Siew E. Chua

Cerebral grey, white matter and csf in never-medicated, first episode schizophrenia.

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<0.005, 2-tailed), which could represent an early biomarker in first-episode, never-medicated schizophrenia.

Distinct patterns of grey matter abnormality in high-functioning autism and Asperger’s syndrome

BACKGROUND Autism exists across a wide spectrum and there is considerable debate as to whether children with Aspergers 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 Aspergers 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 Aspergers syndrome and HFA can be distinguished. METHODS We used voxel-based computational morphometry to map grey matter volume differences in 33 children with either Aspergers 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 Aspergers group. Compared to controls, children with HFA had smaller grey matter volumes in predominantly fronto-pallidal regions, while children with Aspergers 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 Aspergers 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.

Autistic Disorders and Schizophrenia: Related or Remote? An Anatomical Likelihood Estimation

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.

Prenatal Immune Challenge Is an Environmental Risk Factor for Brain and Behavior Change Relevant to Schizophrenia: Evidence from MRI in a Mouse Model

Objectives Maternal infection during pregnancy increases risk of severe neuropsychiatric disorders, including schizophrenia and autism, in the offspring. The most consistent brain structural abnormality in patients with schizophrenia is enlarged lateral ventricles. However, it is unknown whether the aetiology of ventriculomegaly in schizophrenia involves prenatal infectious processes. The present experiments tested the hypothesis that there is a causal relationship between prenatal immune challenge and emergence of ventricular abnormalities relevant to schizophrenia in adulthood. Method We used an established mouse model of maternal immune activation (MIA) by the viral mimic PolyI:C administered in early (day 9) or late (day 17) gestation. Automated voxel-based morphometry mapped cerebrospinal fluid across the whole brain of adult offspring and the results were validated by manual region-of-interest tracing of the lateral ventricles. Parallel behavioral testing determined the existence of schizophrenia-related sensorimotor gating abnormalities. Results PolyI:C-induced immune activation, in early but not late gestation, caused marked enlargement of lateral ventricles in adulthood, without affecting total white and grey matter volumes. This early exposure disrupted sensorimotor gating, in the form of prepulse inhibition. Identical immune challenge in late gestation resulted in significant expansion of 4th ventricle volume but did not disrupt sensorimotor gating. Conclusions Our results provide the first experimental evidence that prenatal immune activation is an environmental risk factor for adult ventricular enlargement relevant to schizophrenia. The data indicate immune-associated environmental insults targeting early foetal development may have more extensive neurodevelopmental impact than identical insults in late prenatal life.

Gray Matter in First-Episode Schizophrenia Before and After Antipsychotic Drug Treatment. Anatomical Likelihood Estimation Meta-analyses With Sample Size Weighting

BACKGROUND Cerebral morphological abnormalities in schizophrenia may be modulated by treatment, chronicity, and duration of illness. Comparing brain imaging studies of individuals with first-episode schizophrenia and neuroleptic naive (NN-FES) with that of their neuroleptic-treated counterparts (NT-FES) can help to dissect out the effect of these potential confounders. METHODS We used the anatomical likelihood estimation method to compare voxel-based morphometric studies of NN-FES (n = 162 patients) and NT-FES (n = 336 patients) studies. The analysis included a sample size weighting step based on the Liptak-Stouffer method to reflect the greater power of larger studies. RESULTS Patient samples were matched for age, gender, and duration of illness. An extensive network of gray matter deficits in frontal, temporal, insular, striatal, posterior cingulate, and cerebellar regions was detected in the NN-FES samples as compared with healthy controls. Major deficits were detected in the frontal, superior temporal, insular, and parahippocampal regions for the NT-FES group compared with the NN-FES group. In addition, the NT-FES group showed minor deficits in the caudate, cingulate, and inferior temporal regions compared with the NN-FES group. There were no regions with gray matter volumetric excess in the NT-FES group. CONCLUSION Frontal, striato-limbic, and temporal morphological abnormalities are present in the early stage of schizophrenia and are unrelated to the effects of neuroleptic treatment, chronicity, and duration of illness. There may be dynamic effects of treatment on striato-limbic and temporal, but not frontal, regional gray matter volumes of the brain.

Abnormal spatiotemporal processing of emotional facial expressions in childhood autism: dipole source analysis of event-related potentials

Previous studies of face processing in autism suggest abnormalities in anatomical development, functioning and connectivity/coordination of distributed brain systems involved in social cognition, but the spatial sequence and time course of rapid (sub‐second) neural responses to emotional facial expressions have not been examined in detail. Source analysis of high‐density event‐related potentials (ERPs) is an optimal means to examine both the precise temporal profile and spatial location of early electrical brain activity in response to emotionally salient stimuli. Therefore, we recorded 128‐channel ERPs from high‐functioning males with autism (aged 6–10 years), and age‐, sex‐ and IQ‐matched typically developing controls during explicit and implicit processing of emotion from pictures showing happy, angry, fearful, sad and neutral facial expressions. Children with autism showed normal patterns of behavioural and ERP (P1, N170 and P2) responses. However, dipole source analysis revealed that ERP responses relating to face detection (visual cortex) and configural processing of faces (fusiform gyrus), as well as mental state decoding (medial prefrontal lobe), were significantly weaker and/or slower in autism compared with controls during both explicit and implicit emotion‐processing tasks. Slower‐ and larger‐amplitude ERP source activity in the parietal somatosensory cortices possibly reflected more effortful compensatory analytical strategies used by the autism group to process facial gender and emotion. Such aberrant neurophysiological processing of facial emotion observed in children with autism within the first 300 ms of stimulus presentation suggests abnormal cortical specialization within social brain networks, which would likely disrupt the development of normal social‐cognitive skills.

Are bipolar disorder and schizophrenia neuroanatomically distinct? An anatomical likelihood meta-analysis

Objective: There is renewed debate on whether modern diagnostic classification should adopt a dichotomous or dimensional approach to schizophrenia and bipolar disorder. This study synthesizes data from voxel-based studies of schizophrenia and bipolar disorder to estimate the extent to which these conditions have a common neuroanatomical phenotype. Methods: A post-hoc meta-analytic estimation of the extent to which bipolar disorder, schizophrenia, or both conditions contribute to brain gray matter differences compared to controls was achieved using a novel application of the conventional anatomical likelihood estimation (ALE) method. 19 schizophrenia studies (651 patients and 693 controls) were matched as closely as possible to 19 bipolar studies (540 patients and 745 controls). Result: Substantial overlaps in the regions affected by schizophrenia and bipolar disorder included regions in prefrontal cortex, thalamus, left caudate, left medial temporal lobe, and right insula. Bipolar disorder and schizophrenia jointly contributed to clusters in the right hemisphere, but schizophrenia was almost exclusively associated with additional gray matter deficits (left insula and amygdala) in the left hemisphere. Limitation: The current meta-analytic method has a number of constraints. Importantly, only studies identifying differences between controls and patient groups could be included in this analysis. Conclusion: Bipolar disorder shares many of the same brain regions as schizophrenia. However, relative to neurotypical controls, lower gray matter volume in schizophrenia is more extensive and includes the amygdala. This fresh application of ALE accommodates multiple studies in a relatively unbiased comparison. Common biological mechanisms may explain the neuroanatomical overlap between these major disorders, but explaining why brain differences are more extensive in schizophrenia remains challenging.

Age-related grey matter volume correlates of response inhibition and shifting in attention-deficit hyperactivity disorder

BACKGROUND Children with attention-deficit hyperactivity disorder (ADHD) have difficulties with executive function and impulse control which may improve with age. AIMS To map the brain correlates of executive function in ADHD and determine age-related changes in reaction times and brain volumes. METHOD Attention-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. RESULTS Individuals 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. CONCLUSIONS Our evidence supports delayed brain maturation in ADHD and implies that some features of ADHD improve with age.

Remembering our past: Schizophrenic delusions and the construction of autobiographical memory

In recent years, the study of normal cognitive function has gained substantially from the study of patients with cognitive deficits. Research on autobiographical memory is no exception, and research on retrograde amnesia and on confabulation in patients suffering from brain damage featured prominently in an earlier volume on this topic (Rubin, 1986). However, while the contribution of neuropsychology to the understanding of normal function is well established, neuropsychiatry has so far been less influential. One of the reasons is that psychiatry itself has been far from unanimous in its approach to the most appropriate conceptualization of its subject matter. There has, for example, been prolonged controversy as to whether schizophrenia should be regarded as a physical disorder resulting from some form of dysfunction of the brain, or as others would claim, a psychological response to psychosocial stress. While there is still little agreement as to what, if any, physical changes in the brain are associated with schizophrenia (see Waddington, 1993, for an overview), the application of neuropsychological techniques to the study of schizophrenic patients makes it clear that cognitive deficits are characteristic, and in particular tend to produce an impairment in memory (see McKenna, Clare, & Baddeley, 1995, for a review), and in executive functions (see Frith, 1992). These deficits do not appear to be a result of drug treatment, nor can they readily be explained in terms of problems of motivation, or disruption by positive symptoms such as hallucinations and delusions.

Immediate and sustained psychological impact of an emerging infectious disease outbreak on health care workers.

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.