Florey Department of Neuroscience and Mental Health - Research Publications

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    Novel approaches to alcohol rehabilitation: Modification of stress-responsive brain regions through environmental enrichment
    Pang, TY ; Hannan, AJ ; Lawrence, AJ (PERGAMON-ELSEVIER SCIENCE LTD, 2019-02)
    Relapse remains the most prominent hurdle to successful rehabilitation from alcoholism. The neural mechanisms underlying relapse are complex, but our understanding of the brain regions involved, the anatomical circuitry and the modulation of specific nuclei in the context of stress and cue-induced relapse have improved significantly in recent years. In particular, stress is now recognised as a significant trigger for relapse, adding to the well-established impact of chronic stress to escalate alcohol consumption. It is therefore unsurprising that the stress-responsive regions of the brain have also been implicated in alcohol relapse, such as the nucleus accumbens, amygdala and the hypothalamus. Environmental enrichment is a robust experimental paradigm which provides a non-pharmacological tool to alter stress response and, separately, alcohol-seeking behaviour and symptoms of withdrawal. In this review, we examine and consolidate the preclinical evidence that alcohol seeking behaviour and stress-induced relapse are modulated by environmental enrichment, and these are primarily mediated by modification of neural activity within the key nodes of the addiction circuitry. Finally, we discuss the limited clinical evidence that stress-reducing approaches such as mindfulness could potentially serve as adjunctive therapy in the treatment of alcoholism. This article is part of the Special Issue entitled "Neurobiology of Environmental Enrichment".
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    HPA axis regulation and stress response is subject to intergenerational modification by paternal trauma and stress
    Batchelor, V ; Pang, TY (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2019-09-01)
    There is increasing evidence that one's risk for psychiatric disturbances and metabolic syndromes is influenced by their parents' own health history, lifestyle and living environment. For example, paternal high fat diet is strongly linked to neuroendocrine dysregulation in offspring and increased risk for diabetes. The potential intergenerational impact of paternal stress has only just begun to emerge, with the initial evidence suggestive of greater risk for anxiety-related disorders. The hypothalamic-pituitary-adrenal (HPA)-axis is a key neuroendocrine signalling system involved in physiological homeostasis and stress response. In individuals, dysregulation of this system is closely associated with behavioral deficits and mood disorders. Various preclinical models of paternal stress have demonstrated robust behavioral shifts but little is known about the intergenerational modification of HPA axis function. This review will present evidence drawn from a range of laboratory mouse and rat models that the intergenerational influence of paternal stress on offspring behavioral phenotypes involve some level of HPA axis dysregulation. It makes the case that further investigations to comprehensively profile HPA axis function in offspring generations is warranted.
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    Scavenger Receptor Class A1 Mediates Uptake of Morpholino Antisense Oligonucleotide into Dystrophic Skeletal Muscle
    Miyatake, S ; Mizobe, Y ; Tsoumpra, MK ; Lim, KRQ ; Hara, Y ; Shabanpoor, F ; Yokota, T ; Takeda, S ; Aoki, Y (CELL PRESS, 2019-03-01)
    Exon skipping using phosphorodiamidate morpholino oligomers (PMOs) is a promising treatment strategy for Duchenne muscular dystrophy (DMD). The most significant limitation of these clinically used compounds is their lack of delivery systems that target muscles; thus, cell-penetrating peptides are being developed to enhance uptake into muscles. Recently, we reported that uptake of peptide-conjugated PMOs into myofibers was mediated by scavenger receptor class A (SR-A), which binds negatively charged ligands. However, the mechanism by which the naked PMOs are taken up into fibers is poorly understood. In this study, we found that PMO uptake and exon-skipping efficiency were promoted in dystrophin-deficient myotubes via endocytosis through a caveolin-dependent pathway. Interestingly, SR-A1 was upregulated and localized in juxtaposition with caveolin-3 in these myotubes and promoted PMO-induced exon skipping. SR-A1 was also upregulated in the skeletal muscle of mdx52 mice and mediated PMO uptake. In addition, PMOs with neutral backbones had negative zeta potentials owing to their nucleobase compositions and interacted with SR-A1. In conclusion, PMOs with negative zeta potential were taken up into dystrophin-deficient skeletal muscle by upregulated SR-A1. Therefore, the development of a drug delivery system targeting SR-A1 could lead to highly efficient exon-skipping therapies for DMD.
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    Epigenetic aging in major depressive disorder
    Han, L ; Aghajani, M ; Clark, S ; Chan, R ; Hattab, M ; Shabalin, A ; Zhao, M ; Kumar, G ; Xie, LY ; Jansen, R ; Milaneschi, Y ; Dean, B ; Aberg, K ; Van den Oord, E ; Penninx, B (ELSEVIER, 2019-01-01)
    Major depressive disorder (MDD) is associated with increased risk of mortality and aging-related diseases [1–3]. The authors examined whether MDD is associated with higher epigenetic aging (EA) [4] in blood as measured by DNA methylation (DNAm) patterns, whether clinical characteristics of MDD have a further impact on these patterns, and whether findings replicate in brain tissue. DNAm age was estimated using all methylation sites in blood of 811 depressed patients and 319 control subjects from the Netherlands Study of Depression and Anxiety. The residuals of the DNAm age estimates regressed on chronological age were calculated to indicate EA. MDD diagnosis and clinical characteristics were assessed with questionnaires and psychiatric interviews. Analyses were adjusted for sociodemographic characteristics, lifestyle, and health status. Postmortem brain samples of 74 depressed patients and 64 control subjects were used for replication. Pathway enrichment analysis was conducted using ConsensusPathDB to gain insight into the biological processes underlying EA in blood and brain. Significantly higher EA was observed in MDD patients compared with control subjects, with a significant dose effect with increasing symptom severity in the overall sample. In the depression group, EA was positively and significantly associated with childhood trauma score. The case-control difference was replicated in an independent dataset of postmortem brain samples. The top significantly enriched Gene Ontology terms included neuronal processes. As compared with control subjects, MDD patients exhibited higher EA in blood and brain tissue, suggesting that they are biologically older than their corresponding chronological age. This effect was even more profound in the presence of childhood trauma.
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    Carotid endarterectomy: the change in practice over 11years in a stroke centre
    Tse, GTW ; Kilkenny, MF ; Bladin, C ; Grigg, M ; Dewey, HM (WILEY, 2019-04)
    BACKGROUND: Recent research evidence has impacted the practice of carotid endarterectomy (CEA). We aim to characterize changes in the practice and outcome of CEA over time in a single large-volume stroke centre. METHODS: All patients who underwent CEA from 2004 to 2014 and carotid angioplasty and stenting (CAS) from 2003 to 2008 at an Australian metropolitan tertiary stroke centre hospital were included. Clinical data were analysed to identify time trends in choice of intervention, patient selection, preoperative imaging utilization, surgical timing and outcome. RESULTS: There were 510 CEAs performed during 2004-2014 and 95 CASs during 2003-2008. The proportion of patients undergoing CEA compared to CAS increased from 60% to 90% from 2004 to 2008 (P < 0.001). CAS patients were more likely to have cardiac co-morbidities. From 2004 to 2014, the proportion of CEA patients aged ≥80 years increased (P = 0.001) and the proportion of asymptomatic patients decreased (P = 0.003) over time. Median time from symptom onset to surgery decreased from 52 days (Q1: 25, Q3: 74) in 2004 to 8 days (Q1: 5, Q3: 37) in 2014 (P < 0.001). Use of preoperative ultrasonography decreased whilst CT angiography and the number of imaging modalities applied to each patient increased over time (P < 0.001). Overall, 5.9% of CEAs were complicated by death, stroke or acute myocardial infarction with no significant change over time. CONCLUSION: The trends in CEA practice at our centre align with international trends and guidelines. This study provides a representative indicator of Australian hospital practice, and illustrates how evidence from research is translated into clinical care.
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    Comparing Participation Outcome Over Time Across International Stroke Cohorts: Outcomes and Methods
    Verberne, D ; Tse, T ; Matyas, T ; Baum, C ; Post, M ; Carey, L ; van Heugten, C (W B SAUNDERS CO-ELSEVIER INC, 2019-11)
    OBJECTIVE: To enable a direct comparison of participation levels in the first year post-stroke, assessed by different outcome measures internationally. DESIGN: Two prospective stroke cohort studies following persons from stroke onset to 12 months post-stroke. SETTING: Community. PARTICIPANTS: Persons with stroke (N=495), not living at a nursing home, from Australia STroke imAging pRevention and Treatment-Prediction and Prevention to Achieve optimal Recovery Endpoints after stroke (START-PrePARE; n=100) and the Netherlands (Restore4stroke; n=395). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Activity Card Sort-Australia and Utrecht Scale for Evaluation of Rehabilitation-Participation. Activity domains were matched across measures to find common denominators and original scoring methods were recoded, hereby enabling a direct comparison of retained activities. RESULTS: Ninety-one (START-PrePARE) and 218 (Restore4stroke) persons with stroke were included for analyses. No major differences in background characteristics were observed between the cohorts; the Dutch cohort suffered from slightly more severe stroke. A higher level of participation was observed (radar charts) in the first months post-stroke for the Australian cohort than in the Dutch cohort, especially for unpaid work (P<.003). At 12 months post-stroke, participation levels were similar, without significant differences in retained activities using the defined common denominators (P>.003). CONCLUSIONS: An international comparison of actual activities that persons re-engage in in the first year post-stroke was achieved using a new method and recoding of data. High levels of participation were observed in both cohorts. Unpaid work showed different frequencies at 2-3 months, contributing to different trajectories over time across cultures. Important insights were gained. Although valuable information is inevitably lost with recoding, the approach may assist future studies on the harmonization of data across cohorts, particularly for 1 of the key outcomes of stroke: participation.
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    The importance of sex differences in pharmacology research
    Gogos, A ; Langmead, C ; Sullivan, JC ; Lawrence, AJ (WILEY, 2019-11)
    This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.
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    Quantitative analysis of phenotypic elements augments traditional electroclinical classification of common familial epilepsies
    Abou-Khalil, B ; Afawi, Z ; Allen, AS ; Bautista, JF ; Bellows, ST ; Berkovic, SF ; Bluvstein, J ; Burgess, R ; Cascino, G ; Cossette, P ; Cristofaro, S ; Crompton, DE ; Delanty, N ; Devinsky, O ; Dlugos, D ; Ellis, CA ; Epstein, MP ; Fountain, NB ; Freyer, C ; Geller, EB ; Glauser, T ; Glynn, S ; Goldberg-Stern, H ; Goldstein, DB ; Gravel, M ; Haas, K ; Haut, S ; Heinzen, EL ; Kirsch, HE ; Kivity, S ; Knowlton, R ; Korczyn, AD ; Kossoff, E ; Kuzniecky, R ; Loeb, R ; Lowenstein, DH ; Marson, AG ; McCormack, M ; McKenna, K ; Mefford, HC ; Motika, P ; Mullen, SA ; O'Brien, TJ ; Ottman, R ; Paolicchi, J ; Parent, JM ; Paterson, S ; Petrou, S ; Petrovski, S ; Pickrell, WO ; Poduri, A ; Rees, MI ; Sadleir, LG ; Scheffer, IE ; Shih, J ; Singh, R ; Sirven, J ; Smith, M ; Smith, PEM ; Thio, LL ; Thomas, RH ; Venkat, A ; Vining, E ; Von Allmen, G ; Weisenberg, J ; Widdess-Walsh, P ; Winawer, MR (WILEY, 2019-11)
    OBJECTIVE: Classification of epilepsy into types and subtypes is important for both clinical care and research into underlying disease mechanisms. A quantitative, data-driven approach may augment traditional electroclinical classification and shed new light on existing classification frameworks. METHODS: We used latent class analysis, a statistical method that assigns subjects into groups called latent classes based on phenotypic elements, to classify individuals with common familial epilepsies from the Epi4K Multiplex Families study. Phenotypic elements included seizure types, seizure symptoms, and other elements of the medical history. We compared class assignments to traditional electroclinical classifications and assessed familial aggregation of latent classes. RESULTS: A total of 1120 subjects with epilepsy were assigned to five latent classes. Classes 1 and 2 contained subjects with generalized epilepsy, largely reflecting the distinction between absence epilepsies and younger onset (class 1) versus myoclonic epilepsies and older onset (class 2). Classes 3 and 4 contained subjects with focal epilepsies, and in contrast to classes 1 and 2, these did not adhere as closely to clinically defined focal epilepsy subtypes. Class 5 contained nearly all subjects with febrile seizures plus or unknown epilepsy type, as well as a few subjects with generalized epilepsy and a few with focal epilepsy. Family concordance of latent classes was similar to or greater than concordance of clinically defined epilepsy types. SIGNIFICANCE: Quantitative classification of epilepsy has the potential to augment traditional electroclinical classification by (1) combining some syndromes into a single class, (2) splitting some syndromes into different classes, (3) helping to classify subjects who could not be classified clinically, and (4) defining the boundaries of clinically defined classifications. This approach can guide future research, including molecular genetic studies, by identifying homogeneous sets of individuals that may share underlying disease mechanisms.
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    Endovascular treatment of a hepatic artery pseudoaneurysm using a novel pericardium covered stent
    Larner, B ; Maingard, J ; Ren, Y ; Kok, HK ; Chandra, RV ; Lee, MJ ; Schelleman, A ; Brooks, DM ; Asadi, H (WILEY, 2019-12)
    Visceral and renal artery aneurysms (VRAAs) and pseudoaneurysms are rare. Their increasing incidence is largely thought to be due to advances in medical imaging. Twenty percent of VRAAs occur in hepatic arteries, with approximately fifty percent of these represented by pseudoaneurysms, which are prone to spontaneous rupture. Many treatments for VRAAs exist, with the endovascular approach being favoured. Treatment aims to preserve visceral perfusion and exclude the aneurysm; however, complex aneurysms may require parent artery or end-organ sacrifice. Covered stents allow rapid aneurysm exclusion while preserving parent artery patency, a favourable outcome when parent artery or end-organ sacrifice is undesirable. The AneuGraft pericardium covered stent (PCS) combines the benefits of a low-profile covered stent with those of a low immunogenic material. We describe the endovascular treatment of a patient with a hepatic artery pseudoaneurysm, where parent artery sacrifice was considered unacceptable. The AneuGraft PCS was used to provide immediate and complete exclusion, with dual antiplatelet therapy for 1 week, followed by single antiplatelet use. The procedure was a technical success, with preservation of the hepatic arteries and complete exclusion of the pseudoaneurysm. There were no complications immediately following the procedure or on post-procedural follow-up. The pseudoaneurysm remained excluded at 6-week CT angiogram (CTA) follow-up. This case describes a safe and effective method for completely excluding a complex pseudoaneurysm, utilising the AneuGraft PCS, allowing for the potential management of a wider range of aneurysms with unfavourable morphology.
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    Tranexamic acid modulates the cellular immune profile after traumatic brain injury in mice without hyperfibrinolysis
    Draxler, DF ; Daglas, M ; Fernando, A ; Hanafi, G ; McCutcheon, F ; Ho, H ; Galle, A ; Gregory, J ; Larsson, P ; Keragala, C ; Wright, DK ; Tavancheh, E ; Au, AE ; Niego, B ; Wilson, K ; Plebanski, M ; Sashindranath, M ; Medcalf, RL (WILEY, 2019-12)
    BACKGROUND: Traumatic brain injury (TBI) is known to promote immunosuppression, making patients more susceptible to infection, yet potentially exerting protective effects by inhibiting central nervous system (CNS) reactivity. Plasmin, the effector protease of the fibrinolytic system, is now recognized for its involvement in modulating immune function. OBJECTIVE: To evaluate the effects of plasmin and tranexamic acid (TXA) on the immune response in wild-type and plasminogen-deficient (plg-/- ) mice subjected to TBI. METHODS: Leukocyte subsets in lymph nodes and the brain in mice post TBI were evaluated by flow cytometry and in blood with a hemocytometer. Immune responsiveness to CNS antigens was determined by Enzyme-linked Immunosorbent Spot (ELISpot) assay.  Fibrinolysis was determined by thromboelastography and measuring D-dimer and plasmin-antiplasmin complex levels. RESULTS: Plg-/-  mice, but not plg+/+  mice displayed increases in both the number and activation of various antigen-presenting cells and T cells in the cLN 1 week post TBI. Wild-type mice treated with TXA also displayed increased cellularity of the cLN 1 week post TBI together with increases in innate and adaptive immune cells. These changes occurred despite the absence of systemic hyperfibrinolysis or coagulopathy in this model of TBI. Importantly, neither plg deficiency nor TXA treatment enhanced the autoreactivity within the CNS. CONCLUSION: In the absence of systemic hyperfibrinolysis, plasmin deficiency or blockade with TXA increases migration and proliferation of conventional dendritic cells (cDCs) and various antigen-presenting cells and T cells in the draining cervical lymph node (cLN) post TBI. Tranexamic acid might also be clinically beneficial in modulating the inflammatory and immune response after TBI, but without promoting CNS autoreactivity.