Search PubMed⌕ Search

Biomedical subjects

John J McGrath

Publications and source records attributed to John J McGrath.

At least 19 recordsLinked to original sources
PubMed2026

Big data and psychiatry: advances, constraints and future directions.

Early work in psychiatry research, often involving single sites, small samples, and limited variables, has shifted to contemporary research involving multiple sites, large samples, and many variables. Such research raises important questions, including concerns about data quality and methodological rigor, uncertainty about its key lessons, issues regarding clinical relevance, and questions about how to optimize future advances. Here we consider these questions and concerns against the context of big data work on community and register-based surveys, cohort and biobank studies, electronic health records, digital phenotyping, brain imaging, genomics and other -omics, and randomized controlled trials. The development of large datasets allowing well-powered analyses is a major milestone, but sample size alone does not guarantee more precise estimates, and ongoing attention to the quality and rigor of big data collation and analysis is needed. Big data research has fostered trans-disciplinarity and given insights into mechanisms underlying psychiatric disorders, but also emphasizes the intricacy, heterogeneity and variability of such mechanisms, and the importance of triangulating between large-scale and small-scale research. The complexity of psychiatric phenotypes and psychobiological mechanisms contributes to the difficulty in bridging from big data to clinical application; big data research reinforces the importance of holding our diagnoses of psychiatric disorders lightly and providing explanations of these conditions humbly; and future work needs to be more attentive to clinical issues. There is enormous scope for further building databases relevant to psychiatry, but advances in conceptual models and asking the right questions are equally valuable. The full impact of big data, including artificial intelligence analyses, remains to be seen, but overenthusiastic support should be tempered by a better understanding of its strengths and limitations. At its best, such work will contribute in an iterative and integrative way to advancing our knowledge of psychiatric disorders and mental health.

Big data↗
PubMed2006

Hyperlocomotion associated with transient prenatal vitamin D deficiency is ameliorated by acute restraint.

Transient prenatal vitamin D deficiency produces hyperlocomotion in the adult rat. The aim of this study was to examine the effects of acute restraint on the behaviour of DVD and control rats in the open field. Rats were conceived and born to developmentally vitamin D (DVD) deficient or replete (control) dams and, at 8 weeks of age, were monitored for 30 min in an open field using automated video tracking software. Half of the rats were restrained within a towel for 5 min immediately before the open field test. The remainder received minimal handling prior to the open field test. Repeating previous findings, DVD deficient animals had enhanced locomotion during the first 10 min of the open field test compared to control rats. By contrast, there were no differences in locomotor activity after acute restraint stress. The time rats spent in the corners and side of the open field was affected by prenatal diet. DVD rats spent less time in the corners and more time in the side than control rats across the whole 30 min test. This difference was not seen in rats with acute restraint stress. The time spent in the centre was not altered by prenatal diet or acute restraint. Thus, transient prenatal vitamin D deficiency induces a transient spontaneous hyperlocomotion in adulthood that is modulated by acute restraint stress.

Analysis of Variance↗
PubMed2006

Developmental vitamin D deficiency alters MK 801-induced hyperlocomotion in the adult rat: An animal model of schizophrenia.

BACKGROUND: Developmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. The behavioral phenotype of adult rats subjected to transient low prenatal vitamin D is characterized by spontaneous hyperlocomotion but normal prepulse inhibition of acoustic startle (PPI). The aim of this study was to examine the impact of selected psychotropic agents and one well-known antipsychotic agent on the behavioral phenotype of DVD deplete rats. METHODS: Control versus DVD deplete adult rats were assessed on holeboard, open field and PPI. In the open field, animals were given MK-801 and/or haloperidol. For PPI, the animals were given apomorphine or MK-801. RESULTS: DVD deplete rats had increased baseline locomotion on the holeboard task and increased locomotion in response to MK-801 compared to control rats. At low doses, haloperidol antagonized the MK-801 hyperactivity of DVD deplete rats preferentially and, at a high dose, resulted in a more pronounced reduction in spontaneous locomotion in DVD deplete rats. DVD depletion did not affect either baseline or drug-mediated PPI response. CONCLUSIONS: These results suggest that DVD deficiency is associated with a persistent alteration in neuronal systems associated with motor function but not those associated with sensory motor gating. In light of the putative association between low prenatal vitamin D and schizophrenia, the discrete behavioral differences associated with the DVD model may help elucidate the neurobiological correlates of schizophrenia.

Acoustic Stimulation↗
PubMed2006

Evidence of altered prefrontal-thalamic circuitry in schizophrenia: an optimized diffusion MRI study.

MRI diffusion tensor imaging (DTI), optimized for measuring the trace of the diffusion tensor, was used to investigate microstructural changes in the brains of 12 individuals with schizophrenia compared with 12 matched control subjects. To control for the effects of anatomic variation between subject groups, all participants' diffusion images were nonlinearly registered to standard anatomical space. Significant statistical differences in mean diffusivity (MD) measures between the two groups were determined on a pixel-by-pixel basis, using Gaussian random field theory. We found significantly elevated MD measures within temporal, parietal and prefrontal cortical regions in the schizophrenia group (P > 0.001), especially within the medial frontal gyrus and anterior cingulate. The dorsal medial and anterior nucleus of the thalamus, including the caudate, also exhibited significantly increased MD in the schizophrenia group (P > 0.001). This study has shown for the first time that MD measures offer an alternative strategy for investigating altered prefrontal-thalamic circuitry in schizophrenia.

Brain↗
PubMed2006

Cell cycle alterations in biopsied olfactory neuroepithelium in schizophrenia and bipolar I disorder using cell culture and gene expression analyses.

We previously demonstrated that olfactory cultures from individuals with schizophrenia had increased cell proliferation compared to cultures from healthy controls. The aims of this study were to (a) replicate this observation in a new group of individuals with schizophrenia, (b) examine the specificity of these findings by including individuals with bipolar I disorder and (c) explore gene expression differences that may underlie cell cycle differences in these diseases. Compared to controls (n = 10), there was significantly more mitosis in schizophrenia patient cultures (n = 8) and significantly more cell death in the bipolar I disorder patient cultures (n = 8). Microarray data showed alterations to the cell cycle and phosphatidylinositol signalling pathways in schizophrenia and bipolar I disorder, respectively. Whilst caution is required in the interpretation of the array results, the study provides evidence indicating that cell proliferation and cell death in olfactory neuroepithelial cultures is differentially altered in schizophrenia and bipolar disorder.

Adult↗
PubMed2006

Developmental vitamin D (DVD) deficiency in the rat alters adult behaviour independently of HPA function.

Developmental vitamin D deficiency (DVD) has been shown to alter the orderly pattern of brain development. Even though the period of vitamin D deficiency is restricted to gestation this is sufficient to induce behavioural abnormalities in the adult offspring consistent with those seen in many animal models of schizophrenia. Given that some of these behavioural alterations could also be an indirect result of either impaired maternal hypothalamic pituitary axis (HPA) function (which in turn could influence maternal care) or the result of a permanent alteration in HPA function in the adult offspring we have examined HPA status in both maternal animals and adult offspring. In this study we have established that HPA function is normal in the maternally vitamin D deficient rat. We replicate the behavioural phenotype of hyperlocomotion whilst establishing that HPA function is also unchanged in the adult male offspring. We conclude that the behavioural alterations induced by DVD deficiency are due to some adverse event in brain development rather than via an alteration in stress response.

Animals↗
PubMed2006

Association study of the dystrobrevin-binding gene with schizophrenia in Australian and Indian samples.

Numerous studies have reported association between variants in the dystrobrevin binding protein 1 (dysbindin) gene (DTNBP1) and schizophrenia. However, the pattern of results is complex and to date, no specific risk marker or haplotype has been consistently identified. The number of single nucleotide polymorphisms (SNPs) tested in these studies has ranged from 5 to 20. We attempted to replicate previous findings by testing 16 SNPs in samples of 41 Australian pedigrees, 194 Australian cases and 180 controls, and 197 Indian pedigrees. No globally significant evidence for association was observed in any sample, despite power calculations indicating sufficient power to replicate several previous findings. Possible explanations for our results include sample differences in background linkage disequilibrium and/or risk allele effect size, the presence of multiple risk alleles upon different haplotypes, or the presence of a single risk allele upon multiple haplotypes. Some previous associations may also represent false positives. Examination of Caucasian HapMap phase II genotype data spanning the DTNBP1 region indicates upwards of 40 SNPs are required to satisfactorily assess all nonredundant variation within DTNBP1 and its potential regulatory regions for association with schizophrenia. More comprehensive studies in multiple samples will be required to determine whether specific DTNBP1 variants function as risk factors for schizophrenia.

Alleles↗
PubMed2005

Swimming behaviour and post-swimming activity in Vitamin D receptor knockout mice.

Animal experiments have shown that Vitamin D plays a role in both brain development and adult brain function. The adult Vitamin D receptor null mutant mouse (VDR -/-) is reported to be less active and more anxious than wild-type litter mate controls and to have poor swimming ability. However, an "anxious" behavioural phenotype is inferred from differences in locomotor behaviour. This is a general problem in behavioural phenotyping where a neurological phenotype is inferred from changes in locomotion which will be affected by non-neurological factors, such as muscle fatigue. In this study of VDR -/-, we conducted a detailed examination of one form of motor behaviour, swimming, compared to wildtype littermate controls. Swimming was assessed using a forced swim test, a laneway swimming test and a watermaze test using a visible platform. Post-swimming activity was assessed by comparing grooming and rearing behaviour before, and 5 min after, the forced swimming test. We replicated previous findings in which VDR -/- mice demonstrate more sinking episodes than wildtype controls in the forced swim test but they were similar to controls in the time taken to swim a 1m laneway, and in the time taken to reach a visible platform in the watermaze. Thus, the VDR -/- mice were able to swim but were not able to float. Grooming and rearing behaviour of the VDR -/- mice was similar to wildtype controls before the forced swim but the VDR -/- were much less active after the swim compared with wildtype mice which displayed high levels of grooming and rearing. We conclude that VDR -/- mice have muscular and motor impairments that do not affect their ability to swim but significantly alters the ability to float as well as their post-swimming activity. Differences in muscle strength may confound tests of activity that are used to infer an "anxious" phenotype.

Animals↗
PubMed2005

Season of birth is associated with anthropometric and neurocognitive outcomes during infancy and childhood in a general population birth cohort.

The 'season of birth' effect is one of the most consistently replicated associations in schizophrenia epidemiology. In contrast, the association between season of birth and development in the general population is relatively poorly understood. The aim of this study was to explore the impact of season of birth on various anthropometric and neurocognitive variables from birth to age seven in a large, community-based birth cohort. A sample of white singleton infants born after 37 weeks gestation (n = 22,123) was drawn from the US Collaborative Perinatal Project. Anthropometric variables (weight, head circumference, length/height) and various measures of neurocognitive development, were assessed at birth, 8 months, 4 and 7 years of age. Compared to summer/autumn born infants, winter/spring born infants were significantly longer at birth, and at age seven were significantly heavier, taller and had larger head circumference. Winter/spring born infants were achieving significantly higher scores on the Bayley Motor Score at 8 months, the Graham-Ernhart Block Test at age 4, the Wechsler Intelligence Performance and Full Scale scores at age 7, but had significantly lower scores on the Bender-Gestalt Test at age 7 years. Winter/spring birth, while associated with an increased risk of schizophrenia, is generally associated with superior outcomes with respect to physical and cognitive development.

Anthropometry↗
PubMed2005

Variations in the incidence of schizophrenia: data versus dogma.

The schizophrenia research community has shared a belief that the incidence of schizophrenia shows little variation. This belief is related to the dogma that schizophrenia affects all individuals equally, regardless of sex, race, or nationality. However, there is now robust evidence that the incidence of schizophrenia is characterized by substantial variability. There is prominent variation in the incidence of schizophrenia between sites. The incidence of schizophrenia is significantly higher in males than in females (male:female ratio = 1.4). Migrants and those living in urban areas have a higher incidence of schizophrenia. The incidence of schizophrenia has fluctuations across time. In addition, the prevalence of schizophrenia is also characterized by prominent variation. The realization that schizophrenia is characterized by rich and informative gradients will serve as a catalyst for future research.

Emigration and Immigration↗
PubMed2005

Transient prenatal vitamin D deficiency is associated with subtle alterations in learning and memory functions in adult rats.

Based on clues from epidemiology, low prenatal vitamin D has been proposed as a candidate risk factor for schizophrenia. Recent animal experiments have demonstrated that transient prenatal vitamin D deficiency is associated with persistent alterations in brain morphology and neurotrophin expression. In order to explore the utility of the vitamin D animal model of schizophrenia, we examined different types of learning and memory in adult rats exposed to transient prenatal vitamin D deficiency. Compared to control animals, the prenatally deplete animals had a significant impairment of latent inhibition, a feature often associated with schizophrenia. In addition, the deplete group was (a) significantly impaired on hole board habituation and (b) significantly better at maintaining previously learnt rules of brightness discrimination in a Y-chamber. In contrast, the prenatally deplete animals showed no impairment on the spatial learning task in the radial maze, nor on two-way active avoidance learning in the shuttle-box. The results indicate that transient prenatal vitamin D depletion in the rat is associated with subtle and discrete alterations in learning and memory. The behavioural phenotype associated with this animal model may provide insights into the neurobiological correlates of the cognitive impairments of schizophrenia.

Analysis of Variance↗
PubMed2005

Executive control of working memory in schizophrenia.

There is considerable evidence that working memory impairment is a common feature of schizophrenia. The present study assessed working memory and executive function in 54 participants with schizophrenia, and a group of 54 normal controls matched to the patients on age, gender and estimated premorbid IQ, using traditional and newer measures of executive function and two dual tasks-Telephone Search with Counting and the Memory Span and Tracking Task. Results indicated that participants with schizophrenia were significantly impaired on all standardised measures of executive function with the exception of a composite measure of the Trail Making Test. Results for the dual task measures demonstrated that while the participants with schizophrenia were unimpaired on immediate digit span recall over a 2-min period, they recalled fewer digit strings and performed more poorly on a tracking task (box-crossing task) compared with controls. In addition, participants with schizophrenia performed more poorly on the tracking task when they were required to simultaneously recall digits strings than when they performed this task alone. Contrary to expectation, results of the telephone search task under dual conditions were not significantly different between groups. These results may reflect the insufficient complexity of the tone-counting task as an interference task. Overall, the present study showed that participants with schizophrenia appear to have a restricted impairment of their working memory system that is evident in tasks in which the visuospatial sketchpad slave system requires central executive control.

Adult↗
PubMed2005

Behavioural characterization of vitamin D receptor knockout mice.

Vitamin D (calcitriol) is a nuclear transcription regulator acting via a nuclear hormone receptor (VDR). In addition to its role in the regulation of calcium and phosphate homeostasis and in bone formation, Vitamin D is also thought to be involved in brain function. The aim of this study was to behaviourally phenotype VDR knockout mice. We characterized the behaviour of VDR null mutant mice and wildtype littermate controls by subjecting them to a range of tests including a primary behavioural screen (using the SHIRPA protocol), rotarod, gait analysis, Y-maze, marble burying test, bedding test, holeboard test, elevated plus maze, open field test and prepulse inhibition of the acoustic startle response. There were no effects of genotype on most of the scores from the SHIRPA protocol except that VDR -/- mice had alopecia, were shorter and weighed less than VDR +/+ mice. VDR -/- mice had a shorter gait as well as impairments on the rotarod, in the bedding test and impaired habituation in both the open field and on the acoustic startle response. The VDR -/- mice had normal acoustic startle responses but had impaired PPI at long (256 ms) but not short (64 ms) prepulse to pulse intervals. The VDR -/- mice were less active in the open field and buried fewer marbles in the marble burying test. However, there were no differences in the time spent on the open arms of the elevated plus maze or in working memory as assessed by repeat arm entries on the Y-maze. Therefore, it appears that VDR -/- mice have muscular and motor impairments that significantly affects locomotor behaviour but seemingly no impairments in cognition as indicated by exploration, working memory or anxiety.

Acoustic Stimulation↗
PubMed2005

Seasonal fluctuations in birth weight and neonatal limb length; does prenatal vitamin D influence neonatal size and shape?

BACKGROUND: Birth weight is known to fluctuate with season of birth, however, there is little information about seasonal variation in neonatal anthropometric measures. AIMS: The aim of this study was to examine seasonal fluctuations in birth weight and selected anthropometric measures. STUDY DESIGN AND SUBJECTS: The birth weight of singletons born after at least 37 weeks gestation was extracted from a perinatal register in south-east Queensland (n=350,171). Mean monthly birth weights for this period were examined. Based on a separate birth cohort, principal component analysis was undertaken on neonatal anthropometric measures (n=1233). Seasonality was assessed by (a) spectral analysis of time series data, (b) monthly and seasonal comparison of outcomes. RESULTS: Based on register data, birth weight displayed clear annual periodicity. Birth weight differed significantly when compared by month and season. Infants born in October were the heaviest (3484 g), while May-born infants were the lightest (3459 g; P=0.001). Based on the cohort anthropometric data, three components were identified related to (a) overall size, (b) limb length, and (c) head size and skin-fold thickness. Each of these components displayed significant seasonal variation. In particular, prominent seasonal fluctuations in limb length were identified, with peak limb length associated with winter/spring birth. CONCLUSION: Environmental factors that have regular seasonal fluctuation influence both the size and shape of neonates. Animal experiments suggest that prenatal hypovitaminosis D may underlie greater limb length. Because birth weight and limb length are associated with a broad range of important health outcomes, the seasonal exposures underlying these effects warrant further scrutiny from a public health perspective.

Birth Weight↗
PubMed2005

Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain.

Despite a growing body of evidence that Vitamin D is involved in mammalian brain functioning, there has been a lack of direct evidence about its role in the human brain. This paper reports, for the first time, the distribution of the 1,25-dihydroxyvitamin D3 receptor (VDR), and 1alpha-hydroxylase (1alpha-OHase), the enzyme responsible for the formation of the active vitamin in the human brain. The receptor and the enzyme were found in both neurons and glial cells in a regional and layer-specific pattern. The VDR was restricted to the nucleus whilst 1alpha-OHase was distributed throughout the cytoplasm. The distribution of the VDR in human brain was strikingly similar to that reported in rodents. Many regions contained equivalent amounts of both the VDR and 1alpha-OHase, however the macrocellular cells within the nucleus basalis of Meynert (NBM) and the Purkinje cells in the cerebellum expressed 1alpha-OHase in the absence of VDR. The strongest immunohistochemical staining for both the receptor and enzyme was in the hypothalamus and in the large (presumably dopaminergic) neurons within the substantia nigra. The observed distribution of the VDR is consistent with the proposal that Vitamin D operates in a similar fashion to the known neurosteroids. The widespread distribution of 1alpha-OHase and the VDR suggests that Vitamin D may have autocrine/paracrine properties in the human brain.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2005

Regulation of adult olfactory neurogenesis by insulin-like growth factor-I.

Insulin-like growth factor-I (IGF-I) has multiple effects within the developing nervous system but its role in neurogenesis in the adult nervous system is less clear. The adult olfactory mucosa is a site of continuing neurogenesis that expresses IGF-I, its receptor and its binding proteins. The aim of the present study was to investigate the roles of IGF-I in regulating proliferation and differentiation in the olfactory mucosa. The action of IGF-I was assayed in serum-free culture combined with bromodeoxyuridine-labelling of proliferating cells and immunochemistry for specific cell types. IGF-I and its receptor were expressed by globose basal cells (the neuronal precursor) and by olfactory neurons. IGF-I reduced the numbers of proliferating neuronal precursors, induced their differentiation into neurons and promoted morphological differentiation of neurons. The evidence suggests that IGF-I is an autocrine and/or paracrine signal that induces neuronal precursors to differentiate into olfactory sensory neurons. These effects appear to be similar to the cellular effects of IGF-I in the developing nervous system.

Animals↗