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Innovative Otago brain research supported by Neurological Foundation

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Tuesday 5 July 2016 1:16pm

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University of Otago scientists have gained a total of around $912,000 to pursue eight brain research projects in the Neurological Foundation’s July funding round announced today.
The new Otago projects include investigations into a new mode of treatment for epilepsy, brain activity involved in impulsivity, and a potential therapeutic protein that could grow new brain cells.

Also among the projects are efforts to develop reliable methods for examining the effect of cannabidiol in epilepsy and a new approach to using deep brain stimulation to treat stroke patients.

Other projects focus on mechanisms of proteins in oxidative stress in brain disorders, measuring impact forces to the head and brain-injury mechanisms, and studying changes in brain circuitry to increase knowledge of the anatomical basis of schizophrenia and ADHD-like hyperactivity.

Announcing the latest grants, Neurological Foundation Executive Director Max Ritchie says the round illustrates the breadth of brain research in New Zealand as it continues to contribute to and progress global knowledge of neurological disorders.

Otago’s project grants:

Professor Cliff Abraham (Department of Psychology)

Stimulation of neurogenesis by a potential therapeutic protein
(The investigation of a neuroprotective protein’s potential to rescue memory function)

Lead investigator Professor Cliff Abraham, one of New Zealand’s top Alzheimer’s disease researchers, and co-investigators from the University’s Department of Biochemistry, Dr Stephanie Hughes and Professor Warren Tate, aim to investigate the ability of a neuroprotective protein called secreted amyloid precursor protein-alpha (sAPPα) to enhance the birth of new nerve cells in the adult brain. Then, in an animal model of Alzheimer’s disease, they will attempt to rescue this neurogenesis capability through an innovative gene therapy approach. Finally, the team will determine in these animals whether restoring the birth of new neurons correlates with the rescue of spatial memory abilities, something that is severely impaired in Alzheimer’s patients. The discovery of a neurogenic protein/peptide that can be administered non-invasively will be an important step in the development of therapeutic approaches for Alzheimer’s disease. sAPPα’s therapeutic potential may also extend to traumatic brain injury and stroke.

Dr John Ashton (Department of Pharmacology and Toxicology)

Finding tools to investigate the anti-epileptic effects of cannabidiol
(A laboratory-based study to determine reliable methods for examining the effect of cannabidiol in epilepsy)

One third of epilepsy patients are resistant to therapy. This is particularly true for childhood epilepsy, leading some parents in the USA to try using an atypical cannabinoid drug, cannabidiol (CBD). Some reports suggest children gain relief from treatment with oral CBD oil. However, this is anecdotal, low quality evidence, and although early trials on adults appeared positive, these were again of low quality with a high risk of bias, highlighting the need for high-quality randomised controlled trials. A recently completed placebo controlled trial however has reported promising results, with CBD reducing seizures significantly compared to patients receiving placebo. How CBD reduces seizures is not known. Answering this question could help the development of other drugs for epilepsy. A first step is to find experimental methods that can be used to study the effect of CBD on epileptic-like activity in the laboratory, and this is the aim of Dr Ashton’s project. Any positive results will be followed with investigations into mechanisms in subsequent research.

Professor Mark Hampton (Department of Pathology, University of Otago, Christchurch)

Regulation of neurite formation and growth by oxidative stress
(Investigating the mechanisms of proteins in oxidative stress in brain disorders)

Brain function depends on the ability of neurons to transfer information via a network of axons and dendrites (neurites). Disruption of these networks can occur during development and during the course of several neurological diseases. Oxidative stress has been previously linked to neurological disease through the destruction of neurons. Professor Hampton and co-investigators Dr Paul Pace and Professor Christine Winterbourn from the Department of Anatomy at the University of Otago, Christchurch, and Associate Professor Christine Jasoni from the Department of Anatomy at the University of Otago, propose that oxidative stress has more subtle effects through interfering with neurite structure. The team has preliminary evidence for a critical interaction between two proteins that triggers neurite collapse, and will investigate whether this collapse can be prevented by a peptide that separates the two proteins. If the team can confirm a specific pathway that relies on a selective protein interaction, it will provide a new and feasible opportunity for therapeutic intervention.

Professor Neil McNaughton (Department of Psychology)

Investigating the role of sub-thalamic nucleus activity in impulsivity in a model using optogenetic technology
(Using innovative technology to investigate brain activity involved in impulsivity, a common side effect of treatments used in Parkinson’s disease)

Deep brain stimulation (DBS) is an important alternative or supplement to pharmacological treatment for many disorders. In particular it treats the debilitating motor (movement) symptoms in Parkinson’s disease (PD). The sub-thalamic nucleus (STN) is the most frequently targeted brain structure for DBS in PD. Despite highly efficacious therapeutic effects, DBS into a part of the brain known as the sub-thalamic nucleus (known as STN-DBS surgery) has been linked to various cognitive, emotional and behavioural side-effects. Particularly, deficits in impulse control have been reported as a consequence of STN-DBS in PD. Conversely, improvements in impulse control have been reported with STN-DBS in obsessive compulsive disorder (OCD). Professor McNaughton and his team including leading optogenetics researcher Dr Louise Parr-Brownlie will address the role of sub-thalamic nucleus activity in impulsivity by dissecting brain network activity with an innovative technology called optogenetic stimulation, and use high-density neurophysiological recordings. The team will modulate STN activity in a model at different frequencies and test for selective changes among key areas in the brain and in different aspects of motor inhibition. The results will improve the understanding of how normal and pathological activity are related in disorders such as PD and OCD; and will determine if different patterns of STN-DBS can selectively mediate its therapeutic and off-target effects at a single site – providing a basis for improved DBS treatment outcomes across a range of disorders.

Associate Professor Dorothy Oorschot (Department of Anatomy)

Opposite changes in midbrain dopamine circuitry in schizophrenia versus ADHD-like hyperactivity
(Measuring changes in brain circuitry to increase knowledge of the anatomical basis of schizophrenia and ADHD-like hyperactivity)

The relation between the anatomy of brain cell circuits and their functions is central to understanding information processing in the brain. A wealth of information exists about the brain disorders schizophrenia and attention deficit hyperactivity disorder (ADHD), yet little is known about the microscopic changes in neural circuits that may contribute to the manifestations of each disorder.

Associate Professor Dorothy Oorschot and colleagues including Professor David Bilkey, Dr Louise Parr-Brownlie and Dr Stephanie Hughes, hypothesise that a major causal factor in both disorders is altered synaptic input onto specific midbrain dopamine neurons resulting in excessive or diminished release of the neurotransmitter dopamine. (Neurons in the brain receive thousands of synaptic inputs from other neurons). The team will combine a cutting-edge technology to selectively label inhibitory input neurons, and electron microscopy to identify excitatory inputs, onto midbrain dopamine neurons. This will enable the measure of the number of structural changes that potentially underlie long-term changes in synaptic input. An understanding of these structural alterations and relationships, should they exist, will significantly increase knowledge on the anatomical basis of schizophrenia and of ADHD-like hyperactivity, and will provide a marked step forward in understanding the core biology and thus allow for a mechanism-driven approach to new opportunities for treatment.

Associate Professor John Reynolds (Department of Anatomy)

Harnessing metaplasticity for stroke recovery using transcranial magnetic stimulation
(Investigating a new approach to brain stimulation in a model of stroke to optimise recovery)

Stroke is the leading cause of adult disability in New Zealand. Aside from the devastating effects on the individual, stroke-induced disability places a heavy social and financial burden on New Zealand society. Treatments that accelerate and enhance maximal recovery would therefore provide significant benefit to the individual and community. Repetitive transcranial magnetic stimulation (rTMS) uses an externally placed magnetic coil to repeatedly non-invasively stimulate the brain, and has been recognised as a therapy with the potential to induce lasting changes in brain function. Unfortunately, despite intensive investigation, using rTMS to facilitate the strengthening of neural circuits to compensate for lost function has not shown sustained enhancement for stroke recovery. Associate Professor Reynolds and his team have preliminary scientific evidence indicating a different way of applying rTMS that may achieve this aim. This approach is grounded in cellular neuroscience, and they will apply this approach to a model of stroke to determine if neural circuits can be similarly strengthened, and will use recording techniques that allow the recording of brain cells during the application of rTMS. This work may point towards a rethink as to how rTMS should be applied in terms of protocols and how intensity of stimulation is set.

Dr Shakila Rizwan (School of Pharmacy)

A novel intranasal mucoadhesive carrier for delivering anticonvulsant drugs to attenuate seizures in a model
(A proof-of-principle study of a tailor-made, intranasal anti-convulsant drug carrier system)

It has been estimated that 20-40 per cent of epilepsy patients become resistant to available antiepileptic drugs (AEDs) over time, leading to a lack of seizure control. The underlying causes of this resistance are complex and multifactorial. Dr Rizwan and her team’s long-term goal is to develop a new non-invasive treatment strategy for delivering AEDs to suppress drug-resistant seizures. They aim to achieve this by packaging AEDs inside very small drug carriers administered via the nose. The nasal cavity is a site for direct absorption of drugs into the brain; however it is important that the compound stays in the cavity long enough for effective delivery. In this proof-of-principle study, they will test, in a model, if their tailor-made, adhesive drug carrier system can deliver sufficient AED to the brain to stop seizures. Proof of efficacy in this model will be the first step towards testing this technology in drug-resistant models of epilepsy and progress re-clinical development.

Dr Rizwan will collaborate on this project with Associate Professor Nigel Jones from the Royal Melbourne Hospital. Dr Jones is a specialist in epilepsy modelling.

Associate Professor Neil Waddell (Department of Oral Rehabilitation)

Development of a skin/skull/brain model to measure impact forces to the head and brain-injury mechanisms

In professional contact sports and martial arts, there are increasing reports linking mild traumatic brain injuries (concussion and subconcussion) to early onset dementia and chronic traumatic encephalopathy. Subconcussive brain injury is defined as cranial impact that does not show obvious symptoms and is therefore not diagnosed as a clinical concussion. Associate Professor Neil Waddell and colleagues including Professor Darryl Tong (whose research interests include maxillofacial research, trauma and reconstruction as well as subconcussion in sports) wish to study subconcussive brain injury because it is very difficult to diagnose clinically as no minimum threshold has yet been established. When the human head is subjected to impact, kinetic energy is transmitted to the brain. The literature describing various animal head models cannot be realistically compared to the human head, yet obtaining in vivo data from cranial impact in humans is unethical. Instead, an accurate biomechanical model of the human head would be preferable for impact testing. The aim of this research is to develop a skin/skull/brain model to measure impact forces to the head and brain, (by subjecting the prototype to impact testing with a bamboo sword in the martial art of kendo, where head strikes are routine) to help in the understanding of the biomechanics of brain injury in concussion and subconcussion. A range of impact forces will be used to calculate the degradation of energy transfer through the skin/skull/brain system. The knowledge from this study will also be translational to fall injuries, the design of industrial personal protective equipment, and the detection of physical abuse.

A list of Otago experts available for media comment is available elsewhere on this website.

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