Composite brains: towards a systems theory of recovery following neural reconstruction

Submission note: A thesis submitted in total fulfilment of the requirements for the degree of Doctor of Philosophy to the School of Health Sciences and Human Biosciences, Faculty of Health Sciences, La Trobe University, Bundoora.

There is an active international program translating the breakthroughs in stem cell biology into viable, best-practice interventions for brain disorders such as Parkinson's disease (PD). The central question addressed is how can scientific advances translate into effective treatments? This thesis aims to: 1. Critically evaluate the methods used to report and interpret research findings, and suggest improvements consistent with principles of evidence-based practice. 2. Critically appraise the present heuristic guiding clinical research and propose an alternative model. 3. Apply the alternative model to new research, in particular, combining neurological rehabilitation and cellular therapies. The thesis consists of seven publications organized into seven chapters: Chapter 1 introduces the field of reconstructive cellular therapies and focuses on the research program developing effective treatments for patients with PD. Chapter 2 includes a systematic review and meta-analysis of neural transplants for PD. Chapter 3 is an evaluation of the progress of reconstructive neurosurgery as best practice treatment for PD. Chapter 4 critiques the methodology of clinical trials for PD. Existing problems are addressed by using (i) statistical methods consistent with the principles of evidence-based practice and (ii) qualitative methods to understand the experiences of patients undergoing intracerebral transplantation. Chapter 5 includes two papers examining the ethics of sham surgery in double-blind trials evaluating the efficacy of reconstructive cellular therapies. It is argued that as there is no evidence for the methodological utility of sham surgery, the practice is unethical. Chapter 6 consists of two publications aiming to indentify [i.e. identify] the strengths and limitations of the currently used heuristic, Repair Model and propose an alternative theoretical approach: the Composite Brain Model. The development of the reconstructed brain is shaped by the actions of the patient and optimized by the provision of neurological rehabilitation. Chapter 7 is an overview of the ideas discussed in the thesis.