents. Our model, which showed a good fit to the data demonstrated that stigmatizing attitude and life satisfaction were directly associated with willingness to disclose illness. Younger age was correlated with more recent experience of SLEs, lower life satisfaction and less willingness to disclose illness. Women's disclosure willingness was positively associated with their life satisfaction, which was sensitive to recent exposure to single SLE. In contrast, men's was negatively associated with their stigmatizing attitude, which increased significantly upon exposure to two or more recent SLEs. Conclusion Encouraging the public to help their family to seek treatment should be a focal point of a successful mental health public education campaign. Cultural-specific and integrated interventions should be developed targeting the vulnerable groups including people with high recent life stress, particularly woman and those with younger age.

RationaleRodents 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.ObjectivesWe 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.MethodsPregnant C57BL/6N mice received a single subcutaneous injection of 100 or 200 mg/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.ResultsCompared 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.ConclusionsOur 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.

Testis specific protein, Y-encoded-like 2 (TSPYL2) regulates the expression of genes encoding glutamate receptors. Glutamate pathology is implicated in neurodevelopmental conditions such as autism spectrum disorder, attention deficit hyperactivity disorder (ADHD) and schizophrenia. In line with this, a microduplication incorporating the TSPYL2 locus has been reported in people with ADHD. However, the role of Tspyl2 remains unclear. Therefore here we used a Tspyl2 loss-of-function mouse model to directly examine how this gene impacts upon behavior and brain anatomy. We hypothesized that Tspyl2 knockout (KO) would precipitate a phenotype relevant to neurodevelopmental conditions. In line with this prediction, we found that Tspyl2 KO mice were marginally more active, had significantly impaired prepulse inhibition, and were significantly more ‘sensitive’ to the dopamine agonist amphetamine. In addition, the lateral ventricles were significantly smaller in KO mice. These findings suggest that disrupting Tspyl2 gene expression leads to behavioral and brain morphological alterations that mirror a number of neurodevelopmental psychiatric traits. Electronic supplementary material The online version of this article (doi:10.1007/s10519-015-9777-8) contains supplementary material, which is available to authorized users.

Background Language Disorganisation is central to the conceptualization of psychosis. Disruptions in semantic processing have been observed both as a “state”, and a “trait” phenomena in psychotic disorders. Quantification of semantic abnormalities have been improved with recent advances in semantic modeling. The current study applied such computational methods on a word association task, using immediate response to cue words to explore semantic associations. We employed a longitudinal design to investigate semantic relationships during a psychotic episode compared with the same patients after remission six months later, in order to clarify the state-trait status of the semantic variables, and their relationships with clinical symptoms. We hypothesized that semantic distance would be significantly greater in patients than controls at baseline, and would decrease upon follow-up. Methods A continued word association task (WAT) was employed to elicit three associations per cue from a set of 200 cue-words. The set of cues were previously established as being representative of words in general speech, in terms of valence, concreteness and part-of-speech composition. The task was administered to 47 patients with schizophrenia spectrum disorders and 44 matched healthy control participants. Data was collected at two time points, at baseline when patients were actively psychotic and then at 6-months follow-up. In addition, extensive clinical and cognitive measures were collected at both time points. Patterns of word associations were explored using vector representations, derived from Word2Vec, that encompass semantic meaning. Semantic distance of each cue-response pairing is defined using the cosine angle of their vectors. Changes in semantic distance were further examined on their correlation with symptom change over time. Results There was a significant interaction between group and time point on semantic distance (F = 6.865, p = 0.009), where measures of the semantic distance of patients’ responses were significantly greater than healthy controls at both time-points (p < 0.001).There is a significant time effect: the semantic distance reduced significantly over time (p < 0.001). Within the patient group, a change in semantic distance was correlated with symptom change over time, specifically with general psychopathology (p =0.024), depressive (p = 0.046) and manic symptoms (p < 0.01). Discussion Measures of semantic distance were significantly greater in patients both at baseline during a psychotic episode, and at follow-up upon clinical remission. There is a significant but not full normalization of semantic distance upon remission. Increase in semantic distance is therefore both a state and a trait marker in psychosis. We have employed a novel technique to quantify semantic distance of a word association task using Word2Vec to generate vector representations of responses in a high-dimensional semantic space. The findings illustrate the feasibility of applying Word2Vec to a word association task to detect subtle changes in language. Subsequent research possibilities using this approach includes exploration of the semantic content of responses, by grouping similar meaning responses into conceptual clusters, and its correlation with symptom change.

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, temporoparietal 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 e 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.

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. Electronic supplementary material The online version of this article (doi:10.1007/s00429-014-0907-5) contains supplementary material, which is available to authorized users.

The term "neurodevelopmental disorder" broadly encompasses conditions thought to arise early in development and includes schizophrenia, bipolar disorder and autism among others. These conditions share a number of genetic and environmental risk factors postulated to lead to common difficulties in socio-emotional processing, communication and cognitive function. The alternative position is that, while the same traits are affected across these conditions, the nature or direction in which they are modified may be distinct. MRI studies provide a rapidly expanding and rich database which we propose can be used to contribute to this debate. Anatomical likelihood estimation (ALE) is a method of meta-analysis applied to voxel-based MRI studies. We have adapted this method to explore the extent to which schizophrenia and bipolar disorder and schizophrenia and autism share a common brain structural phenotype. We will review this work here and discuss whether there is sufficient other evidence to justify a common framework for further research into the inter-relatedness of such conditions.

Autism is a highly heritable condition, but there is strong epidemiological evidence that environmental factors, especially prenatal exposure to immune challenge, contribute to it. This evidence is largely indirect, and experimental testing is necessary to directly examine causal mechanisms. Mouse models reveal that prenatal immune perturbation disrupts postnatal brain maturation with alterations in gene and protein expression, neurotransmitter function, brain structure and behavioral indices reminiscent of, but not specific to, autism. This likely reflects a neurodevelopmental spectrum in which autism and schizophrenia share numerous genetic and environmental risk factors for difficulties in social interaction, communication, emotion processing and executive function. Recent epidemiological studies find that early rather than late pregnancy infection confers the greater risk of schizophrenia. The autism literature is more limited, but exposures in the 2nd half of pregnancy may be important. Mouse models of prenatal immune challenge help dissect these observations and show some common consequences of early and late gestational exposures, as well as distinct ramifications potentially relevant to schizophrenia and autism. Although nonspecificity of immune-stimulated mouse models could be considered a disadvantage, we propose a broadened perspective, exploiting the possibility that advances made investigating a target condition can contribute towards the understanding of related conditions.

BackgroundChildren with attention-deficit hyperactivity disorder (ADHD) have difficulties with executive function and impulse control which may improve with age.AimsTo map the brain correlates of executive function in ADHD and determine age-related changes in reaction times and brain volumes.MethodAttention-deficit hyperactivity disorder and control groups were compared on the change task measures of response inhibition (stop signal reaction time, SSRT) and shifting (change response reaction time, CRRT). Voxel-wise magnetic resonance imaging (MRI) correlations of reaction times and grey matter volume were determined, along with bivariate correlations of reaction times, brain volumes and age.ResultsIndividuals in the ADHD group had longer SSRTs and CRRTs. Anterior cingulate, striatal and medial temporal volumes highly correlated with SSRT. Striatal and cerebellar volumes strongly correlated with CRRT. Older children had faster reaction times and larger regional brain volumes. In controls, orbitofrontal, medial temporal and cerebellar volumes correlated with CRRT but not SSRT. Neither reaction times nor regional brain volumes were strongly age-dependent.ConclusionsOur evidence supports delayed brain maturation in ADHD and implies that some features of ADHD improve with age.

We report the first voxel-based morphometric (VBM) study to examine cerebral grey and white matter and cerebrospinal fluid (CSF) using computational morphometry in never-medicated, first-episode psychosis (FEP). Region-of-interest (ROI) analysis was also performed blind to group membership. 26 never-medicated individuals with FEP (23 with DSM-IV schizophrenia) and 38 healthy controls had MRI brain scans. Groups were balanced for age, sex, handedness, ethnicity, paternal socio-economic status, and height. Healthy controls were recruited from the local community by advertisement. Grey matter, white matter, and CSF: global brain volume ratios were significantly smaller in patients. Patients had significantly less grey matter volume in L and R caudate nuclei, cingulate gyri, parahippocampal gyri, superior temporal gyri, cerebellum and R thalamus, prefrontal cortex. They also had significantly less white matter volume in the R anterior limb of the internal capsule fronto-occipital fasciculus and L and R fornices, and significantly greater CSF volume especially in the R lateral ventricle. Excluding the 3 subjects with brief psychotic disorder did not alter our results. Our data suggest that fronto-temporal and subcortical-limbic circuits are morphologically abnormal in never-medicated, schizophrenia. ROI analysis comparing the schizophrenia group (n=23) with the healthy controls (n=38) confirmed caudate volumes were significantly smaller bilaterally by 11%, and lateral ventricular volume was significantly larger on the right by 26% in the patients. Caudate nuclei and lateral ventricular volume measurements were uncorrelated (Pearson correlation coefficient 0.30, p=0.10), ruling out the possibility of segmentation artefact. Ratio of lateral ventricle to caudate volume was bilaterally significantly increased (p

Autism is a disorder of neurodevelopment resulting in pervasive abnormalities in social interaction and communication, repetitive behaviours and restricted interests. There is evidence for functional abnormalities and metabolic dysconnectivity in 'social brain' circuitry in this condition, but its structural basis has proved difficult to establish reliably. Explanations for this include replication difficulties inherent in 'region of interest' approaches usually adopted, and variable inclusion criteria for subjects across the autism spectrum. Moreover, despite a consensus that autism probably affects widely distributed brain regions, the issue of anatomical connectivity has received little attention. Therefore, we planned a fully automated voxel-based whole brain volumetric analysis in children with autism and normal IQ. We predicted that brain structural changes would be similar to those previously shown in adults with autism spectrum disorder and that a correlation analysis would suggest structural dysconnectivity. We included 17 stringently diagnosed children with autism and 17 age-matched controls. All children had IQ >80. Using Brain Activation and Morphological Mapping (BAMM) software, we measured global brain and tissue class volumes and mapped regional grey and white matter differences across the whole brain. With the expectation that volumes of interconnected regions correlate positively, we carried out a preliminary exploration of 'connectivity' in autism by comparing the nature of inter-regional grey matter volume correlations with control. Children with autism had a significant reduction in total grey matter volume and significant increase in CSF volume. They had significant localized grey matter reductions within fronto-striatal and parietal networks similar to findings in our previous study, and additional decreases in ventral and superior temporal grey matter. White matter was reduced in the cerebellum, left internal capsule and fornices. Correlation analysis revealed significantly more numerous and more positive grey matter volumetric correlations in controls compared with children with autism. Thus, using similar diagnostic criteria and image analysis methods in otherwise healthy populations with an autistic spectrum disorder from different countries, cultures and age groups, we report a number of consistent findings. Taken together, our data suggest abnormalities in the anatomy and connectivity of limbic-striatal 'social' brain systems which may contribute to the brain metabolic differences and behavioural phenotype in autism.

Retrogenesis refers to the phenomenon by which degenerative processes in aging reverse the sequence of acquisition in development. Although there has been some evidence for brain retrogenesis in abnormal aging, e.g., Alzheimer's disease (AD), it has not been explicitly addressed in the normal aging. Using diffusion tensor imaging and tractography, we explored the effects of normal and abnormal aging on the integrity of white matter (WM) in fifty participants, including 18 AD patients, 17 normal elderly, and 15 normal young adults. Compared with young adults, the traditional voxel-based analysis, and the quantitative fiber tracking methods revealed lower fractional anisotrophy (FA) for both normal elderly and AD patients, indicating WM disintegrity in the anterior part of the brain with developmentally late-myelinating fiber bundles. Furthermore, AD patients showed lower FA in the posterior part of the brain with relatively early-myelinating fiber bundles. Additional analysis on axial diffusion and radial diffusion measures suggest that demyelination may be the main mechanism underlying the observed microstructural impairments. Consistent with a proposal of retrogenesis, our results demonstrate an anteroposterior pattern of white matter disintegrity in both normal aging and AD, with the pattern being more salient in the latter than in the former.

Background: The question of whether Asperger syndrome can be distinguished from autism has attracted much debate and may even incur delay in diagnosis and intervention. Accordingly, there has been a proposal for Asperger syndrome to be subsumed under autism in the forthcoming Diagnostic and Statistical Manual of Mental Disorders, fifth edition, in 2013. One approach to resolve this question has been to adopt the criterion of absence of clinically significant language or cognitive delay - essentially, the "absence of language delay." To our knowledge, this is the first meta-analysis of magnetic resonance imaging (MRI) studies of people with autism to compare absence with presence of language delay. It capitalizes on the voxel-based morphometry (VBM) approach to systematically explore the whole brain for anatomic correlates of delay and no delay in language acquisition in people with autism spectrum disorders. Methods: We conducted a systematic search for VBM MRI studies of grey matter volume in people with autism. Studies with a majority (at least 70%) of participants with autism diagnoses and a history of language delay were assigned to the autism group (n = 151, control n = 190). Those with a majority (at least 70%) of individuals with autism diagnoses and no language delay were assigned to the Asperger syndrome group (n = 149, control n = 214). We entered study coordinates into anatomic likelihood estimation meta-analysis software with sampling size weighting to compare grey matter summary maps driven by Asperger syndrome or autism. Results: The summary autism grey matter map showed lower volumes in the cerebellum, right uncus, dorsal hippocampus and middle temporal gyrus compared with controls; grey matter volumes were greater in the bilateral caudate, prefrontal lobe and ventral temporal lobe. The summary Asperger syndrome map indicated lower grey matter volumes in the bilateral amygdala/hippocampal gyrus and prefrontal lobe, left occipital gyrus, right cerebellum, putamen and precuneus compared with controls; grey matter volumes were greater in more limited regions, including the bilateral inferior parietal lobule and the left fusiform gyrus. Both Asperger syndrome and autism studies reported volume increase in clusters in the ventral temporal lobe of the left hemisphere. Limitations: We assigned studies to autism and Asperger syndrome groups for separate analyses of the data and did not carry out a direct statistical group comparison. In addition, studies available for analysis did not capture the entire spectrum, therefore we cannot be certain that our findings apply to a wider population than that sampled. Conclusion: Whereas grey matter differences in people with Asperger syndrome compared with controls are sparser than those reported in studies of people with autism, the distribution and direction of differences in each category are distinctive. © 2011 Canadian Medical Association., link_to_OA_fulltext

Background: MPAs (minor physical anomalies) frequently occur in neurodevelopmental disorders because both face and brain are derived from neuroectoderm in the first trimester. Conventionally, MPAs are measured by evaluation of external appearance. Using MRI can help overcome inherent observer bias, facilitate multi-centre data acquisition, and explore how MPAs relate to brain dysmorphology in the same individual. Optical MPAs exhibit a tightly synchronized trajectory through fetal, postnatal and adult life. As head size enlarges with age, inter-orbital distance increases, and is mostly completed before age 3 years. We hypothesized that optical MPAs might afford a retrospective 'window' to early neurodevelopment; specifically, inter-orbital distance increase may represent a biomarker for early brain dysmaturation in autism. Methods: We recruited 91 children aged 7-16; 36 with an autism spectrum disorder and 55 age- and gender-matched typically developing controls. All children had normal IQ. Inter-orbital distance was measured on T1-weighted MRI scans. This value was entered into a voxel-by-voxel linear regression analysis with grey matter segmented from a bimodal MRI data-set. Age and total brain tissue volume were entered as covariates. Results: Intra-class coefficient for measurement of the inter-orbital distance was 0.95. Inter-orbital distance was significantly increased in the autism group (p = 0.03, 2-tailed). The autism group showed a significant relationship between inter-orbital distance grey matter volume of bilateral amygdalae extending to the unci and inferior temporal poles. Conclusions: Greater inter-orbital distance in the autism group compared with healthy controls is consistent with infant head size expansion in autism. Inter-orbital distance positively correlated with volume of medial temporal lobe structures, suggesting a link to "social brain" dysmorphology in the autism group. We suggest these data support the role of optical MPAs as a "fossil record" of early aberrant neurodevelopment, and potential biomarker for brain dysmaturation in autism. © 2011 Cheung et al., published_or_final_version

Shared genetic and environmental risk factors have been identified for autistic spectrum disorders (ASD) and schizophrenia. Social interaction, communication, emotion processing, sensorimotor gating and executive function are disrupted in both, stimulating debate about whether these are related conditions. Brain imaging studies constitute an informative and expanding resource to determine whether brain structural phenotype of these disorders is distinct or overlapping. We aimed to synthesize existing datasets characterizing ASD and schizophrenia within a common framework, to quantify their structural similarities. In a novel modification of Anatomical Likelihood Estimation (ALE), 313 foci were extracted from 25 voxel-based studies comprising 660 participants (308 ASD, 352 first-episode schizophrenia) and 801 controls. The results revealed that, compared to controls, lower grey matter volumes within limbic-striato-thalamic circuitry were common to ASD and schizophrenia. Unique features of each disorder included lower grey matter volume in amygdala, caudate, frontal and medial gyrus for schizophrenia and putamen for autism. Thus, in terms of brain volumetrics, ASD and schizophrenia have a clear degree of overlap that may reflect shared etiological mechanisms. However, the distinctive neuroanatomy also mapped in each condition raises the question about how this is arrived in the context of common etiological pressures. © 2010 Cheung et al., published_or_final_version

Maternal infection during prenatal life is a risk factor for neurodevelopmental disorders, including schizophrenia and autism, in the offspring. We and others have reported white mater microstructure abnormalities in prefrontal-striato-temporal networks in these disorders. In addition we have shown that early rather than late maternal immune challenge in the mouse model precipitates ventricular volume change and impairs sensorimotor gating similar to that found in schizophrenia. However, it is not known whether the timing of maternal infection has a differential impact upon white matter microstructural indices. Therefore this study directly tested the effect of early or late gestation maternal immune activation on post-natal white matter microstructure in the mouse. The viral mimic PolyI:C was administered on day 9 or day 17 of gestation. In-vivo diffusion tensor imaging (DTI) was carried out when the offspring reached adulthood. We describe a novel application of voxel-based analysis to evaluate fractional anisotrophy (FA). In addition we conducted a preliminary immunohistochemical exploration of the oligodendrocyte marker, 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), to determine whether differences in myelination might contribute to any changes in FA observed. Our results provide experimental evidence that prenatal exposure to inflammation elicits widespread differences in FA throughout fronto-striatal-limbic circuits compared to control saline exposure. Moreover, FA changes were more extensive in the group exposed earliest in gestation.

Anti-psychotic treatment appears to be associated with striatal volume increase, but how early this change occurs is still unknown. A single prospective cohort of 20 anti-psychotic-naive patients, newly diagnosed with schizophrenia, underwent magnetic resonance imaging brain scan at baseline. This was repeated following up to 8 weeks of anti-psychotic treatment. Ten patients had repeat scan within only 3 weeks. The choice of anti-psychotic medication was naturalistic, i.e., clinician-led. Well-matched healthy individuals were also scanned to control for non-specific changes over a 3-week period. After 3 weeks of anti-psychotic treatment, significant grey matter volume increase in the right caudate, superior and inferior frontal gyrus, precentral gyrus, and left inferior parietal lobule was noted. However, after 8 weeks of anti-psychotic treatment, volume increase in the right thalamus and bilateral cerebellum was observed. Significant grey matter reduction was detected in the left medial frontal gyrus at both 3- and 8-week intervals. Early increase in striatal volume change occurs as early as 3 weeks after anti-psychotic treatment, whilst thalamic volume increase is apparent later, by 8 weeks of treatment. We speculate that drug-mediated neuroplasticity may provide a biomarker for clinical recovery.

Background: Autism exists across a wide spectrum and there is considerable debate as to whether children with Asperger’s syndrome, who have normal language milestones, should be considered to comprise a subgroup distinct other from high-functioning children with autism (HFA), who have a history of delayed language development. Magnetic resonance imaging (MRI) studies of autism are in disagreement. One possible reason is that the diagnosis of autism takes precedence over Asperger’s syndrome and a distinction in language acquisition is rarely made. We therefore planned to examine a whole brain hypothesis that the patterns of grey matter differences in Asperger’s syndrome and HFA can be distinguished. Methods: We used voxel-based computational morphometry to map grey matter volume differences in 33 children with either Asperger’s syndrome or high-functioning autism compared to 55 typical developing control children balanced for age, IQ, gender, maternal language and ethnicity. Results: Children with HFA had significantly smaller grey matter volumes in subcortical, posterior cingulate and precuneus regions than the Asperger’s group. Compared to controls, children with HFA had smaller grey matter volumes in predominantly fronto-pallidal regions, while children with Asperger’s had less grey matter in mainly bilateral caudate and left thalamus. In addition we found a significant negative correlation between the size of a grey matter cluster around BA44 language area and the age of acquisition of phrase speech in the children with HFA. When the groups were combined we confirmed a mixed picture of smaller grey matter volumes in frontal, basal ganglia, temporal and parietal regions. Conclusions: Our study suggests that the underlying neurobiology in HFA and Asperger’s syndrome is at least partly discrete. Future studies should therefore consider the history of language acquisition as a valuable tool to refine investigation of aetiological factors and management options in pervasive developmental disorders. Keywords: Asperger’s disorder, autistic disorder, brain imaging. Abbreviations: HFA: high-functioning autism; LFA: low-functioning autism; ADI-R: Autism Diagnostic Interview – Revised; AC-PC: anterior commissure–posterior commissure. Autism exists across a spectrum. Although features of impaired social reciprocity, communication difficulty, and repetitive interests or motor activities are common to all individuals suffering the disorder, the autism spectrum accommodates individuals with and without learning impairment. Individuals without learning disability can be further categorised according to their history of phrase language development; delayed acquisition of phrase language distinguishes those with high-functioning autism (HFA) from others with Asperger’s syndrome, who use phrase language prior to 36 months (Gilchrist et al., 2001; Howlin, 2003; Ozonoff, Rogers, & Pennington, 1991; Szatmari, Archer, Fisman, Streiner, & Wilson, 1995). However, as discussed by Lotspeich and colleagues (2004), the diagnosis of autism takes precedence over Asperger’s syndrome, resulting in some degree of diagnostic overlap, and it is unclear whether the unique language features of Asperger’s

Objective: Our study examined the stress level and psychological distress of severe acute respiratory syndrome (SARS) survivors 1 year after the outbreak. Method: During the SARS outbreak in 2003, we used the 10-item Perceived Stress Scale (PSS-10) to assess SARS survivors treated in 2 major hospitals (non–health care workers, n = 49; health care workers, n = 30). We invited SARS survivors from the same hospitals (non–health care workers, n = 63; health care workers, n = 33) to complete the PSS-10 again in 2004. At that time, they were also asked to complete the General Health Questionnaire (GHQ-12) and measures of depression, anxiety, and posttraumatic symptoms. PSS-10 scores were also obtained from matched community control subjects during the outbreak ( n = 145) and again in 2004 ( n = 112). Results: SARS survivors had higher stress levels during the outbreak, compared with control subjects (PSS-10 scores =19.8 and 17.9, respectively; P < 0.01), and this persisted 1 year later (PSS-10 scores =19.9 and 17.3, respectively; P < 0.01) without signs of decrease. In 2004, SARS survivors also showed worrying levels of depression, anxiety, and posttraumatic symptoms. An alarming proportion (64%) scored above the GHQ-12 cut-off that suggests psychiatric morbidity. During the outbreak, health care worker SARS survivors had stress levels similar to those of non–health care workers, but health care workers showed significantly higher stress levels in 2004 (PSS-10 score = 22.8, compared with PSS-10 score = 18.4; P < 0.05) and had higher depression, anxiety, posttraumatic symptoms, and GHQ-12 scores. Conclusions: One year after the outbreak, SARS survivors still had elevated stress levels and worrying levels of psychological distress. The situation of health care worker SARS survivors is particularly worrying. The long-term psychological implications of infectious diseases should not be ignored. Mental health services could play an important role in rehabilitation.

Objective: To assess the immediate and sustained psychological health of health care workers who were at high risk of exposure during the severe acute respiratory syndrome (SARS) outbreak. Methods: At the peak of the 2003 SARS outbreak, we assessed health care workers in 2 acute care Hong Kong general hospitals with the Perceived Stress Scale (PSS-10). One year later, we reassessed these health care workers with the PSS-10, the 21-Item Depression and Anxiety Scale (DASS-21), and the Impact of Events Scale-Revised (IES-R). We recruited high-risk health care workers who practised respiratory medicine and compared them with nonrespiratory medicine workers, who formed the low-risk health care worker control group. Results: In 2003, high-risk health care workers had elevated stress levels (PSS-10 score = 17.0) that were not significantly different from levels in low-risk health care worker control subjects (PSS-10 score = 15.9). More high-risk health care workers reported fatigue, poor sleep, worry about health, and fear of social contact, despite their confidence in infection-control measures. By 2004, however, stress levels in the high-risk group were not only higher (PSS-10 score = 18.6) but also significantly higher than scores among low-risk health care worker control subjects (PSS-10 score = 14.8, P < 0.05). In 2004, the perceived stress levels in the high-risk group were associated with higher depression, anxiety, and posttraumatic stress scores ( P < 0.001). Posttraumatic stress scores were a partial mediator of the relation between the high risk of exposure to SARS and higher perceived stress. Conclusions: Health care workers who were at high risk of contracting SARS appear not only to have chronic stress but also higher levels of depression and anxiety. Front-line staff could benefit from stress management as part of preparation for future outbreaks.

The neuroanatomical basis of attention deficit-hyperactivity disorder (ADHD) is postulated to involve brain circuitry responsible for attention and executive function. Relatively new automated methods of MRI analysis allow rapid examination of each volume element (voxel) of whole brain, therefore we planned a comprehensive quantitative examination of brain anatomy in children with ADHD using voxel-based methods. We aimed to quantify whole brain, global tissue class and regional grey and white matter volume differences in 28 male children with ADHD and 31 closely matched controls. Since ADHD is often complicated by comorbid oppositional defiant disorder (ODD) and conduct disorder (CD), we also conducted post-hoc analyses of subgroups of children with ADHD with and without these comorbidities. Significant regional deficits in ADHD were observed within a predominantly right-sided frontal-pallidal-parietal grey matter network and bilateral white matter tracts. Post-hoc comparisons suggested that comorbid ODD or CD did not greatly alter the extent of regional pathology in ADHD. The exceptions being cerebellar and striatal volume deficits which were significantly greater in children with ADHD plus comorbidities, but not those with ADHD alone, compared to controls. Overall, restricted structural brain abnormalities caused by ADHD were localized to brain systems known to be necessary for attention and executive function.

This paper reports a cross-sectional questionnaire study that investigated perceived stress and psychological responses to the SARS outbreak in healthcare students at the height of the outbreak in Hong Kong in 2003. Non-healthcare university students served as controls. All the groups reported high levels of perceived stress. Despite being similarly confident in infection control procedures, nursing students were significantly more stressed than medical students, possibly reflecting a perceived higher risk of infection due to more prolonged contact with patients. Non-healthcare students also had high stress levels due to the perceived risks of dying from SARS, reflecting a fear of the unknown. Suitable psychological and occupational support services should be made available in case of future outbreaks.

following transfer into the dark side they were conditioned by receiving light and tone paired with a mild unavoidable foot shock on three occasions. On return to the dark side of the chamber 24 and 48 h later the total time spent freezing was recorded to monitor learning and memory. Results: Isolated animals exhibited hyperactivity during the first 30 minutes of LMA compared with GH controls (477.7+130.6 vs 609.6+165.6 counts, respectively) but this just failed to reach statistical significance (p>0.05 by one-way ANOVA). AM630 had no significant effect on LMA. Saline injected GH rats successfully discriminated the novel object (p 0.05). GH controls froze significantly longer than SI rats irrespective of whether they had received AM630 or not both at 24 h and 48 h after the foot shock in the CER (p

Objective: To examine stress and psychological impact in severe acute respiratory syndrome (SARS) patients during the 2003 outbreak. SARS is a novel, highly infectious pneumonia, and its psychological impact is still unclear. Method: At the peak of the outbreak, SARS patients ( n = 79) and healthy control subjects ( n = 145) completed the Perceived Stress Scale (PSS) and documented a range of psychological responses. Groups were balanced for age, sex, education, and living circumstances. Results: Stress was significantly higher in SARS patients than in healthy control subjects. Stress correlated significantly with negative psychological effects. Of SARS patients, 39% ( n = 30) were infected health care workers; these individuals reported significantly more fatigue and worries about health than did other patients. Of patients, 25% ( n = 20) requested psychological follow-up. Conclusions: General stress and negative psychological effects are increased in SARS patients, particularly among infected health care workers. This may increase the risk of mood and stress-related disorders. Functional impairment is apparent in the postrecovery phase.