Human drug neurochemistry
2004 – 2006 Dr Hadwen Trust Research Fellowship
Dr G Barnes, Dr A Hillebrand, Dr P Furlong & Dr S Hall, Aston University
Combining non-invasive techniques MRS and MEG, to find safe new ways to study the effect of drugs on the human brain as an alternative to animal experiments.
The main focus of the Neurosciences Research Group at Aston University is the development and application of non-invasive functional imaging techniques in the study of cortical structure and function.
Their work encompasses both fundamental neuroscience and clinical research aimed at understanding and improving treatment of a range of neurological illnesses.
Dr Stephen Hall was supported by a postdoctoral Dr Hadwen Trust Research Fellowship for the duration of this project.
Currently less than 10% of drugs tested on animals succeed in human clinical trials and reach the market [1], suggesting that animal models are frequently only approximations to human physiology. In particular, many mental conditions, such as depression, are difficult to characterise in other species. Despite this, a range of animal species, including non-human primates, continue to be used in research into human mental illness – a field of study that is likely to increase.
The World Health Organization estimates that the numbers affected by mental and neurological disorders will surge over the next 15 years. To understand, and ultimately combat, diseases such as schizophrenia, dementia, depression and developmental disorders such as autism, we need to study human beings. There is now a range of functional neuroimaging techniques that allows non-invasive measurements from the intact human brain.
The long-term goal of this project is to provide models of human neurochemistry linked to the electrical behaviour in the cerebral cortex. The ability to directly and accurately measure the electrical profile of drug-induced change in the brain would have a wide spectrum of applications, relating to the understanding of normal brain function, treatment of neurological disorders and the targeted design of new drugs.
As a first step towards this goal, the Dr Hadwen Trust supported work to investigate the use of two non-invasive imaging techniques being pioneered at Aston: magnetoencephalography (MEG) and magnetic resonance spectroscopy (MRS). Combining these two techniques permits more detailed information to be collected than is possible with either method singly.
MEG uses highly sensitive magnetic field sensors to determine neuronal electrical activity on a millisecond by millisecond basis. It provides high spatial and temporal resolution images of the electrical behaviour of the cortex, but no chemical or anatomical information. The Aston research group has demonstrated that non-invasive MEG studies can effectively replace certain invasive experiments on primates [2].
MRS uses high-strength magnetic fields to determine the chemical composition of regions of the brain, based on the resonant frequency of particular atoms, such as hydrogen. It can show the distribution of targeted neurotransmitters and various metabolites across the brain [3].
With funding from the Dr Hadwen Trust, studies were undertaken with the benzodiazepine drug diazepam (Valium). Diazepam is a well characterized and widely taken anti-anxiety drug, also used as a sedative, muscle relaxant and in the treatment of epilepsy. Diazepam modulates the function of the GABAA receptors located in almost every neuronal type, in all regions of the brain, making it an ideal tool for these studies.
MEG proved to be extremely successful at identifying the cortical areas affected by the modulation of the GABAA receptor and at monitoring changes in activity over time following the administration of diazepam. The results have provided an extensive and multi-faceted profile of diazepam pharmacodynamics (paper submitted).
MEG showed diazepam-modulated cortical activity in frontal, occipital and somatomotor cortices. Comparative data was collected with targeted pharmacological MRS during diazepam uptake, to provide anatomically relevant chemical measures.
This combination of MEG and MRS into a pharmaco-imaging method is a novel approach [4] that possesses great potential for drug development and the replacement of primate experiments. Work is continuing to further develop and optimise this pharmaco-imaging method, and to investigate painkillers and the drug zolpidem used in the treatment of brain injury.
Summary
• At present many neurological conditions are modelled in rodents and monkeys, although these are frequently poor approximations to the human conditions. To understand and combat the rising tide of neurological and mental diseases we ultimately need to study human beings.
• Using safe and improved ways to study the human brain, with non-invasive functional imaging techniques such as MEG and MRS, will help to eliminate these animal experiments.
• Combining MEG and MRS permits more detailed information to be collected than is possible with either method singly.
• MEG and MRS were combined in a novel approach to measure changes in the electrical behaviour and biochemistry of the cortex of the brain in response to diazepam.
• An extensive and multi-faceted profile of diazepam pharmacodynamics was achieved.
• Further developments will improve and enhance the combination of MEG and MRS into a pharmaco-imaging method, with great potential for improving drug development and the replacing primate experiments.
• Investigations are now underway into the modulation of pain in the human brain, and into the drug zolpidem used in the treatment of brain injury.
References
1. Food and Drug Administration (2004). Innovation and Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products. http://www.fda.gov/oc/initiatives/criticalpath/
2. Hall SD, Holliday IE, Hillebrand A et al (2005). The Missing Link: analogous human and primate cortical gamma oscillations. Neuroimage 26:13-17.
3. Ugurbil K, Adriany G, Andersen P et al (2000). Magnetic resonance studies of brain function and neurochemisty. Ann Rev Biomed Eng 2:633-660.
4. Hall SD & Adjamian P (2006). The Chemistry of Cognition. In: Gazzaniga MS, Senior C & Russel T (eds), Methods in Mind..Cambridge USA: MIT Press.