Daniel Rock

Genetic Evidence for a Distinct Subtype of Schizophrenia Characterized by Pervasive Cognitive Deficit

A novel phenotyping strategy in schizophrenia, targeting different neurocognitive domains, neurobehavioral features, and selected personality traits, has allowed us to identify a homogeneous familial subtype of the disease, characterized by pervasive neurocognitive deficit. Our genome scan data indicate that this subtype, which accounts for up to 50% of our sample, has a distinct genetic basis and explains linkage to chromosome 6p24 reported previously. If representative of other populations, the ratio of schizophrenia subtypes observed in our families could have a profound impact on sample heterogeneity and on the power of genetic studies to detect linkage and association. Our proposed abbreviated battery of tests should facilitate phenotype characterization for future genetic analyses and allow a focus on a crisply defined schizophrenia subtype, thus promoting a more informed search for susceptibility genes.

Duration and frequency mismatch negativity in schizophrenia

OBJECTIVES The aim of the present study was to elucidate the reasons for apparent inconsistencies in the schizophrenia literature with respect to the mismatch negativity (MMN) waveform of the event-related potential (ERP). While most previous research has shown that MMN is reduced in schizophrenia, there are a small number of studies reporting that frequency MMN is not reduced. METHODS We recorded ERPs to auditory stimuli with different frequencies and durations from patients with schizophrenia (N = 14) and control subjects (N = 17) of similar age and sex. MMNs to small but discriminable frequency deviants were contrasted with large frequency deviants and duration deviants. RESULTS Only the MMN to duration deviants was significantly reduced in patients, although there was evidence of a similar trend for large frequency deviants. CONCLUSIONS The results together with a review of the frequency MMN literature suggest that there are 3 variables which are important in determining whether patients exhibit a reduced MMN to frequency deviants: deviant probability, degree of deviance and interstimulus interval. The results also indicated that patients with schizophrenia may have particular deficits in processing the temporal properties of auditory stimuli. This finding has implications for the pathophysiology of the disorder as time-dependent processing is reliant on the integrity of an extensive network of brain areas consisting of auditory cortex, areas of pre-frontal cortex, the basal ganglia and cerebellum.

Phenotypic markers as risk factors in schizophrenia: neurocognitive functions

OBJECTIVE To review the literature on neurocognitive measures as risk markers for schizophrenia and to present data from the Perth family study of schizophrenia. Of all the risk markers that have been identified, the most promising are deficits in sustained attention. METHOD Inclusion in the review was determined by whether the research addressed a number of key questions: methods of assessing sustained attention; evidence of sustained attention deficits in patients and first-degree relatives including children; the importance of attentional dysfunction in the schizophrenic process and functional outcome; and the biological basis of sustained attention deficits. RESULTS Sustained attention deficits are evident in both patients and a proportion of their first-degree relatives, a finding replicated in preliminary data from the Perth family study. The literature suggests that the attention deficit is a stable enduring trait that is independent of clinical state. The neural basis of the deficit may be a functional disconnection between prefrontal and parietal cortex. Attention impairment is an important predictor of functional outcome in patients and the development of social dysfunction in adulthood in the at-risk offspring of patients. However, sustained attention deficits that are measured in childhood results in an unacceptable high false-positive rate (21%) when predicting which at-risk offspring of parents with schizophrenia will develop a schizophrenia spectrum disorder, although the overall classification accuracy (78%) is impressive. CONCLUSIONS The main findings are that sustained attention deficits are important risk markers for schizophrenia but need to be supplemented by other neurocognitive risk markers to improve predictive accuracy.

Spatial Working Memory and Planning Ability: Contrasts between Schizophrenia and Bipolar I Disorder

Working memory may be conceptualized as a multi-component system involving the active maintenance and manipulation of stored information in the service of planning/guiding behaviour. Impaired spatial working memory is a robust finding in schizophrenia patients which has been related to an impairment in frontostriatal connectivity. The purpose of this study was to examine the specificity of this impairment by comparing the mnemonic and executive aspects of working memory performance in schizophrenia and bipolar disorder with psychotic features, focusing particularly on the functional dynamics between task components. Twenty-four patients with schizophrenia, 14 patients with bipolar I disorder (manic phase) and 33 healthy control subjects were assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB): including the spatial working memory (between search errors and strategy scores) spatial span (storage capacity) and spatial planning (Stockings of Cambridge: accuracy and latency) tasks. Both patient groups were impaired on the spatial span task, which requires the maintenance and retrieval of stored information. In contrast, only schizophrenia patients showed a significant deficit in between search errors, which requires both maintenance and manipulation of information in working memory. That is, they exhibited both a mnemonic and an executive dysfunction. Spatial span was particularly important to accurate planning ability in bipolar patients. In contrast, in patients with schizophrenia poor spatial working memory was a significant predictor of planning impairments, consistent with failures in goal selection, evaluation and/or execution. Furthermore, initial planning time was positively correlated with the latency to complete a planning sequence. This pattern of slow cognitive processing in schizophrenia patients only, resembled that reported previously in patients with basal ganglia disorders. These findings are discussed in terms of a possible common disturbance in fronto-parietal circuitry in the two disorders together with a specific disturbance of fronto-striatal circuitry in schizophrenia, that is not present in bipolar disorder.

Increasing seasonality of suicide in Australia 1970–1999

Previous studies have found that rates of suicide have a distinct annual rhythm with a peak in spring. Two recent European studies, however, have found that the amplitude of this rhythm has decreased over time. The purpose of this study was to examine whether such effects are found in Australia. Australian Bureau of Statistics data on all suicides in Australia 1970-1999 were analysed by spectral analysis. We found that suicide, violent suicide and suicide by males are seasonal and that the seasonal amplitude has increased over time. Males who use violent methods determine the seasonal effect. These results support previous findings that suicide and particularly violent suicide have a characteristic seasonal rhythm. However, the progressive increase in the amplitude of this rhythm over time in Australia is in direct contrast to other European findings. We suggest that this may be related to differences in patterns of anti-depressant use and also the effect of migration on the number of seasonally vulnerable individuals in Australia.

Disrupted seasonal biology impacts health, food security and ecosystems

The rhythm of life on earth is shaped by seasonal changes in the environment. Plants and animals show profound annual cycles in physiology, health, morphology, behaviour and demography in response to environmental cues. Seasonal biology impacts ecosystems and agriculture, with consequences for humans and biodiversity. Human populations show robust annual rhythms in health and well-being, and the birth month can have lasting effects that persist throughout life. This review emphasizes the need for a better understanding of seasonal biology against the backdrop of its rapidly progressing disruption through climate change, human lifestyles and other anthropogenic impact. Climate change is modifying annual rhythms to which numerous organisms have adapted, with potential consequences for industries relating to health, ecosystems and food security. Disconcertingly, human lifestyles under artificial conditions of eternal summer provide the most extreme example for disconnect from natural seasons, making humans vulnerable to increased morbidity and mortality. In this review, we introduce scenarios of seasonal disruption, highlight key aspects of seasonal biology and summarize from biomedical, anthropological, veterinary, agricultural and environmental perspectives the recent evidence for seasonal desynchronization between environmental factors and internal rhythms. Because annual rhythms are pervasive across biological systems, they provide a common framework for trans-disciplinary research.

Linkage analysis of candidate regions using a composite neurocognitive phenotype correlated with schizophrenia

As schizophrenia is genetically and clinically heterogeneous, systematic investigations are required to determine whether ICD-10 or DSM-IV categorical diagnoses identify a phenotype suitable and sufficient for genetic research, or whether correlated phenotypes incorporating neurocognitive performance and personality traits provide a phenotypic characterisation that accounts better for the underlying variation. We utilised a grade of membership (GoM) model (a mathematical typology developed for studies of complex biological systems) to integrate multiple cognitive and personality measurements into a limited number of composite graded traits (latent pure types) in a sample of 61 nuclear families comprising 80 subjects with ICD-10/DSM-IV schizophrenia or schizophrenia spectrum disorders and 138 nonpsychotic first-degree relatives. GoM probability scores, computed for all subjects, allowed individuals to be partly assigned to more than one pure type. Two distinct and contrasting neurocognitive phenotypes, one familial, associated with paranoid schizophrenia, and one sporadic, associated with nonparanoid schizophrenia, accounted for 74% of the affected subjects. Combining clinical diagnosis with GoM scores to stratify the entire sample into liability classes, and using variance component analysis (SOLAR), in addition to parametric and nonparametric multipoint linkage analysis, we explored candidate regions on chromosomes 6, 10 and 22. The results indicated suggestive linkage for the familial neurocognitive phenotype (multipoint MLS 2.6 under a low-penetrance model and MLS>3.0 under a high-penetrance model) to a 14 cM area on chromosome 6, including the entire HLA region. Results for chromosomes 10 and 22 were negative. The findings suggest that the familial neurocognitive phenotype may be a pleiotropic expression of genes underlying the susceptibility to paranoid schizophrenia. We conclude that use of composite neurocognitive and personality trait measurements as correlated phenotypes supplementing clinical diagnosis can help stratify the liability to schizophrenia across all members of families prior to linkage, allow the search for susceptibility genes to focus selectively on subsets of families at high genetic risk, and augment considerably the power of genetic analysis.

Research ArticleSpatial Working Memoryand Planning Ability: Contrasts between Schizophreniaand Bipolar i Disorder

Working memory may be conceptualized as a multi-component system involving the active maintenance and manipulation of stored information in the service of planning/guiding behaviour. Impaired spatial working memory is a robust finding in schizophrenia patients which has been related to an impairment in frontostriatal connectivity. The purpose of this study was to examine the specificity of this impairment by comparing the mnemonic and executive aspects of working memory performance in schizophrenia and bipolar disorder with psychotic features, focusing particularly on the functional dynamics between task components. Twenty-four patients with schizophrenia, 14 patients with bipolar I disorder (manic phase) and 33 healthy control subjects were assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB): including the spatial working memory (between search errors and strategy scores) spatial span (storage capacity) and spatial planning (Stockings of Cambridge: accuracy and latency) tasks. Both patient groups were impaired on the spatial span task, which requires the maintenance and retrieval of stored information. In contrast, only schizophrenia patients showed a significant deficit in between search errors, which requires both maintenance and manipulation of information in working memory. That is, they exhibited both a mnemonic and an executive dysfunction. Spatial span was particularly important to accurate planning ability in bipolar patients. In contrast, in patients with schizophrenia poor spatial working memory was a significant predictor of planning impairments, consistent with failures in goal selection, evaluation and/or execution. Furthermore, initial planning time was positively correlated with the latency to complete a planning sequence. This pattern of slow cognitive processing in schizophrenia patients only, resembled that reported previously in patients with basal ganglia disorders. These findings are discussed in terms of a possible common disturbance in fronto-parietal circuitry in the two disorders together with a specific disturbance of fronto-striatal circuitry in schizophrenia, that is not present in bipolar disorder.

Daily variations in sleep–wake patterns and severity of psychopathology: A pilot study in community-dwelling individuals with chronic schizophrenia

The daily co-occurrence of change in sleep characteristics and psychopathology was examined in six individuals with schizophrenia and seven healthy controls using a prospective assessment of rest-activity patterns conducted in the persons home for up to 28 days. The results provide preliminary evidence that a change in sleep-wake timing is followed by a change in symptom severity.

Obstetric and neonatal outcomes of pregnant women with severe mental illness at a specialist antenatal clinic

OBJECTIVE To evaluate the obstetric and neonatal outcomes of pregnant women with severe mental illness (SMI) who attended a specialist multidisciplinary antenatal clinic in Perth, Western Australia. DESIGN, SETTING AND PARTICIPANTS A retrospective case-note audit of outcomes from the Childbirth and Mental Illness Antenatal Clinic (CAMI clinic) at King Edward Memorial Hospital for pregnant women with severe mental illness (SMI), aged 18-41 years, who gave birth between December 2007 and April 2011, and their babies. MAIN OUTCOME MEASURES Obstetric and neonatal outcomes for 138 women and newborns from singleton live births. Data were compared between three diagnostic groups (schizophrenia, bipolar and non-psychotic SMI), and with WA obstetric and perinatal statistics for 2008. RESULTS 44 women with schizophrenia, 56 with bipolar disorder and 38 with non-psychotic SMI attended antenatal care for an average of 7.7 (SD, 3.3) visits. The proportion of women who smoked tobacco was significantly higher than that in the WA antenatal population (46% v 15%; P < 0.0001). Alcohol use, illicit substance use and psychotropic medication exposure during pregnancy were high. The women were at increased risk of developing gestational diabetes mellitus (15% v 4%; P < 0.0001) and pre-eclampsia (9% v 3%; P < 0.0001), and birth complications were more common. Babies born to CAMI clinic women were less likely to have Apgar scores ≥ 8 at 1 minute and 5 minutes. Pregnant women with schizophrenia had more psychiatric relapses during pregnancy, and had more statutory child welfare involvement. Gestational age at birth and infant birth weights were similar for the pregnant women with SMI and the WA population in 2008. CONCLUSIONS Women attending our specialist clinic had increased rates of obstetric and neonatal complications compared with the general population, and were exposed to a cluster of risk factors. We report encouraging trends in antenatal attendance, gestational age at birth, and birth weights. Managing pregnant women with SMI will require a comprehensive approach aimed at early detection of obstetric complications and psychosocial difficulties, as well as neonatal monitoring. Optimising prepregnancy maternal health and welfare may also be of benefit.