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Iverson G.L.,Harvard University | Gardner A.J.,University of Newcastle | McCrory P.,The Florey Institute of Neuroscience and Mental Health | Zafonte R.,Harvard University | Castellani R.J.,University of Maryland Baltimore County
Neuroscience and Biobehavioral Reviews

Chronic traumatic encephalopathy (CTE) has been described in the literature as a neurodegenerative disease with: (i) localized neuronal and glial accumulations of phosphorylated tau (p-tau) involving perivascular areas of the cerebral cortex, sulcal depths, and with a preference for neurons within superficial cortical laminae; (ii) multifocal axonal varicosities and axonal loss involving deep cortex and subcortical white matter; (iii) relative absence of beta-amyloid deposits; (iv) TDP-43 immunoreactive inclusions and neurites; and (v) broad and diverse clinical features. Some of the pathological findings reported in the literature may be encountered with age and other neurodegenerative diseases. However, the focality of the p-tau cortical findings in particular, and the regional distribution, are believed to be unique to CTE. The described clinical features in recent cases are very similar to how depression manifests in middle-aged men and with frontotemporal dementia as the disease progresses. It has not been established that the described tau pathology, especially in small amounts, can cause complex changes in behavior such as depression, substance abuse, suicidality, personality changes, or cognitive impairment. Future studies will help determine the extent to which the neuropathology is causally related to the diverse clinical features. © 2015 Elsevier Ltd. Source

Lynch E.,University of South Australia | Hillier S.,University of South Australia | Cadilhac D.,The Florey Institute of Neuroscience and Mental Health | Cadilhac D.,Monash University
International Journal of Stroke

Background: Knowing when to commence physical rehabilitation after stroke is important to ensure optimal benefit for stroke survivors and efficient health care. The aims of this review were to: determine the effects on mortality, function and complications when physical rehabilitation commences 'early' (within seven days of stroke); and describe the effects of early transfer to rehabilitation wards/hospitals when sustained rehabilitation is unavailable in acute stroke units. Review summary: From 3751 potential articles we included 5 randomized controlled trials and 38 cohort studies. Meta-analysis was performed with 3 randomized controlled trials involving 159 people to investigate the effects of commencing physical rehabilitation within 24 h of stroke compared to 48 h. Commencing physical rehabilitation within 24 h trended towards greater mortality (Mantel-Haenszel odds ratio 2·58; 95% confidence interval 0·98 to 6·79, P=0·06), with no differences in complications or health outcomes. The cohort studies provided evidence of benefits when physical rehabilitation was commenced on the day of admission (n=1), within 3 days of stroke (n=3), or 'sooner rather than later' (3 of 4 studies). The effect of earlier transfer to rehabilitation was reported in 32 cohort studies. In 23/26 (88%) cohort studies that accounted for age and stroke severity, results favored earlier transfer for improving post-stroke function, with no consensus on timeframes. Conclusion: In summary, the benefits of commencing physical rehabilitation within 24 h of stroke remain unclear from the current literature. Commencing physical rehabilitation or transferring to rehabilitation services 'early' may provide better functional outcomes. © 2014 World Stroke Organization. Source

Subramanian H.H.,The Florey Institute of Neuroscience and Mental Health
Journal of Physiology

Emotional reactions such as vocalization take place during expiration, and thus expression of emotional behaviour requires a switch from inspiration to expiration. I investigated how the midbrain periaqueductal grey (PAG), a known behavioural modulator of breathing, influences the inspiratory-to-expiratory phase transition. Contemporary models propose that late inspiratory (late-I) and post-inspiratory (post-I) neurones found in the medulla, which are active during the inspiratory-to-expiratory phase transition are involved in converting inspiration to expiration. I examined the effect of excitatory amino acid (d,l-homocysteic acid; DLH) stimulation of the PAG on the discharge function of late-I and post-I neurones. The data show a topographical organization of DLH-induced late-I and post-I neuronal modulation within the PAG. Dorsal PAG stimulation induced tachypnoea and caused excitation of both the late-I and post-I neurones. Lateral PAG induced inspiratory prolongation and caused an excitation of late-I neurones but inhibition of post-I neurones. Ventrolateral PAG induced expiratory prolongation and caused a persistent activation of post-I neurones. As well, PAG stimulation modulated both the late-I and post-I cells for least two-three breaths even prior to the change in respiratory motor pattern. This indicates that the PAG influences the late-I and post-I cells independent of pulmonary or other sensory afferent feedback. I conclude that the PAG modulates the activity of the medullary late-I and post-I neurones, and this modulation contributes to the conversion of eupnoea into a behavioural breathing pattern. © 2012 The Physiological Society. Source

Li M.,The Florey Institute of Neuroscience and Mental Health | Jazayeri D.,The Florey Institute of Neuroscience and Mental Health | Corry B.,Australian National University | McSweeney K.M.,Columbia University | And 4 more authors.
Neurobiology of Disease

Objective: Mutations in ATP1A3, the gene that encodes the α3 subunit of the Na+/K+ ATPase, are the primary cause of alternating hemiplegia of childhood (AHC). Correlations between different mutations and AHC severity were recently reported, with E815K identified in severe and D801N and G947R in milder cases. This study aims to explore the molecular pathological mechanisms in AHC and to identify functional correlates for mutations associated with different levels of disease severity. Methods: Human wild type ATP1A3, and E815K, D801N and G947R mutants were expressed in Xenopus laevis oocytes and Na+/K+ ATPase function measured. Structural homology models of the human α3 subunit containing AHC mutations were created. Results: The AHC mutations examined all showed similar levels of reduction in forward cycling. Wild type forward cycling was reduced by coexpression with any mutant, indicating dominant negative interactions. Proton transport was measured and found to be selectively impaired only in E815K. Homology modeling showed that D801 and G947 lie within or near known cation binding sites while E815 is more distal. Despite its effect on proton transport, E815K was also distant from the proposed proton transport route. Interpretation: Loss of forward cycling and dominant negativity are common and likely necessary pathomechanisms for AHC. In addition, loss of proton transport correlated with severity of AHC. D801N and G947R are likely to directly disrupt normal Na+/K+ binding while E815K may disrupt forward cycling and proton transport via allosteric mechanisms yet to be elucidated. © 2015 Elsevier Inc. Source

Ma S.,The Florey Institute of Neuroscience and Mental Health | Ma S.,University of Melbourne | Gundlach A.L.,The Florey Institute of Neuroscience and Mental Health | Gundlach A.L.,University of Melbourne
Journal of Neuroendocrinology

Arousal is a process that involves the activation of ascending neural pathways originating in the rostral pons that project to the forebrain through the midbrain reticular formation to promote the activation of key cortical, thalamic, hypothalamic and limbic centres. Established modulators of arousal include the cholinergic, serotonergic, noradrenergic and dopaminergic networks originating in the pons and midbrain. Recent data indicate that a population of largely GABAergic projection neurones located in the nucleus incertus (NI) are also involved in arousal and motivational processes. The NI has prominent efferent connections with distinct hypothalamic, amygdalar and thalamic nuclei, in addition to dense projections to key brain regions associated with the generation and pacing of hippocampal activity. The NI receives strong inputs from the prefrontal cortex, lateral habenula and the interpeduncular and median raphe nuclei, suggesting it is highly integrated in circuits regulating higher cognitive behaviours (hippocampal theta rhythm) and emotion. Anatomical and functional studies have revealed that the NI is a rich source of multiple peptide neuromodulators, including relaxin-3, and may mediate extra-hypothalamic effects of the stress hormone corticotrophin-releasing factor, as well as other key modulators such as orexins and oxytocin. This review provides an overview of earlier studies and highlights more recent research that implicates this neural network in the integration of arousal and motivated behaviours and has begun to identify the associated mechanisms. Future research that should help to better clarify the connectivity and function of the NI in major experimental species and humans is also discussed. © 2015 British Society for Neuroendocrinology. Source

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