Julia Rachel Plank

All Publications

• Genotype-phenotype correlations with autism spectrum disorder-related traits in noonan syndrome and noonan syndrome with multiple lentigines: a cross-sectional study. Molecular autism McGhee, C. A., Plank, J. R., Pannone, L., Russo, O., Fuhrmann, N., Ruggeri, A., Radio, F. C., Martinelli, S., Tartaglia, M., Green, T. 2025; 16 (1): 51

  Abstract

  Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are neurodevelopmental conditions caused by genetic variants leading to upregulated signaling in the RAS-MAPK pathway. While previous research has focused on genetic variability in cognitive and cardiac phenotypes, behavioral phenotypes, and their correlations across genetic variants and within the PTPN11 gene remain poorly characterized.This study included 121 individuals with NS (PTPN11: 88, SOS1: 18, RAF1: 6, KRAS: 2, RIT1: 3, NRAS: 2, LZTR1: 2, SOS2: 1) and seven individuals with NSML (PTPN11), compared to age- and sex-matched typically developing (TD) (N = 71). Behavioral questionnaires assessed social responsiveness and ASD-related traits (using SRS-2), and emotional problems (using CBCL) to identify genetic variant-specific behavioral profiles. Biochemical profiling of SHP2 activity in PTPN11-associated NS variants examined genotype-phenotype relationships.Compared to TD individuals, those with PTPN11-associated NS, NSML, and SOS1-associated NS exhibited clinically elevated scores, indicating increased ASD-related behaviors, poorer social functioning, and heightened emotional problems. Genetic variant comparisons revealed that individuals with PTPN11-associated NS and NSML exhibited greater ASD-related challenges than those with RAF1. Individuals with NSML exhibit elevated attention problems compared to all other genetic groups. Logistic regression results suggested each one-unit increase in SHP2 fold activation for PTPN11-associated NS corresponded to a 64% higher likelihood of markedly elevated restricted and repetitive behaviors, suggesting genotype-phenotype links.Small sample sizes for rarer variants, leading to unequal group sizes across subgroups, with PTPN11 variants comprising most of the NS group. Future research should address these sampling constraints and conduct functional studies to clarify variant impacts. Longitudinal assessments could elucidate behavioral phenotype trajectories.This study underscores the importance of genetic variant-specific research to understand unique behavioral phenotypes in NS and NSML. Our findings indicate a higher risk for ASD-related symptoms in PTPN11-associated NS and NSML compared to other variants. Additionally, individuals with PTPN11-associated NS and higher SHP2 fold activation exhibited greater impairments in restricted and repetitive behaviors, suggesting SHP2 activation variations may contribute to phenotypic variability. By linking ASD-related symptoms to biochemical predictors in PTPN11-associated NS, this study may inform future targeted treatment approaches.

  View details for DOI 10.1186/s13229-025-00681-1

  View details for PubMedID 41074228

  View details for PubMedCentralID PMC12514806

• Transdiagnostic similarities and distinctions in brain networks associated with ASD symptoms: A prospective cohort study. medRxiv : the preprint server for health sciences Bruno, J. L., Plank, J. R., Leder, S., Lake, E. M., Finn, E. S., Green, T. 2025

  Abstract

  Background: Despite high rates of autism spectrum disorder (ASD), understanding of pathophysiology is limited. The RAS-mitogen-activated protein kinase (RAS-MAPK) pathway plays a crucial role in ASD and is altered in children with Noonan syndrome (NS). Children with NS offer a unique model to disentangle genetic and neurological underpinnings of ASD.Methods: This study aimed to examine functional brain network anatomy underlying ASD symptoms in children with NS (n=28, mean age=8.24), and tested generalizability of models developed in a non-syndromic cohort enriched for ASD (Autism Brain Imaging Data Exchange (ABIDE), n=352, mean age=11.0). Connectome-based predictive modeling (CPM) was applied to fMRI data to predict the severity of autism symptoms, indexed by the Social Responsive Scale (SRS), in children with NS. Next, we tested if a model developed to predict autism symptoms in an autism-enriched sample of children without genetic diagnosis (ABIDE) could predict autism symptoms in children with NS.Results: Predicted SRS scores were significantly associated with observed SRS scores in NS (r s =0.43, p=.011). Application of the predictive model generated in the autism-enriched cohort (ABIDE) significantly predicted observed SRS scores in NS (r s =0.460, p=.018). Predictive brain networks in both NS and the non-syndromic cohorts included subcortical-cerebellar networks and visual processing networks.Limitations: The size of our NS cohort is small, given the rarity of NS. However, the significant cross-dataset comparison yielded in this study suggests that use of large publicly available datasets can be useful in contextualizing smaller and harder to collect datasets in rare genetic syndromes.Conclusions: The presence of shared brain networks suggests a converging pattern of functional connectivity underlying autism symptoms, irrespective of genetic diagnosis. Evidence of shared brain networks in children with idiopathic autism and NS highlights the role of RAS-MAPK in autism symptoms and points to the value of leveraging human genetic models to enhance our understanding of idiopathic ASD.

  View details for DOI 10.1101/2025.09.17.25336005

  View details for PubMedID 41001444

• T1w/T2w ratio suggests reduced intracortical myelin content in youth with RASopathies. medRxiv : the preprint server for health sciences Plank, J. R., Pardej, S. K., Raman, M. M., McNab, J., Green, T. 2025

  Abstract

  Background Myelin may represent a modifiable treatment target in neurodevelopmental disorders, however, a reliable tool for in vivo assessment of myelin alterations in clinical settings is needed. Prior work shows commonly acquired T1-weighted (T1w) and T2-weighted (T2w) scans can be transformed into ratio maps and subsequently provide a reasonable estimate of cortical myelin content. We investigated T1w/T2w ratios for measuring cortical myelin in children with neurodevelopmental disorders of the RAS-MAPK signaling pathway. Methods In this prospective study, 112 children (86 RASopathies, 26 typical developing (TD), aged 6-17 years) completed T1w and T2w MRI scans and NIH Toolbox cognitive assessments. Parent-rated mobility and strength impact scores were also acquired. T1w/T2w ratio maps were calculated at three levels of the cortex in FreeSurfer, and average values were extracted from 68 regions-of-interest (ROIs) at each level across the brain and from eight subcortical ROIs. Group differences were assessed using analyses of covariance, including a false discovery rate adjustment for multiple comparisons. As an exploratory analysis, differences in cognitive scores and parent-rated health were assessed across quartiles of whole-brain T1w/T2w ratios. Results Widespread decreases in T1w/T2w ratios were found in the RASopathies group, suggesting decreased cortical myelin content. Of the T1w/T2w ratios sampled along the midline, 63 of 68 cortical ROIs were significantly reduced in RASopathies (pFDR<.050). Of the subcortical ROIs, only the T1w/T2w ratio in the accumbens was significantly reduced in RASopathies compared to TD (Cohens d=0.520, pFDR=.024). Exploratory quartile analyses across the whole sample indicated significant effects of T1w/T2w ratio quartile on mobility (p=.002) and strength impact ratings (p<.001), such that subjects in higher T1w/T2w ratio quartiles had better physical health ratings. Conclusions These results support the utility of T1w/T2w ratio mapping as a sensitive tool for detecting cortical myelin alterations in genetically defined neurodevelopmental disorders. Exploratory analyses suggest a relationship between cortical myelin content and physical mobility and stamina. Future work should explore the clinical relevance of these findings for cognitive and functional outcomes and assess their potential as biomarkers for targeted therapeutic interventions.

  View details for DOI 10.1101/2025.09.16.25335916

  View details for PubMedID 41001496

• Mapping neuroinflammation with diffusion-weighted MRI: randomized crossover study. Biological psychiatry. Cognitive neuroscience and neuroimaging Plank, J. R., Morgan, C. A., Dell'Acqua, F., Sundram, F., Hoeh, N. R., Muthukumaraswamy, S., Lin, J. C. 2025

  Abstract

  The pathophysiology of neuroinflammation in psychiatric conditions remains poorly understood, highlighting the need for non-invasive tools that can measure neuroinflammation in vivo. We explored advanced diffusion-weighted MRI techniques for detection of low-level neuroinflammation induced by typhoid vaccine, with potential applications to psychiatric disorders.Twenty healthy volunteers (10 males, median age 34, range 18-44 years) participated in a randomized, placebo-controlled, crossover design study. Participants underwent MRI before and after receiving placebo or vaccine in alternating sessions, separated by a washout period. Diffusion tensor (multi-shell and single-shell), diffusion kurtosis, and neurite orientation density and dispersion imaging parameter maps were generated. Probabilistic tractography investigated differences in tract volume, fractional anisotropy (FA), and mean diffusivity (MD) of the tracts. Thirteen tracts and 15 regions were analyzed using a region-of-interest approach entered into linear mixed models to evaluate treatment effects.A treatment effect was observed on white matter tracts derived from XTRACT, with a global reduction in MD (p=.040). White matter tracts-of-interest showed increased axial kurtosis (p<.001) while grey matter regions-of-interest demonstrated increased mean and radial kurtosis (both p=.038). Additionally, several correlations were found between the inflammatory marker interleukin (IL)-6 and diffusion parameters.Our findings demonstrate that diffusion-weighted MRI may be sensitive to inflammation-induced microstructural changes in the brain. Future studies should integrate complementary techniques and clinical assessments to deepen our understanding of inflammatory pathophysiology and its implications for health outcomes in clinical populations.

  View details for DOI 10.1016/j.bpsc.2025.05.002

  View details for PubMedID 40379248

• Quantitative T1 mapping indicates elevated white matter myelin in children with RASopathies. Biological psychiatry Plank, J. R., Gozdas, E., Bruno, J., McGhee, C. A., Wu, H., Raman, M. M., Saggar, M., Green, T. 2025

  Abstract

  Evidence suggests a pathological role of myelination in neurodevelopmental disorders with links to cognitive difficulties, but in vivo assessment remains challenging. Quantitative T1 mapping (QT1) has been used in prior clinical studies (e.g., of multiple sclerosis) and shows promise for reliable measurement of myelin alterations. We investigated QT1 for measuring myelination in children with neurodevelopmental disorders of the RAS-MAPK signaling pathway (RASopathies).We collected QT1, diffusion-weighted, and structural MRI scans from 72 children (49 RASopathies, 23 typical developing (TD)). QT1 myelin content measures included white matter macromolecular tissue volume (MTV) and cortical R1 (1/T1 relaxation). Group differences were assessed across 39 white matter tracts. Principal components analysis captured cortical myelination patterns across 360 regions, followed by a MANOVA. A support vector machine (SVM) identified the most discriminative features between-groups.Thirty-four of 39 tracts were higher in MTV in RASopathies relative to TD (pFDR<.05), indicating widespread elevation in myelination. MANOVA revealed a group effect on cortical R1 (p=.002, η2=.028), suggesting cortical myelination differences between-groups. The SVM yielded an accuracy of 87% and identified cognitive and cortical R1 features as the most discriminant between-groups.We found widespread elevated white matter tract myelin and region-dependent cortical myelination patterns in children with RASopathies. Leveraging preclinical models showing oligodendrocyte dysfunction, QT1 revealed precocious myelination. Further work is needed to explore relationships with cognition. QT1 is a promising tool for identification and monitoring of myelin as a treatment target in neurodevelopmental disorders, offering significant potential for advancing current therapeutic strategies.

  View details for DOI 10.1016/j.biopsych.2025.04.014

  View details for PubMedID 40316128

• The Effects of Neuroinflammation Induced by Typhoid Vaccine on Resting and Task-Based Electroencephalography BRAIN AND BEHAVIOR Plank, J. R., Chen, J. C. C., Sundram, F., Hoeh, N., Muthukumaraswamy, S., Lin, J. C. 2025; 15 (1): e70249

  Abstract

  Considerable evidence suggests a pathophysiological role of neuroinflammation in psychiatric disorders. Lumbar puncture and positron emission tomography (PET) show increased levels of inflammation in psychiatric disorders. However, the invasive nature of these techniques, as well as their expense, make them undesirable for routine use in patients. Electroencephalography (EEG) is noninvasive, affordable and shows potential as a clinical tool for detection of neuroinflammation.In this randomized, crossover design, placebo-controlled, double-blind study, typhoid vaccine was administered to 20 healthy volunteers to induce a low level of neuroinflammation. EEG was recorded before and after placebo/vaccine administration during resting-state and during performance of the Attention Network Test (ANT). Resting-state EEG was analyzed using spectral power analysis, and time-frequency analysis was used for the EEG from the ANT. Behavioral data were assessed using linear mixed models and Spearman's correlations.Behavioral results from the ANT showed no decrement in performance following the vaccine, consistent with previous studies. During eyes-open resting, there was a relative decrease in right-frontal delta power in the vaccine condition compared to placebo. There was a trend toward greater alpha power suppression in the alerting response of the attentional network; however, this finding did not reach significance.Decreased resting-state delta power may reflect an unpleasant internal state conferred by the vaccine. Inflammation did not significantly affect attention networks. The absence of significant alterations may be due to an insufficient inflammatory response. Further studies are needed to assess the feasibility of EEG as a technique for detection of neuroinflammation.

  View details for DOI 10.1002/brb3.70249

  View details for Web of Science ID 001386251000001

  View details for PubMedID 39740795

  View details for PubMedCentralID PMC11688119

• Elucidating Microstructural Alterations in Neurodevelopmental Disorders: Application of Advanced Diffusion-Weighted Imaging in Children With Rasopathies. Human brain mapping Plank, J. R., Gozdas, E., Dai, E., McGhee, C. A., Raman, M. M., Green, T. 2024; 45 (17): e70087

  Abstract

  Neurodevelopmental disorders (NDDs) can severely impact functioning yet effective treatments are limited. Greater insight into the neurobiology underlying NDDs is critical to the development of successful treatments. Using a genetics-first approach, we investigated the potential of advanced diffusion-weighted imaging (DWI) techniques to characterize the neural microstructure unique to neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). In this prospective study, children with NF1, NS, and typical developing (TD) were scanned using a multi-shell DWI sequence optimized for neurite orientation density and dispersion imaging (NODDI) and diffusion kurtosis imaging (DKI). Region-of-interest and tract-based analysis were conducted on subcortical regions and white matter tracts. Analysis of covariance, principal components, and linear discriminant analysis compared between three groups. 88 participants (Mage = 9.36, SDage = 2.61; 44 male) were included: 31 NS, 25 NF1, and 32 TD. Subcortical regions differed between NF1 and NS, particularly in the thalamus where the neurite density index (NDI; estimated difference 0.044 [95% CI: -0.034, 0.053], d = 2.36), orientation dispersion index (ODI; estimate 0.018 [95% CI: 0.010, 0.026], d = 1.39), and mean kurtosis (MK; estimate 0.049 [95% CI: 0.025, 0.072], d = 1.39) were lower in NF1 compared with NS (all p < 0.0001). Reduced NDI was found in NF1 and NS compared with TD in all 39 white matter tracts investigated (p < 0.0001). Reduced MK was found in a majority of the tracts in NF1 and NS relative to TD, while fewer differences in ODI were observed. The middle cerebellar peduncle showed lower NDI (estimate 0.038 [95% CI: 0.021, 0.056], p < 0.0001) and MK (estimate 0.057 [95% CI: 0.026, 0.089], p < 0.0001) in NF1 compared to NS. Multivariate analyses distinguished between groups using NDI, ODI, and MK measures. Principal components analysis confirmed that the clinical groups differ most from TD in white matter tract-based NDI and MK, whereas ODI values appear similar across the groups. The subcortical regions showed several differences between NF1 and NS, to the extent that a linear discriminant analysis could classify participants with NF1 with an accuracy rate of 97%. Differences in neural microstructure were detected between NF1 and NS, particularly in subcortical regions and the middle cerebellar peduncle, in line with pre-clinical evidence. Advanced DWI techniques detected subtle alterations not found in prior work using conventional diffusion tensor imaging.

  View details for DOI 10.1002/hbm.70087

  View details for PubMedID 39665502

  View details for PubMedCentralID PMC11635693

• The Value of a Peer Mentorship Programme for Postgraduate Students in New Zealand: A Qualitative Study MEDICAL SCIENCE EDUCATOR Chen, J. C. C., Plank, J. R., Tsai, A., Lyndon, M., Henning, M. A. 2024

  View details for DOI 10.1007/s40670-024-02189-4

  View details for Web of Science ID 001341239000002

• Detection of Neuroinflammation Induced by Typhoid Vaccine Using Quantitative Magnetization Transfer MR: A Randomized Crossover Study. Journal of magnetic resonance imaging : JMRI Plank, J. R., Morgan, C. A., Smith, A. K., Sundram, F., Hoeh, N. R., Muthukumaraswamy, S., Lin, J. C. 2023

  Abstract

  The role of neuroinflammation in psychiatric disorders is not well-elucidated. A noninvasive technique sensitive to low-level neuroinflammation may improve understanding of the pathophysiology of these conditions.To test the ability of quantitative magnetization transfer (QMT) MR at 3 T for detection of low-level neuroinflammation induced by typhoid vaccine within a clinically reasonable scan time.Randomized, crossover, placebo-controlled.Twenty healthy volunteers (10 males; median age 34 years).Magnetization prepared rapid gradient-echo and MT-weighted 3D fast low-angle shot sequences at 3 T.Participants were randomized to either vaccine or placebo first with imaging, then after a washout period received the converse with a second set of imaging. MT imaging, scan time, and blood-based inflammatory marker concentrations were assessed pre- and post-vaccine and placebo. Mood was assessed hourly using the Profile of Mood States questionnaire. QMT parameter maps, including the exchange rate from bound to free pool (kba ) were generated using a two-pool model and then segmented into tissue type.Voxel-wise permutation-based analysis examined inflammatory-related alterations of QMT parameters. The threshold-free cluster enhancement method with family-wise error was used to correct voxel-wise results for multiple comparisons. Region of interest averages were fed into mixed models and Bonferroni corrected. Spearman correlations assessed the relationship between mood scores and QMT parameters. Results were considered significant if corrected P < 0.05.Scan time for the MT-weighted acquisition was approximately 11 minutes. Blood-based analysis showed higher IL-6 concentrations post-vaccine compared to post-placebo. Voxel-wise analysis found three clusters indicating an inflammatory-mediated increase in kba in cerebellar white matter. Cerebellar kba for white matter was negatively associated with vigor post-vaccine but not post-placebo.This study suggested that QMT at 3 T may show some sensitivity to low-level neuroinflammation. Further studies are needed to assess the viability of QMT for use in inflammatory-based disorders.1 TECHNICAL EFFICACY: Stage 2.

  View details for DOI 10.1002/jmri.28938

  View details for PubMedID 37540052

• A randomized, double-blind, placebo-controlled, hybrid parallel-arm study of low-dose naltrexone as an adjunctive anti-inflammatory treatment for major depressive disorder. Trials Plank, J. R., Glover, S. C., Moloney, B. D., Hoeh, N. R., Sundram, F., Sumner, R. L., Muthukumaraswamy, S., Lin, J. C. 2022; 23 (1): 822

  Abstract

  Major depressive disorder (MDD) is a leading cause of disability worldwide. The current treatments are ineffective in approximately one-third of patients, resulting in a large economic burden and reduced quality of life for a significant proportion of the global population. There is considerable evidence that increased inflammation may distinguish a sub-type of MDD, and there are no validated diagnostic tools or treatments for neuroinflammation in MDD patients. The current study aims to explore the potential role of low-dose naltrexone (LDN), a drug with purported anti-inflammatory properties in the central nervous system, as an adjunctive treatment in patients with MDD.This double-blind placebo-controlled hybrid parallel arm study enables the exploration of peripheral and central inflammatory markers with LDN as an approach to investigate inflammation as a pathophysiological contributor to MDD. Eligible participants with MDD (n = 48) will be stratified into the high and low inflammatory groups according to the levels of high-sensitivity C-reactive protein (hs-CRP) and then randomized to receive LDN or placebo for an initial 12 weeks, followed by a further 12 weeks during which all participants will receive LDN. The primary outcome measure will be the Montgomery-Åsberg Depression Rating Scale (MADRS) administered at baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 14 weeks, 16 weeks, 20 weeks, and 24 weeks, to assess the effectiveness of the anti-depressant response. The secondary outcomes include the use of MRI techniques including quantitative magnetization transfer (qMT), echo-planar spectroscopic imaging (EPSI), and diffusion-weighted imaging (DWI) to help to elucidate the neurobiological mechanism of LDN, and the inflammatory mechanisms in action in MDD. Electroencephalography, blood samples, cognitive tasks, and additional questionnaires will also be used to determine if there is a specific profile of symptoms in individuals with inflammatory MDD. Healthy participants (n = 24) will be recruited for baseline outcome measures only, to enable comparison with patients with MDD.This trial contributes to the literature on inflammation in MDD, including the understanding of the pathophysiology and efficacy of anti-inflammatory treatments. The investigation of inflammatory mechanisms in MDD is an important first step in the development of biomarkers to classify patient sub-groups, increase the accuracy of diagnosis, and tailor the approach to patients in clinical practice. This study may provide evidence of the benefit of LDN for the groups in whom conventional anti-depressants are ineffective and lead the way for translation into clinical practice.Australian New Zealand Clinical Trials Registry ACTRN12622000881730 . Registered on 21 June 2022.

  View details for DOI 10.1186/s13063-022-06738-3

  View details for PubMedID 36175917

  View details for PubMedCentralID PMC9524133

• Brain temperature as an indicator of neuroinflammation induced by typhoid vaccine: Assessment using whole-brain magnetic resonance spectroscopy in a randomised crossover study. NeuroImage. Clinical Plank, J. R., Morgan, C., Sundram, F., Plank, L. D., Hoeh, N., Ahn, S., Muthukumaraswamy, S., Lin, J. C. 2022; 35: 103053

  Abstract

  Prior studies indicate a pathogenic role of neuroinflammation in psychiatric disorders; however, there are no accepted methods that can reliably measure low-level neuroinflammation non-invasively in these individuals. Magnetic resonance spectroscopic imaging (MRSI) is a versatile, non-invasive neuroimaging technique that demonstrates sensitivity to brain inflammation. MRSI in conjunction with echo-planar spectroscopic imaging (EPSI) measures brain metabolites to derive whole-brain and regional brain temperatures, which may increase in neuroinflammation. The validity of MRSI/EPSI for measurement of low level neuroinflammation was tested using a safe experimental model of human brain inflammation - intramuscular administration of typhoid vaccine. Twenty healthy volunteers participated in a double-blind, placebo-controlled crossover study including MRSI/EPSI scans before and 3 h after vaccine/placebo administration. Body temperature and mood, assessed using the Profile of Mood States, were measured every hour up to four hours post-treatment administration. A mixed model analysis of variance was used to test for treatment effects. A significant proportion of brain regions (44/47) increased in temperature post-vaccine compared to post-placebo (p < 0.0001). For temperature change in the brain as a whole, there was no significant treatment effect. Significant associations were seen between mood scores assessed at 4 h and whole brain and regional temperatures post-treatment. Findings indicate that regional brain temperature may be a more sensitive measure of low-level neuroinflammation than whole-brain temperature. Future work where these measurement techniques are applied to populations with psychiatric disorders would be of clinical interest.

  View details for DOI 10.1016/j.nicl.2022.103053

  View details for PubMedID 35617872

  View details for PubMedCentralID PMC9136180