Research Fellow and Group Leader, NeuRA
Chair of Infant, Child, and Adolescent Psychiatry, UNSW
Clinical Director of Child and Adolescent Mental Health Services, SESLHD
+612 9399 1884
Prof Lenroot received her medical degree and training in Adult, Child, and Adolescent Psychiatry at the University of New Mexico in the United States. She began her work in psychiatric research in New Mexico with a project using spectroscopy to study glutamate abnormalities in adolescents with early onset schizophrenia. She then moved to Bethesda, Maryland, to work on longitudinal studies of brain development with the Child Psychiatry Branch of the National Institutes of Mental Health. There her research focussed on understanding influences on brain development, including sex differences, the impact of having different numbers of sex chromosomes, and twin studies to parse out the relative of influences of genetic and environmental factor across development. In May of 2009 Rhoshel relocated to Sydney to begin her work at NeuRA and UNSW using neuroimaging techniques to study healthy and atypical brain development in children and adolescents.
In addition to genes identified in our own laboratory, we have also been involved in assessing the risk attributed by genes identified by other groups and in sharing data and samples in large international collaborative studies. We are contributors to the Psychiatric Genomics Consortium (PGC) and Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortia, which aim to identify risk genes which contribute to disease, and examine their effect on brain structure, function and disease.
Together with Professor Peter Schofield (NeuRA) and Professor Philip Mitchell (Black Dog Institute), our group is investigating the genetic contributors to bipolar disorder using Australian families with multiple individuals who have been diagnosed with the disorder.
The group previously identified a bipolar susceptibility locus located on chromosome 15 in a pooled analysis of 35 families. More detailed analysis of this region has identified a single gene, which confers an increased susceptibility to both bipolar disorder and schizophrenia, and has also been implicated as a risk factor for autism.
The group is now aiming to understand how alterations in ST8SIA2 translate into an increased genetic susceptibility by characterising alterations in the DNA, RNA and protein product of this gene and its interaction partners in patients with either bipolar disorder or schizophrenia.
The offspring of individuals with bipolar disorder are at increased risk of mental illness, but our tools to predict which of these genetically at-risk young people will eventually develop disorder are very imprecise. Longitudinal studies that ascertain at-risk participants and monitor them prospectively are an effective approach for identifying early clinical and biological markers of future illness. In collaboration with the Black Dog Institute plus groups from four independent US-based sites, including: Johns Hopkins University; University of Michigan; Washington University in St. Louis; Indiana University; we are following a cohort of young kids and siblings of bipolar disorder patients with annual clinical, neurocognitive and lifestyle assessments; plus bi-annual brain imaging of the Australian participants. We are assessing the genetic load of multiple risk variants across the genome in these at-risk individuals to determine if we can use genetic information to help predict which individuals will ultimately transition to illness, and whether genetic load will influence early structural brain changes which are seen prior to onset of symptoms which lead to a clinical diagnosis.
We are also examining whether epigenetic changes – which occur on-top-of the DNA sequence in response to environmental influences – are involved in transition from health to illness. Early identification of those most likely to develop illness will provide a firm basis on which to develop preventive and early intervention strategies to reduce the impact of this devastating disorder.
A large body of evidence indicates alterations in brain regional cellular energy metabolism and blood flow in schizophrenia. Among the different molecules regulating blood flow, vascular endothelial growth factor (VEGF) is generally accepted as the major factor involved in the process of angiogenesis. In the present study, we examined whether peripheral VEGF levels correlate with changes in the prefrontal cortex (PFC) volume in patients with schizophrenia and in healthy controls. Whole-blood samples were obtained from 96 people with schizophrenia or schizoaffective disorder and 83 healthy controls. Serum VEGF protein levels were analyzed by enzyme-linked immunosorbent assay, whereas quantitative PCR was performed to measure interleukin-6 (IL-6, a pro-inflammatory marker implicated in schizophrenia) mRNA levels in the blood samples. Structural magnetic resonance imaging scans were obtained using a 3T Achieva scanner on a subset of 59 people with schizophrenia or schizoaffective disorder and 65 healthy controls, and prefrontal volumes were obtained using FreeSurfer software. As compared with healthy controls, individuals with schizophrenia had a significant increase in log-transformed mean serum VEGF levels (t(177)=2.9, P=0.005). A significant inverse correlation (r=-0.40, P=0.002) between serum VEGF and total frontal pole volume was found in patients with schizophrenia/schizoaffective disorder. Moreover, we observed a significant positive association (r=0.24, P=0.03) between serum VEGF and IL-6 mRNA levels in patients with schizophrenia. These findings suggest an association between serum VEGF and inflammation, and that serum VEGF levels are related to structural abnormalities in the PFC of people with schizophrenia.
People with schizophrenia show probabilistic association learning impairment in conjunction with abnormal neural activity. The selective estrogen receptor modulator (SERM) raloxifene preserves neural activity during memory in healthy older men and improves memory in schizophrenia. Here, we tested the extent to which raloxifene modifies neural activity during learning in schizophrenia. Nineteen people with schizophrenia participated in a twelve-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of the SERM raloxifene administered orally at 120 mg daily to assess brain activity during probabilistic association learning using functional magnetic resonance imaging (fMRI). Raloxifene improved probabilistic association learning and significantly increased fMRI BOLD activity in the hippocampus and parahippocampal gyrus relative to placebo. A separate region of interest confirmatory analysis in 21 patients vs 36 healthy controls showed a positive association between parahippocampal neural activity and learning in patients, but no such relationship in the parahippocampal gyrus of healthy controls. Thus, selective estrogen receptor modulation by raloxifene concurrently increases activity in the parahippocampal gyrus and improves probabilistic association learning in schizophrenia. These results support a role for estrogen receptor modulation of mesial temporal lobe neural activity in the remediation of learning disabilities in both men and women with schizophrenia.